Cancer therapy system for effecting oncolysis of malignant neoplasms

A method for effecting oncolysis, regression, and control of malignant neoplasms in humans and other mammals without adverse effects on normal body cells is described. An ATP-availability depressor may be combined with a defined nutritional regimen, a fatty acid blocker, an amino acid blocker, a lactate export blocker, or any combination thereof.

CONTENTS 
CROSS REFERENCE TO RELATED APPLICATIONS 
BACKGROUND OF THE INVENTION 
Table I. Abbreviations and Symbols 
BRIEF DESCRIPTION OF THE DRAWINGS 
DEFINITIONS 
Definitions of the Primary Metabolic Effectors 
Further Definitions 
BRIEF DESCRIPTION OF THE INVENTION 
DETAILED DESCRIPTION OF THE INVENTION 
Actions of the Primary Metabolic Effectors 
Defined Nutritional Regimen (DNR) 
Fatty Acid Blocking Agents (FAB) 
Amino Acid Blocking agents (AAB) 
ATP-Availability Depressor Agents (AAD) 
Lactate Export Blocking Agents (LEB) 
Combinations of the Metabolic Effectors 
Most Preferred Embodiment 
ILLUSTRATIVE THERAPY SYSTEM FOR HUMAN PATIENTS 
EXAMPLES OF CLINICAL EFFECTIVENESS OF METABOLIC EFFECTOR MALIGNANCY THERAPY 
ACCORDING TO THIS INVENTION (EXAMPLES) 
CLAIMS 
Reference is made to Disclosure Document No. 164,585 filed by the present 
inventor on Feb. 20, 1987, which relates to the present invention. 
Permanent retention thereof is hereby requested. 
BACKGROUND OF THE INVENTION 
When the rate of availability of adenosine triphosphate (ATP.sub.A) for use 
in satisfying the overall metabolic reactions in a cell is depressed below 
the level that must be maintained just to satisfy those cellular energy 
needs for vital metabolic processes, the cell becomes incapable of mitotic 
division and ultimately dies. The rate of change in the ATP pool size 
existing in a cell at a particular time is the difference between the rate 
at which ATP is being produced, primarily by oxidative phosphorylation 
(O/P) along the Respiratory Chain (RC) in the mitochondria, and the rate 
at which ATP is being used up (hydrolyzed) to provide for all the energy 
requirements of the cell. This energy is principally required for all the 
myriad anabolic and catabolic reactions in the metabolism of the cell, 
including powering of the "sodium pumps" of the pericellular 
membrane--whose collective action keeps the intracellular Na.sup.+ 
-concentration relatively low despite the continuous leakage of Na.sup.+ 
through the membrane into the cell from the high Na.sup.+ -concentration 
extracellular fluid. The fundamental pathway involved in ATP production 
and usage (hydrolysis) in all normal body cells is depicted in FIG. 1. 
The abbreviations and symbols used in FIG. 1 and elsewhere throughout this 
application are explained in the following table. Definitions of the 
primary therapeutical factors, the metabolic effectors Defined Nutritional 
Regimen (DNR), Fatty Acid Blocking Agent (FAB), Amino Acid Blocking Agent 
(AAB), ATP-Availability Depressor Agent (AAD) and Lactate Export Blocking 
Agent (LEB) of the present therapy system are given in the section 
entitled "Definitions of the Primary Metabolic Effectors," infra. 
TABLE I 
______________________________________ 
Abbreviations and Symbols 
______________________________________ 
AA amino acids 
AAB amino acid blocking agent 
AAD ATP-availability depressor agent 
AcCoA acetyl coenzyme A 
ADP adenosine diphosphate 
ATP adenosine triphosphate 
[ATP] intracellular ATP concentration 
##STR1## rate of production or degradation of ATP 
ATPase adenosine triphosphatase 
##STR2## rate of availability of ATP for use 
in cellular metabolism 
ATP.sub.EMP 
ATP produced in the EMP 
##STR3## rate of ATP production in the EMP 
ATP.sub.G ATP produced by glycolysis 
##STR4## rate of ATP production by glycolysis 
##STR5## 
##STR6## 
##STR7## rate of ATP produced by O/P in RC 
##STR8## overall rate of production of ATP by cell 
##STR9## rate of utilization of ATP by cell 
##STR10## rate of wasting of ATP by AAD 
##STR11## 
##STR12## 
##STR13## 
##STR14## 
-c "with" (cum) 
Ca calcium 
CAC Citric Acid Cycle 
##STR15## rate of operation of the CAC 
Cl.sup.- chlorine ion 
CO.sub.2 
##STR16## -CoA coenzyme A 
cm centimeter 
CPK creatine phosphokinase 
d day 
DFA DNR + FAB + AAB combination 
dl deciliter (100 ml) 
DNP 2,4-Dinitrophenol 
DNR defined nutritional regimen 
EMP Embden-Meyerhof Pathway 
FA fatty acids 
FAB fatty acid blocking agent 
g gram 
##STR17## rate of operation of the Glycolytic 
(or EMP) Pathway 
##STR18## 
##STR19## 
H hydrogen (atomic) 
hr hour 
I Iodine 
i initial value of a quantity (subscript) 
I.U. international unit 
KCl potassium chloride 
Kg kilogram 
LAC lactic acid (lactate) 
##STR20## rate of production of lactic acid 
in a cell 
##STR21## rate of export of lactic acid from a cell 
LEB lactate export blocking agent 
lO.sub.2 /d 
liters of O.sub.2 consumed metabolically, 
per day (24 hours) 
max maximum 
min minute 
Mg magnesium 
mg milligram 
ml milliliter 
Mn manganese 
Na.sup.+ sodium ion 
NaCl sodium chloride 
NADH reduced nicotinamide adenine dinucleotide 
##STR22## rate of supply of NADH to the RC 
O.sub.2 molecular oxygen 
O/P oxidative phosphorylation (in RC) 
P phosphorus 
PFK phosphofructokinase 
pH intracellular pH (acidity measure) 
pH.sub.L lethal level of intracellular pH 
RC Respiratory Chain 
RC rate of operation of the RC (amount of 
NADH oxidized per unit time) 
Se selenium 
T.sub.3 triiodothyronine 
T.sub.4 thyroxine 
TH thyroid hormone (T.sub.4 and/or T.sub.3) 
UA uncoupling agent of O/P 
Zn zinc 
.mu.g microgram 
.uparw. increase (in a rate) 
.dwnarw. decrease (in a rate) 
RDA recommended daily allowance 
.sup.-s "without" (sine) 
______________________________________ 
In normal (i.e., non-malignant) body ce nutritional component is glucose, 
from which the primary energy supply for synthesizing ATP is derived. 
Glucose is transformed by the sequential reactions of the Glycolytic or 
Embden-Meyerhof Pathway (EMP) into pyruvate. Only about 6% of the total 
energy available in the original glucose molecule is released in the form 
of ATP during degradation in the EMP. Subsequently, pyruvate is 
decarboxylated and forms acetyl coenzyme A (AcCoA) which then enters the 
Citric Acid Cycle (CAC) in the mitochondria. Here each acetate moiety, 
after first being incorporated into a molecule of citric acid, is broken 
down into CO.sub.2 and H with H appearing, inter alia, in molecules of 
reduced nicotinamide adenine dinucleotide (NADH) which then contain a 
large fraction of the energy contained in the original glucose. This NADH 
subsequently is oxidized in the mitochondrial Respiratory Chain with the 
ultimate production of H.sub.2 O by terminal reaction of the H with 
O.sub.2. This O.sub.2 is supplied by the normal vasculature. The energy 
obtained by the transport of electrons down the potential gradient of the 
RC, by a series of redox reactions, is used to produce the ATP of the 
cell. About 94% of the total energy available in the original glucose 
molecule is released in the form of ATP during degradation of the AcCoA in 
the CAC and oxidation of the associated NADH in the RC. Thus, in normal 
cells, the ATP-stored energy is obtained in the major proportion from 
nutritional glucose or from carbohydrates (i.e., starches and sugars) 
which yield glucose upon digestion. Some ATP-energy is obtained in normal 
cells from the oxidation, in the CAC and RC, of fatty acids and amino 
acids obtained from nutritional fats and proteins. When adequate glucose 
is available in the nutriment intake, however, the major ATP-energy needs 
of practically all normal cells are readily obtainable from glucose alone. 
The ATP produced in the EMP and RC enters the cellular "ATP Pool", from 
which it is continuously withdrawn at the net availability rate ATP.sub.A 
to supply the energy needs of total cellular metabolism including energy 
to power the membrane sodium pumps which keep the intracellular Na.sup.+ 
-concentration adequately low by the out-pumping of Na.sup.+. 
This same general pattern of ATP generation and usage exists in malignant 
cells, but with one crucial difference (see FIG. 2). It has been 
extensively demonstrated that the malignant cells of practically all forms 
of malignant neoplasms possess a common, distinctive metabolic aberrancy, 
apparently manifested as an innate consequence of their transformation to 
the malignant state [Niemtzow, R. C. (Ed.), Transmembrane Potentials and 
Characteristics of Immune and Tumor Cells Chapter 9, CRC Press, Boca 
Raton, Fla., (1985)]. Under in vivo conditions, the malignant cells of 
essentially all forms of malignant neoplasms do not substantially convert 
pyruvate to AcCoA (see FIG. 2). The pyruvate instead is essentially 
quantitatively converted to lactate which is exported from the cell by an 
effective lactate transport system [Warburg, O., Uber den Stoffwechsel der 
Tumoren, Springer-Verlag, Berlin and New York (1926); Warburg, O., The 
Metabolism of Tumors Constable, London (1930); Burk, D., Cold Spring 
Harbor Symposia Quant. Biol. 7, 420 (1939); Busch, H., An Introduction to 
the Biochemistry of the Cancer Cell, Chapter 10, Academic Press, New York 
( 1962); Racker et al., Science 209, 203 (1981); Spencer, T. L. et al., 
Biochem. J. 154, 405 (1976); Belt, J. A. et al., Biochem. 18 3506 (1979): 
Weinhouse, S., Cancer Res. 3, 269 (1955); Busch, H. et al., Cancer Res. 20 
50 (1960); Busch, H., Cancer Res. 13 789 (1955); Busch, H. et al., J. 
Biol. Chem. 196, 717 (1952); Nyham, W. L. et al., Cancer Res. 16, 227 
(-957); Cori, C. F. et al., J. Biol. Chem. 64, 11 (1925); Cori, C. G. et 
al., J. Biol. Chem. 65, 397 (1925); Warburg, O. et al., Klin. Wochschr. 5, 
829 (1926); Muramatsu, M., Gann. 52, 135 (1961); Busch, H. et al., Cancer 
Res. 16, 175 (1956)]. The net consequence is that only a small fraction ( 
.about.6%) of the chemical energy in the glucose molecule can be extracted 
and used by the cancer cell, compared to that available to the normal 
cell, where glucose is totally oxidized [White, A. et al., Principles of 
Biochemistry, 5th Ed., p. 441 (1973)]. Since nutritional glucose is by far 
the most prominent and important source of normal cellular ATP energy 
under normal conditions, this transformation aberrancy puts the malignant 
cells at a great disadvantage regarding the maximal rates at which they 
can generate ATP from glucose oxidation via the CAC and RC. This metabolic 
defect is potentially particularly restrictive for the malignant cells, 
which generally need an especially abundant availability rate of ATP to 
support the active anabolic metabolism associated with the frequent 
mitosis characteristic of these proliferative cells. 
However, malignant cells in vivo quite effectively circumvent this energy 
deficiency under usual nutritional conditions by readily oxidizing fatty 
acids and amino acids in the CAC and RC [Busch, H. (1962) supra: Medes, G. 
et al., Cancer Res. 17 127 (1957); Allen, A. et al., J. Biol. Chem. 212, 
921 (1955); Emmelot, C. et al., Experientia 11, 353 (1955); Weinhouse, S. 
et al., Cancer Res. 13, 367 (1953); Weinhouse, S. et al., Cancer Res. 11, 
845 (1951); Kitada, S. et al., Lipids 15 168 (1980); Spector, A. A., J. 
Biol. Chem. 240, 1032 (1965)]. Mitochondria possess a very efficient 
enzyme system capable of effecting the ".beta.-oxidization" of fatty acids 
directly to AcCoA, which then enters the Citric Acid Cycle and is oxidized 
exactly as AcCoA produced from oxidation of glucose in normal cells. The 
amino acids are, after initial deamination, similarly reduced to AcCoA or 
other intermediates of the CAC and then oxidized. Thus, some amino acids, 
after deamination and suitable transformation, which is readily 
accomplished by the enzyme systems of malignant cells, are capable of 
entering the Citric Acid Cycle directly at various intermediate points of 
the cycle [Busch, H. (1962), supra]. Consequently, although substantially 
deprived of the utilization of glucose as a primary energy source, the 
malignant cells make full use of the supply of the energy-rich fatty 
acids, and amino acids, all present in the plasma under usual nutritional 
intake levels. 
Under conditions where the rate of production of ATP by oxidative 
catabolism of free fatty acids (FA) and amino acids (AA) via the CAC-RC is 
inhibited in cancer cells (e.g., because of a limited rate of substrate 
and/or oxygen supply, or presence of an O/P uncoupling agent), or the 
oxidatively derived ATP-availability rate is otherwise depressed (e.g., by 
inappropriately stimulated ATPase activity), the cells are able to 
compensate in part for this energy rate loss by strongly increasing the 
rate of glycolysis (GLY) per se. This increased GLY results in a 
pronounced rise in the rate of production of lactic acid (LAC.sub.P). The 
lactate must concomitantly be rapidly exported from the cell in order to 
prevent the intracellular pH from decreasing to a lethal level because of 
a buildup in the lactate concentration. Under usual physiological 
conditions, the lactate export rate (LAC.sub.E) capacity of cancer cells 
is much more than adequate to prevent such an intracellular lactate 
buildup [e.g., Spencer, T. L. et al. (1976) supra: Belt, J. A. et al. 
(1979) supra]. Consequently, the cancer cells can operate at relatively 
high GLY levels when energy is relatively unavailable from oxidative 
pathways of the CAC and RC. 
In accordance with the present invention, the net availability rate of ATP, 
ATP.sub.A, for satisfying the overall metabolic requirements of malignant 
cells in the body is depressed to a level which is inadequate for the 
maintenance of the essential metabolic processes required for the 
continued viability of the cells, without substantially altering the 
normal ATP.sub.A level in normal cells of the body (see FIG. 3). The 
malignant cells are thus selectively subjected to a lethal energy 
deprivation, resulting in cellular death as a consequence of energy 
starvation. In addition, the present invention provides simultaneously and 
synergistically for the stimulation of the GLY in malignant cells to a 
maximum level while concomitantly effectively limiting the maximum 
LAC.sub.E capability of the cells by inhibition of the lactate export 
system. The malignant cells are thus selectively subjected to a second 
alternate lethal action in which cellular death occurs as a consequence of 
acidity buildup and the depression of the intracellular pH below the level 
permissible for continued viability. 
The most preferred embodiment of the present invention consists of the 
concurrent administration of five primary metabolic effectors (AAD, LEB, 
DNR, FAB and AAB), with sites of action as depicted in FIG. 3. For 
purposes of present dicussion, these metabolic effectors are arbitrarily 
grouped into three regimens which are, for clarity of presentation, 
discussed in the order in which they individually act in the metabolic 
energy pathway of the cancer cells (FIG. 3). As is detailed subsequently, 
other regimens and combinations of these metabolic effectors, although not 
constituting the most preferred embodiment for clinical application, are 
still fully capable of effecting very significant oncolysis. 
The first regimen of metabolic effectors (DNR, FAB, AAB) is designed to 
substantially limit the maximum rate at which NADH can be supplied (NADH) 
to the RC of the cancer cells in the body, thus substantially limiting the 
maximum rate at which ATP can be made oxidatively (i.e., by the CAC-RC) by 
the cells, without limiting the rate of NADH supply (NADH) in the normal 
cells of the body to any significant degree. The second regimen's 
metabolic effector (AAD) is designed to degrade a substantial portion of 
such ATP as is produced or is potentially producible by the cancer cells, 
thus making it unavailable for cellular metabolic requirements. The 
pronounced deficit in the overall ATP.sub.A imposed by the first and 
second parts of the therapy, relative to that necessary to supply just the 
minimal ATP rate requirements of the essential metabolic processes, 
ultimately reduces the ATP pool selectively in the cancer cells to a 
lethal level. The third regimen's metabolic effector (LEB) is designed to 
greatly inhibit the rate at which glycolytically produced lactate can be 
exported from the cancer cells. The strong ATP.sub.A deficiency imposed by 
regimen two (supra) causes a pronounced increase in the cellular GLY and 
consequent LAC.sub.p, thus synergistically insuring, in combination with 
regimen three of the therapy system, an ultimately lethal lactate buildup, 
which acts by producing a lethal depression of the intracellular pH. The 
concurrent use of the combination of the three regimens of the present 
therapy system thus provides two separate, but synergistically related, 
modes of achieving the destruction of cancer cells in the body, either of 
which may be the ultimate cause of lethality in a given cancer cell under 
different physiological conditions. 
The first regimen (see FIG. 3) comprises the administration of a defined 
nutritional regimen (DNR) which consists essentially of a dietary regimen 
designed to maximize the use of nutritional glucose-yielding carbohydrates 
as a source of ATP energy, and to minimize the availability of nutritional 
fatty acids and amino acids for use as a source of ATP energy (FIG. 3). It 
also comprises the concurrent use of one or more fatty acid blocking 
agents or "fatty acid blockers" (FAB) and amino acid blocking agents or 
"amino acid blockers" (AAB) to inhibit the availability of oxidatively 
obtained (i.e., CAC-RC) ATP-energy from endogenously derived (body depot 
or plasma) free fatty acids and amino acids for use by the cancer cells. 
The second regimen (FIG. 3) comprises the concurrent administration of one 
or more ATP-availability depressor agents or "ATP-availability depressors" 
(AAD) which, at adequate levels, results in the lowering or depression to 
a lethal level in the cancer cells of the net rate of the ATP, ATP.sub.A, 
actually available for satisfying cellular metabolic needs, by directly 
inhibiting the synthesis rate of ATP per se (e.g., by use of uncoupling 
agents of O/P) and/or inactivating or hydrolyzing ATP already synthesized 
(e.g., by use of ATPase-hydrolysis-activity enhancing agents). 
Administration of the AAD makes unavailable to the cancer cells a large 
fraction of the maximum potential cellular ATP production per unit time 
otherwise available, a maximum already severely limited by the reduced 
availability of NADH resulting from the restriction of energy availability 
from fatty acids and amino acids by the DNR, FAB and AAB of the first 
part, and results in cell death by energy starvation. Since the normal 
cells of the body can make full use of the abundant carbohydrate (glucose) 
supplied by the DNR for energy purposes, the only effect on the normal 
cells is an increase in O.sub.2 consumption rate (i.e., in increased RC); 
the potential ATP loss in the normal cells due to the AAD is fully 
compensated by a higher rate of glucose-derived NADH oxidation (NADH) by 
the respiratory chain, while the rate of actual ATP production and 
availability ATP.sub.A remains unchanged at its normal level. 
The third regimen (FIG. 3) comprises the administration of one or more 
lactate export blocking agents or "lactate export blockers" (LEB) which 
results in a substantial reduction of the maximum rate at which lactate 
can be exported from the glycolyzing cancer cells in the body. The LEB 
blocks a substantial portion of the normal maximal lactate export rate 
capacity of the cancer cells and allows the lactate to build up in the 
cells adequately to produce a lethal pH level. 
Applicant has previously disclosed a related method of effecting oncolysis 
comprising the use of a defined nutritional regimen (DNR) in combination 
with one or more O/P uncoupling agents (UA) [U.S. Pat. No. 4,724,234]. 
That therapy system may be considered as a special, restricted case of the 
present invention consisting of use of only a DNR and an AAD, wherein the 
AAD is specifically an uncoupling agent of cellular oxidative 
phosphorylation. Applicant has also previously disclosed [U.S. Pat. No. 
4,724,230] a method for effecting oncolysis consisting of a combination of 
a DNR and one or more UA, and the concomitant use of fatty acid oxidation 
inhibiting agents ("FAOI" therein) which result in the inhibition of 
oxidation in cellular mitochondria of free fatty acids. That system may 
likewise be considered as a special, restricted case of the present 
invention, consisting of a DNR, FAB, and AAD, wherein the FAB is 
specifically an inhibitor of mitochondrial free fatty acid oxidation 
(FAOI) and the AAD is specifically an oxidative phosphorylation uncoupling 
agent (UA). 
The potentiality of destroying cancer cells in vitro by depressing their 
intracellular pH to a lethal level by use of substances which inhibit 
lactate export has been previously addressed, based on in vitro 
experiments with cancer cell cultures [Johnson, J. H. et al. Biochemistry 
19 3836 (1980)]. However, no clinical method of effecting oncolysis 
utilizing lactate inhibiting agents has heretofore been advanced. 
Ostensibly, this is because of the in vitro finding that cancer cells have 
an enormous reserve capacity for lactate export, relative to the usual 
rate of GLY (LAC.sub.P) at which they operate. Consequently, the lactate 
export capability must be almost totally blocked before any lactate 
buildup and pH decrease occurs [Spencer, T. L. et al. (1976), supra: Belt, 
J. A. et al. (1979), supra1. Such a high level of blockage would be most 
difficult to achieve and maintain in vivo. Moreover, it is known that the 
GLY level decreases significantly as the intracellular pH decreases 
[Wilhelm, G. et al. FEBS Lett. 17, 158 (1971), Belt, J. A. et al. (1979) 
supra; Suolinna, E.-M. et al., Cancer Res. 35, 1865 (1975)], thus making 
the required degree of blockage essentially total. Without such 100% 
blockage, the LAC.sub.p and hence the pH decline becomes self-limiting, 
and it is not possible generally to effect cancer cell death, even in 
vitro, by use of lactate export inhibiting agents alone. The present 
invention effectively overcomes these basic problems, since the pronounced 
depression of the cancer cell ATP.sub.A effected by the combination of 
parts one (DNR-FAB-AAB) and two (AAD) of the present invention raises the 
GLY and LAC.sub.P and maintains them at levels several fold greater than 
that normally existing (i.e., without such therapeutically imposed GLY 
stimulation) in cancer cells. Consequently, the high LAC.sub.p thereby 
effected not only ensures the maintenance of a high LAC.sub.p against the 
depressing tendency of a decreasing intracellular pH, but also thereby 
reduces substantially the degree of lactate export inhibition which must 
be effected in order to permit cellular lactate buildup and the 
intracellular pH to decrease to a lethal level. The present invention thus 
makes the use of lactate export blocking agents clinically practical and 
most efficacious. 
Applicant has found in evaluative clinical treatment regimens administered 
according to the present invention utilizing far advanced human cancer 
patients having histologically verified malignancies representing a wide 
range of malignancy types (tongue, throat, stomach, cecum, colon, rectum, 
breast, ovary, uterus, lung, kidney, prostate, pancreas, lymphoma, 
melanoma, skin, marrow (leukemia), and bone) that very significant 
oncolysis is effected. These efficacious results were obtained with 
patients whose disease was found to be uncontrollable with conventional 
mitoxin chemotherapy and radiotherapy modalities. Throughout the treatment 
period of the individual patients, the clinical regimen was generally 
found to be free of discernable toxic side effects, and allowed a very 
high quality of life, despite the poor entry condition of most of the 
patients. 
The therapy system of the present invention substantially avoids several of 
the traditional problems and limitations of conventional mitoxin 
chemotherapy. Mitoxin chemotherapy characteristically acts by the 
indiscriminate destruction of all mitotically active cells in the body, 
both normal and malignant. Because of this mass indiscriminate destruction 
of normal proliferative cells by mitoxin chemotherapy, a host of toxic and 
treatment-limiting side-effects are experienced, including anemia (marrow 
destruction), pronounced loss of cellular and humoral immune competence, 
decrease of blood platelets, gastrointestinal ulceration and denudation 
with bleeding, vomiting and diarrhea, destruction of salivary gland 
function, electrolyte imbalance, anorexia, loss of hair, abnormalities of 
the nervous system, kidney damage, skin rash, liver damage, abnormal heart 
beat, myocardial toxicity, and damage to the lungs. The present method of 
metabolic chemotherapy, because it does not adversely affect normal 
dividing cells in the body, is strikingly free of such toxic effects and 
therefore permits continued administration until potentially all malignant 
cells are destroyed, while simultaneously permitting a very high quality 
of life. 
Similarly, since the present method does not destroy blastogenic 
lymphocytes of the immune system as does mitoxin chemotherapy, the body's 
immune competence remains unaltered, thus avoiding the pronounced decrease 
in resistance to infectious diseases usually seen in human patients 
undergoing mitoxin chemotherapy while maximally enhancing potential 
immunological cell-mediated and humoral attack on residual tumor cells.

DEFINITIONS 
Definitions of the Primary Metabolic Effectors 
In order to provide a clear and consistent understanding of the terms used 
in the specification and claims hereof, including the scope given to such 
terms, the following definitions are provided: 
ATP Availability Depressor Agent (AAD): Any clinically tolerable substance, 
means or procedure whose administration acts directly or indirectly to 
wastefully prevent energy transfer via oxidative phosphorylation in the 
RC, or to wastefully hydrolyze ATP already synthesized by the cell or to 
otherwise make unavailable for cellular metabolic use energy from ATP 
synthesized by the cell. 
Lactate Export Blocking Agent (LEB): Any clinically tolerable substance, 
means or procedure whose administration results either directly or 
indirectly in a decrease in the maximum rate at which lactic acid can be 
exported out of malignantly transformed cells. 
Defined Nutritional Regimen (DNR): Any nutritional regimen, oral and/or 
parenteral, which provides substantially all the daily caloric intake from 
sources of glucose, is substantially free of fatty acid sources other than 
of the essential linoleic and linolenic fatty acids, and provides only the 
minimal amount of protein sources of amino acids required to maintain body 
nitrogen balance. 
Fatty Acid Blocking Agent (FAB): Any clinically tolerable substance, means 
or procedure whose administration results either directly or indirectly in 
a decrease in the production rate of ATP energy derived from the overall 
metabolic oxidative degradation of fatty acids. 
Amino Acid Blocking Agent (AAB): Any clinically tolerable substance, means 
or procedure whose administration results either directly or indirectly in 
a decrease in the production rate of ATP energy derived from the overall 
metabolic oxidative degradation of amino acids. 
Further Definitions 
1. Agent: as used herein, refers to a substance, means or procedure for 
effecting a particular metabolic result. 
2. ATP Hydrolysis: as used herein, refers to the catalyzed breaking down of 
ATP into adenosine diphosphate and inorganic phosphate, or into adenosine 
monophosphate and pyrophosphate. 
3. ATP Hydrolyzer: as used herein, refers to an agent capable of effecting 
ATP hydrolysis. 
4. ATP Wasting: as used herein, refers to an imposed reduction in the rate 
of availability of ATP for cellular metabolism achieved by a decrease in 
the rate of production of ATP by wastefully uncoupling oxidation and 
phosphorylation in the RC, or by wastefully hydrolyzing ATP already made 
by the cells, or by wastefully preventing already-made ATP from taking 
part in cellular metabolic reactions. 
5. Cancer Cell: as used herein, refers to any malignantly transformed 
cellular phenotype deriving from a medical malignancy. 
6. Malignancy: as used herein, refers to any of the pathological neoplastic 
disease states medically classified by histological analysis as carcinoma, 
sarcoma, lymphoma, or leukemia. 
7. Mammal: as used herein, refers to any of the class Mammalia of higher 
vertebrates comprising humans and all other animals that nourish their 
young with milk secreted by mammary glands. 
8. Metabolism: as used herein, refers to the totality of biochemical 
reactions and processes ongoing in a cell incidental in the support of 
viability and life. 
9. Neoplasm: as used herein, refers to a new growth of tissue serving no 
physiologic function; a tumor. 
10. Oncolysis: as used herein, refers to the elimination, reduction or 
control of malignant neoplasms by effecting the death and/or 
proliferation-arrest of the malignant cells therein and thereof. 
11. Oxidative Metabolism: as used herein, refers to a hierarchy of cellular 
biochemical reactions by which energy for ATP synthesis is obtained by 
degradation of glucose, fatty acids and amino acids, especially in the 
Citric Acid Cycle and associated Respiratory Chain of mitochondria. 
12. Peg: as used herein, refers to the maximum level of a rate above which 
the rate cannot increase or be increased. 
13. Primary Metabolic Effector: as used herein, refers to an agent capable, 
upon administration, of detrimentally altering the usual metabolism of a 
cancer cell by retarding substrate availability to a pathway, decreasing 
ATP availability, and/or inhibiting membrane transport functions; herein 
they include the ATP-availability depressor agents, lactate export 
blocking agents, defined nutritional regimen, fatty acid blocking agents 
and amino acid blocking agents. 
14. Regimen: as used herein, refers to a systematic course or plan of 
treatment directed toward effecting oncolysis; such plan embraces diet, 
drugs, metabolic effectors and/or therapeutic procedures. 
BRIEF DESCRIPTION OF THE INVENTION 
The present invention affords a novel method of substantially eliminating, 
reducing or controlling (collectively referred to in this disclosure as 
oncolysis) a wide variety of malignant neoplasms in humans and other 
mammals. The effect on the malignancy (i.e., carcinoma, sarcoma, lymphoma, 
leukemia) is oncolysis, and is the result of the death and/or 
proliferation-arrest of malignant cells therein and thereof. 
In accordance with the present invention, the net availability rate of ATP 
(ATP.sub.A) for satisfying the overall metabolic requirements of malignant 
cells in the body is depressed to a level which is inadequate for the 
maintenance of the essential metabolic processes required for the 
continued viability of the cells, without substantially altering the 
normal ATP.sub.A level in the normal cells of the body (see FIG. 3). The 
malignant cells are thus selectively subjected to a lethal ATP-energy 
deprivation, resulting in cellular death as a consequence of energy 
starvation. In addition, the present invention provides in its preferred 
embodiments simultaneously and synergistically for the stimulation of the 
GLY in malignant cells to a maximum level while concomitantly effectively 
limiting the maximum LAC.sub.E capability of these cells by inhibition of 
the lactate export system. The malignant cells are thus selectively 
subjected to a second lethal action in which cellular death occurs as a 
consequence of acidity buildup and the depression of the intracellular pH 
below the level permissible for continued viability. 
In the present invention, the oncolysis of malignant neoplasms is effected 
by administration of an ATP-availability depressor agent (AAD), or a 
combination of an AAD and one or more additional metabolic effectors. Each 
such combination contains an effective amount of ATP-availability 
depressor agent (AAD). Other metabolic effectors which may be present in 
the combination include one or more of the following: 
(1) an effective amount of a lactate export blocking agent (LEB) for 
limiting the rate at which lactic acid is exported from the malignant 
cells; 
(2) an effective amount of a defined nutritional regimen (DNR) for limiting 
the amount of exogenously derived free fatty acids (FA) and amino acids 
(AA) available to the malignant cells, while providing calorically 
adequate glucose for metabolism in the normal cells of the body; 
(3) an effective amount of a fatty acid blocking agent (FAB) for limiting 
the rate of availability of energy to the malignant cells from 
endogenously derived free fatty acids; and 
(4) an effective amount of an amino acid blocking agent (AAB) for limiting 
the rate of availability of energy to the malignant cells from 
endogenously derived amino acids. 
The present invention comprises either (1) administering an AAD solely, or 
(2) concurrently administering an AAD and at least one other metabolic 
effector from among the LEB, DNR, FAB and AAB. See FIG. 3 for reference to 
the sites of action of these metabolic effectors in the energy metabolism 
pathway of the cancer cells. The AAD is designed to degrade a substantial 
portion of the ATP that is produced or is potentially producible by the 
cancer cells, thus making it unavailable for supporting cellular metabolic 
requirements. The AAD may comprise one or more agents which result, in 
adequate amount, in the lowering or depression to a lethal level in the 
cancer cells of the net rate at which ATP (ATP.sub.A) is actually 
available for satisfying cellular metabolic needs, by directly inhibiting 
the synthesis rate of ATP per se (e.g., by use of uncoupling agents of 
O/P) and/or inactivating or hydrolyzing ATP already synthesized (e.g., by 
use of ATPase hydrolysis-activity enhancing agents). 
The additional primary metabolic effectors (LEB, DNR, FAB, AAB) which can 
be used in combination with the AAD are designed to enhance the basic 
effects of the AAD per se and to further enhance the destruction of the 
malignant cells. One or more of the additional metabolic effectors can be 
used in combination with the AAD. These metabolic effectors include: 
(1) one or more Lactate Export Blocking agents (LEB) for limiting the rate 
at which lactic acid is exported from malignant cells; 
(2) a Defined Nutritional Regimen (DNR) which consists essentially of a 
dietary regimen designed to maximize the use of nutritional 
glucose-yielding carbohydrates as a source of ATP energy and to minimize 
the availability of nutritional fatty acids and amino acids for use as a 
source of ATP energy; 
(3) one or more Fatty Acid Blocking agents (FAB) for limiting the rate of 
availability of energy to the malignant cells from endogenously derived 
free fatty acids; and 
(4) one or more Amino Acid Blocking agents (AAB) for limiting the rate of 
availability of energy to the malignant cells from endogenously derived 
amino acids. 
In the present invention, it is preferred to use an AAD in combination with 
an LEB. It is most preferred to use all five components, i.e., AAD, LEB, 
DNR, FAB and AAB, in concurrently administered combination. 
The efficacy of the method of this invention and the absence of toxic or 
untoward side effects have been demonstrated clinically with far advanced, 
previously judged "terminally ill" human cancer patients. Patients with 
histologically diagnosed malignancies representing a wide variety of 
malignant neoplasia types, including all malignancy types of major 
clinical frequency, have all responded clinically to the therapy system of 
the present invention. Because of the substantial absence of any toxic or 
debilitating side effects, the method has great promise for effectively 
treating many malignancies that are substantially uncontrollable by 
currently practiced treatment methods. 
DETAILED DESCRIPTION OF THE INVENTION 
In accordance with the therapy system of the present invention, the net 
availability rate of ATP (ATP.sub.A) for satisfying the overall metabolic 
requirements of malignant cells in the body is depressed to a level which 
is inadequate for the maintenance of the essential metabolic processes 
required for the continued viability of the cells, without substantially 
altering the normal ATP.sub.A level in normal cells of the body (see FIG. 
3). The malignant cells are thus selectively subjected to a lethal energy 
deprivation, resulting in cellular death as a consequence of energy 
starvation. In addition, the present invention in its most preferred 
embodiment provides simultaneously and synergistically for the stimulation 
of the GLY in malignant cells to a maximum level while concomitantly 
effectively limiting the maximum LAC.sub.E capability of the cells by 
inhibition of the lactate export system. The malignant cells are thus 
selectively subjected to a second alternate lethal action in which 
cellular death occurs as a consequence of acidity buildup and the 
depression of the intracellular pH below the level permissible for 
continued viability. At adequate levels of ATP.sub.A depression, but above 
those required for effecting cancer cell death, the present invention 
results in the arrest of mitotic activity because of energy insufficiency, 
and hence in the arrest of tumor growth and progression. 
In the therapy system of the present invention, the destruction or 
proliferation stasis of malignant cells is achieved by utilizing an AAD 
alone, or a combination of an AAD and one or more additional metabolic 
effectors. Each such combination contains an effective amount of 
ATP-availability depressor agent (AAD). Other metabolic effectors which 
may be present in the combination include one or more of the following: 
(1) an effective amount of Lactate Export Blocking agent (LEB) for limiting 
the maximum rate at which lactic acid can be exported from the malignant 
cells; 
(2) an effective amount of a Defined Nutritional Regimen (DNR) for limiting 
the amount of exogenously derived fatty acids and amino acids available to 
the malignant cells while providing calorically adequate glucose for the 
metabolism of the normal cells; 
(3) an effective amount of a Fatty Acid Blocking agent (FAB) for limiting 
the rate of availability of energy to the malignant cells from 
endogenously derived free fatty acids; 
(4) an effective amount of an Amino Acid Blocking agent (AAB) for limiting 
the rate of availability of energy to the malignant cells from 
endogenously derived amino acids. 
The present invention consists of either (1) administering an AAD solely, 
or (2) concurrently administering an AAD and at least one other metabolic 
effector from among the LEB, DNR, FAB and AAB. See FIG. 3 for reference to 
the specific loci of action of these effectors in the energy-metabolism 
chain of malignant cells. The AAD per se is designed to degrade a 
substantial portion of the ATP as is produced or is potentially producible 
by the cancer cells, thus making it unavailable for use in supporting 
cellular metabolic requirements. The AAD may comprise one or more 
ATP-availability depressor agents or "ATP-availability depressors" (AAD), 
which result, at an adequate level of administration, in the lowering or 
depression to a lethal level in the cancer cells of the net rate at which 
ATP (ATP.sub.A) is actually available for satisfying cellular metabolic 
needs, by directly inhibiting the synthesis rate of ATP per se (e.g., use 
of uncoupling agents of O/P) and/or inactivating or hydrolyzing ATP 
already synthesized (e.g., by use of ATPase hydrolysis-activity enhancing 
agents). 
The additional metabolic effectors that can be used in combination with the 
AAD are designed to enhance the oncolytic effectiveness of the AAD, and 
permit achievement of malignant cell destruction in the body with lower 
levels of administration of the AAD per se. One or more of the additional 
metasbolic reflectors can be used in combination with the AAD. These 
metabolic reflectors include: 
(1) one or more Lactate Export Blocking agents (LEB) for limiting the 
maximum rate at which lactic acid can be exported from malignant cells; 
(2) a Defined Nutritional Regimen (DNR) which consists essentially of a 
dietary regimen designed to maximize the use of nutritional 
glucose-yielding carbohydrates as a source of ATP energy and to minimize 
the availability of nutritional fatty acids and amino acids for use as a 
source of ATP energy; 
(3) one or more Fatty Acid Blocking agents (FAB) for limiting the rate of 
availability of energy to the malignant cells from endogenously derived 
free fatty acids; and 
(4) one or more Amino Acid Blocking agents (AAB) for limiting the rate of 
availability of energy to the malignant cells from endogenously derived 
amino acids. 
In the regimens in which the combination of metabolic effectors used 
includes both the AAD and the LEB (with or without the other metabolic 
effectors), death of the malignant cells is effected by imposition of a 
lethally low intracellular pH (pH.sub.L). 
In the present invention, it is preferred to use an AAD in combination with 
a LEB. It is most preferred to use all five components, i.e., AAD, LEB, 
DNR, FAB and AAB, in concurrently administered combination. 
Any of several regimens employing the metabolic effectors can be used, 
within the scope of the present invention, to effect oncolysis. These 
regimens include, but are not limited to, the administration of (a) AAD, 
(b) AAD+LEB, (c) AAD+DNR, (d) AAD+LEB+DNR, (e) AAD+DNR+FAB, (f) 
AAD+LEB+DNR+FAB+AAB, (g) AAD+DNR+AAB, and the like. It is preferred to use 
a regimen of AAD+LEB. It is most preferred to use a regimen of 
AAD+LEB+DNR+FAB+AAB. 
Actions of the Primary Metabolic Effectors 
In order to provide a clear and comprehensive understanding of the 
fundamental metabolic precepts and salient therapeutical features of the 
present invention, the following narrative of this section presents a 
detailed account of the direct actions and synergistic interactions of the 
metabolic effectors. For this purpose, the actions and interactions are 
discussed for the particular case of the most preferred embodiment of the 
invention so as to demonstrate the individual action of each effector and 
the actions of all the effectors in combination. For purposes of 
illustrative clarity, the effectors are arbitrarily grouped into three 
concurrently administered regimens and discussed in the order of their 
specific action loci along the energy metabolism pathway of the cancer 
cells (FIG. 3). 
In normal (i.e., non-malignant) cells in the body, as depicted 
schematically in FIG. energy for ATP production is derived primarily from 
the sequential catabolism of glucose via the EMP, CAC and RC. Secondary 
sources of energy are fatty acids and amino acids which, after degradation 
to acetyl coenzyme A or intermediary metabolites of the CAC, enter the CAC 
for further catabolism. The relatively small amount of energy (per glucose 
molecule) deriving from the degradation of glucose to pyruvate in the EMP 
passes, along with that from the CAC and RC, in the form of ATP into the 
cellular ATP pool, from which it is withdrawn continuously to support 
overall cellular metabolism. 
As illustrated schematically in FIG. 2, malignant cells in the body are 
substantially unable to convert pyruvate, derived from glucose degradation 
in the EMP, to AcCoA, converting it instead to lactic acid which is 
excreted from the cell without further degradation. However, the malignant 
cells are fully capable of complete oxidation of FA and AA via the CAC-RC 
for ATP-energy production, when such substrates are available. When FA and 
AA availability is restricted, the cancer cells are able to generate ATP 
at an appreciable rate by strongly increasing the rate of glycolysis GLY 
(i.e., the rate of conversion of glucose to lactic acid in the EMP), 
producing overall two molecules of ATP for each molecule of glucose 
glycolyzed (as compared to 32 molecules of ATP produced in normal cells by 
oxidation of the pyruvate from each molecule of glucose in the CAC-RC). 
This high rate of cancer-cell GLY requires a commensurately high rate of 
lactate export to prevent the buildup of acidity in the cells to a lethal 
level. 
The integrated mechanism by which cancer cells in the body are selectively 
destroyed by administration of the most preferred embodiment of the 
present therapy system is illustrated schematically in FIG. 3. This 
diagram shows the specific points in the energy-production chain of cancer 
cells where the five primary metabolic effectors DNR, FAB, AAB, AAD, and 
LEB of the present invention, act. The first major provision in the most 
preferred embodiment of the present therapy system is a regimen for 
imposing a limit on the maximum rate of supply of NADH (NADH) to the RC of 
the cancer cells. This requires that the rate of availability of the 
principal oxidative energy-yielding substrates for the CAC of the cancer 
cells, FA and AA, be minimized as much as clinically possible. FA and AA 
for the cancer cells are obtained from two sources, dietary and/or 
parenteral intake (exogenous sources), and mobilization from internal body 
depots or stores (endogenous sources). The latter sources include plasma 
FA which are maintained by continuous turnover of adipose fat stores and 
plasma AA which are derived from the continuous turnover and degradation 
of tissue proteins. 
The control of exogenous FA and AA availability is readily achieved by 
administration of a defined nutritional regimen (DNR) which provides 
orally and/or parenterally the lowest possible level of FA other than the 
essential fatty acids linoleic and linolenic, AA sources such as protein, 
adequate only to maintain body nitrogen balance, and carbohydrate sources 
of glucose which supply substantially all of the daily caloric intake 
required for the daily caloric balance of the body. The DNR thus 
effectively restricts the dietary (exogenous) availability of FA and AA to 
the cancer cells, while providing adequate glucose for the normal cells to 
calorically satisfy overall body energy needs. This pegging of the rate of 
supply of exogenous FA and AA for ultimate metabolism in the CAC of the 
cancer cells, with consequent limitation of the maximum rate of NADH 
supply to the mitochondrial RC, is shown schematically in FIG. 3. (CAC in 
FIG. 3 denotes the rate of operation of the Citric Acid Cycle, i.e., the 
rate at which NADH is produced, e.g., .mu.mol/min.) The daily amount of 
DNR caloric intake (Kcal/d) is readily determined by measurement of the 
individual patient's resting metabolic rate (i.e., patient's oxygen 
consumption per 24 hours under resting conditions) and estimation or 
similar measurement of the active metabolic rate corresponding to the 
level of activity in which the particular patient engages during the day. 
The minimum daily caloric intake is then calculated as one-half of the sum 
of the resting and active metabolic rates in lO.sub.2 /d converted to its 
caloric equivalent in Kcal/d. Detailed procedures for precise DNR 
compositional and caloric balance determinations, suitable for use in the 
present therapy system, are given in U.S. Pat. No. 4,724,234. 
Although control of exogenous FA and (to a lesser extent) AA intake is most 
advantageous in order to limit the availability of these energy substrates 
to the cancer cells, control of the availability of energy from FA and AA 
from endogenous sources is equally important. It has been found clinically 
that cancer patients exhibit in general a pronounced elevation of the free 
fatty acid concentration in the plasma, ranging from 200% to well over 
400% above the average normal human plasma level of 190 .mu.g/ml, as well 
as a substantial elevation in the plasma free amino acid level 
(particularly in patients in advanced malignant disease states). The major 
cause of these endogenous FA and AA elevations in cancer patients appears 
to be the generally existing psychological and physiological stress 
fostered by the disease and, in many cases, by the treatment regimen 
itself, particularly if the treatment is toxic and unduly stressful. 
Sustained elevated secretion rates of stress-responsive adrenal hormones 
(e.g., epinephrine and cortisol) fostered by conditions of chronic stress 
can act to maintain a chronic elevation of FA and AA in the plasma. 
Epinephrine, for example, is the most potent known mobilizer of free fatty 
acids from body adipose tissue and fat depots, while the sustained action 
of the adrenal cortex cortisol results (through pronounced inhibition of 
cellular protein synthesis) in an appreciable elevation in the plasma AA 
concentration, as well as directly producing an elevation in plasma FA 
from adipose depots. Consequently, the overall restriction of the FA and 
AA oxidative energy to the cancer cells requires the administration of 
agents that effectively inhibit the availability or oxidative metabolism 
of endogenously derived FA and AA, in addition to the concurrent 
administration of the DNR. 
In the present invention, oxidative use of endogenously derived FA by the 
cancer cells for ATP-energy production is effectively inhibited by 
administration of one or more free fatty acid blocking agents (FAB), 
acting at the point shown in FIG. 3. A most effective and preferred FAB, 
for example, is long-acting or lente insulin, which is injected 
intramuscularly on a daily basis. Medically, at present, lente insulin is 
conventionally used almost exclusively for control of the plasma glucose 
concentration level in diabetic individuals. However, insulin has long 
been known also to impose a profound inhibition of free fatty acid 
mobilization from body adipose tissues. It has been found in detailed 
clinical studies by the present inventor, for example, that administration 
of a daily dose as small as 10 to 15 I.U. of lente insulin readily 
decreases the plasma FA level of cancer patients from some 400 to 900 
.mu.g/ml to as low as 70 .mu.g/ml, and maintains this low level for nearly 
24 hours in the presence of concurrently administered DNR, while the 
plasma glucose concentration remains within the normal physiological 
range. Thus, lente insulin is capable of reducing the maximum free fatty 
acid availability by some 92%, a most significant reduction considering 
that the endogenously derived free fatty acids constitute the primary 
energy source of the cancer cells after the DNR administration. In 
principle, regular or short-acting insulin could readily be used as a FAB, 
but has the clinical disadvantage of requiring more frequent injections in 
a 24-hour period. In the use of lente insulin as the FAB of the present 
invention, the desired inhibition of FA use for energy production by the 
cancer cells is achieved by means of a pronounced reduction in the rate at 
which endogenous FA can be mobilized from adipose depots. 
An example of another effective type of FAB that has been evaluated 
clinically, but which acts by an entirely different mechanism from that of 
insulin, is the fatty acid oxidation inhibitor, of which the agent 
2-tetradecylglycidate is representative [Tutweiler, G. F. et al., Federn. 
Proc. 37 1308 (1978); Tutweiler, G. F. et al., Clin. and Exper. Metabolism 
27 1539 (1978)]. These FAB act by inhibiting directly one or more enzymes 
in the mitochondrial .beta.-oxidation pathway of cancer cells or, as is 
the case with methyl 2-tetradecylglycidate, by inhibiting transport of the 
FA into the mitochondria for degradation and oxidation by the CAC. The 
point of action of the FAB is shown in FIG. 3, which schematically depicts 
the FAB as blocking or inhibiting endogenously derived FA from being used 
as substrates for the CAC, thereby decreasing the maximum rate CAC at 
which the CAC can operate in producing NADH for the RC. 
Although the oxidation of FA constitutes the major source of the 
oxidatively (CAC-RC) derived energy of cancer cells, considerable evidence 
exists demonstrating the concomitant oxidation of AA for energy production 
in these cells under adverse nutrient-availability conditions. 
Consequently, inhibition of the availability of endogenously derived AA 
for oxidation by administration of an amino acid blocking agent (AAB) 
provides an additional means in the present invention for reducing the 
overall rate at which the cancer cells can produce NADH for their energy 
needs. Generally, actively proliferating cancer cells conserve AA for use 
primarily in protein synthesis, and utilize the energy-rich FA for ATP 
energy production [see U.S. Pat. No. 4,724,234]. Under conditions of low 
FA-energy availability, as imposed by the DNR and the FAB of the present 
therapy system, oxidation of AA may become of considerable importance for 
cancer cell survival, and utilization of the AAB becomes beneficial 
oncolytically. In the present therapy system, the imposed AAB results 
either directly or indirectly in a decrease in the production of ATP 
energy derived from the oxidative degradation of endogenously supplied AA. 
An example of an AAB that has been effectively utilized clinically in the 
present therapy system is the drug aminoglutethimide. This agent acts 
indirectly by inhibiting the first step in the synthesis of cortisol from 
cholesterol in the adrenal cortex. As previously discussed, the primary 
cause of elevated plasma AA concentrations in cancer patients generally is 
chronically elevated cortisol, and both the plasma cortisol and AA levels 
in cancer patients are substantially lowered by administration of 
aminoglutethimide. Another example of an AAB which acts in part by means 
of a plasma cortisol level reduction, accomplished by a quite different 
physiological action, is stress-relieving psychotherapy. Chronically 
elevated cortisol levels due to stress are often significantly lowered by 
such psychotherapeutical regimens, which act to relieve or ameliorate the 
high mental stress levels of cancer patients, with resultant reduction in 
plasma AA (and FA) levels. Similarly, drugs which act to relieve or 
ameliorate stress per se constitute indirectly acting AAB. The point of 
action of the AAB in the present therapy system is shown in FIG. 3, which 
schematically depicts the AAB as blocking or inhibiting endogenously 
derivable AA from being used as substrates for the CAC, thereby decreasing 
the rate CAC at which the CAC can operate in producing NADH for the RC. 
The individual and combined actions of the DNR, FAB, and AAB thus result in 
a lowering of the maximum rate CAC at which the CAC can operate due to the 
limited or pegged rate of substrate availability from combined exogenous 
and endogenous FA and AA, and consequently in a marked lowering of the 
maximum rate NADH at which NADH can be supplied to the RC in the cancer 
cells. This action in turn results in the pegging or limitation of the 
maximum rate of ATP production possible in the RC of cancer cells by 
oxidation of NADH. Simultaneously, the NADH of the normal cells of the 
body is not limited in any way by the administration of the DNR, FAB, and 
AAB, since these cells can fully oxidize the abundant glucose provided by 
the DNR. The cancer cells are thus selectively and effectively limited 
with respect to the maximum rate at which NADH can be provided to and 
oxidized in their RC (i.e., limited in their maximum RC), and consequently 
in the maximum rate at which ATP can be produced by the RC. 
The second major provision in the most preferred embodiment of the present 
therapy system is a regimen for lowering, selectively in the cancer cells, 
the overall rate ATP.sub.A at which ATP is available for supporting the 
total cellular metabolic energy needs. This ATP.sub.A lowering is 
accomplished by the administration of one or more ATP-availability 
depressor agents (AAD). The ultimate action thereof (at adequately high 
levels of administration) is to lower the ATP.sub.A to a level which is 
inadequate to sustain even the minimal vital metabolic processes of the 
cancer cells required to maintain viability, and consequently to effect 
death and lysis of these cells by energy starvation. This lowering of the 
ATP.sub.A is accomplished by the AAD, for example, by decreasing the rate 
of production of ATP per se by uncoupling O/P in the RC, or by wastefully 
hydrolyzing ATP already made, or by sequestering the existing ATP molecule 
so as to make it unreactive in energy-requiring metabolic reactions. These 
actions of the AAD are collectively referred to herein as "ATP wasting," 
since they all result in the wasteful removal of ATP from the ATP pool and 
thus prevent its availability for use in satisfying cellular metabolic 
needs. Since, in the cancer cells, the rate of NADH oxidation in the RC is 
limited to a low level by the DNR-FAB-AAB imposed restriction on the 
availability rate of NADH, the RC cannot increase above this pegged level 
as ATP is wasted by the administered AAD. Consequently, the AAD-wasted ATP 
cannot be compensated for, in the cancer cells, by an increase in the 
operational rate of the RC, i.e., an increase in the rate RC of NADH 
oxidation to produce ATP at a greater rate. As a result, as the level of 
AAD action is increased, the net available-ATP rate, ATP.sub.A, for 
accommodating cellular metabolic reactions and processes decreases, 
ultimately reaching a lethal level of depression, ATP.sub.A =ATP.sub.L, at 
an adequate level of AAD administration. In the normal cells, the AAD also 
acts to waste ATP, but since the normal cells can fully utilize the 
abundant glucose of the DNR, they experience no restrictive limit on the 
CAC or NADH to the RC. Consequently, the RC increases as much as is 
necessary to compensate for the AAD-wasted ATP, thus insuring maintenance 
of a normal level of the ATP.sub.A for satisfying all normal cellular 
metabolic needs. The normal cells are thus unaffected energywise by the 
administration of the AAD, while the cancer cells are energy-starved to a 
lethal level, ATP.sub.L, at an adequately high level of AAD. 
As the ATP.sub.A in the cancer cells is depressed by the action of the AAD, 
the concentration of cellular ATP will ultimately begin to decrease, since 
the rate of useup of ATP is then transiently greater than the rate at 
which it can be supplied. This ATP concentration decrease stimulates an 
increase in the rate of glycolysis (GLY) which yields additional usable 
ATP (2 moles of ATP per mole of glucose glycolyzed). The overall AAD 
wasting action must be adequate, therefore, to also overcome the increased 
availability of this glycolytically derived ATP. In general, however, the 
production of ATP by glycolysis is very inefficient and metabolically 
demanding. For example, to fully compensate for the AAD wasting in the 
malignant cells of a malignant neoplasm of the ATP derived from complete 
oxidation via the CAC-RC of the energy equivalent of one mole of glucose 
per unit time would require the glycolytic degradation of 16 moles of 
glucose per unit time, with the concomitant production of 32 moles of 
lactic acid, which must be immediately exported. Consequently, the GLY 
would have to increase 1,600% and the LAC.sub.p 1,600%. In general, the 
LAC export rate capability of cancer cells is very large, so that it is 
most likely in the usual situation that the GLY per se will reach a 
maximum limit (peg), as ATP.sub.A decreases, before the LAC export 
capability becomes saturated. Consequently, the LAC.sub.p will reach a 
maximum and there will be no lethal buildup of acidity in the cells; 
ATP.sub.A will continue to decrease to the lethal level ATP.sub.L and the 
cancer cells will die from energy starvation. It is possible, in 
principle, that under certain conditions GLY may not reach a rate-limited 
state before the LAC export capability becomes saturated (i.e., before 
LAC.sub.E becomes maximally rate-limited or pegged), whence the cells will 
die from a lethal acidity buildup, pH=pH.sub.L, before ATP.sub.A reaches 
the ATP.sub.L level. However, cancer cell death by pH.sub.L would not 
generally be expected because of the large LAC export capability. Thus, 
the cancer cells will generally die from energy starvation rather than 
from a lethal pH depression to pH.sub.L when exposed to the 
DNR-FAB-AAB-AAD metabolic effector combination of the present therapy 
system. However, great therapeutical advantage is taken of the strong 
stimulation of the GLY by the AAD-mediated ATP.sub.A depression by 
additional administration in the present system of lactate export blocking 
agents (LEB), as is described subsequently. 
An example of one very effective class of AAD which has been extensively 
evaluated in clinical administrations of the present therapy system 
comprises agents which uncouple phosphorylation from oxidation in the 
mitochondrial RC (i.e., the so-called O/P uncoupling agents (UA)). The 
clinical use of this form of AAD has been described in detail previously 
[U.S. Pat. No. 4,724,234]. The UA act to release the energy derivable from 
the oxidation of NADH in the RC of cells as heat, thereby preventing 
synthesis of an equivalent amount of ATP. In the normal cells, the CAC and 
RC increase so as to exactly maintain a normal ATP.sub.A, since these 
cells can fully use the abundant glucose provided by the DNR. In the 
cancer cells, since the CAC and RC are rate-limited (or pegged) by the 
DNR-FAB-AAB, the UA results in a net decrease in ATP.sub.A (once the ATP 
available from the increased GLY becomes maximal). Another example of a 
highly preferred AAD is thyroid hormone (TH). The administration of TH 
(i.e., T.sub.4 and/or T.sub.3, or their pharmacological equivalent in 
thyroglobulin or dessicated thyroid gland) results in an increase of the 
overall pericellular membrane Na.sup.+ /K.sup.+ -dependent ATPase activity 
of cells, which results in an increased rate of active outpumping of 
Na.sup.+ through the pericellular membrane to accommodate a concomitant 
increase in membrane permeability to Na.sup.+ [Smith, T. J. et al. 
Federn. Proc. 38 2150 (1979); Guernsey, D. L. et al. Molecular Basis of 
Thyroid Hormone Action Chapter 10, Academic Press, New York (1983)]. This 
action produces the pronounced calorigenesis characteristic of thyroid 
hormone elevation in the body, and serves as a primary means for 
maintaining body temperature in warm blooded animals by wasting 
already-synthesized ATP. In the present therapy system, when used as an 
AAD, TH indirectly effectively hydrolyzes and wastes cellular ATP after it 
is synthesized, for wasteful (calorigenic) out-pumping of Na.sup.+. This 
ATP-wasting in the cancer cells acts in the present therapy system to 
strongly depress the ATP.sub.A, since their CAC and RC are already rate 
limited by the DNR-FAB-AAB. In normal cells, this TH-mediated ATP-wasting 
is precisely compensated for by a commensurate increase in the CAC and RC 
using glucose supplied by the DNR. For the purposes of the present 
invention, any clinically tolerable agent (i.e., substance, means or 
procedure) which acts to waste the energy of potentially synthesizable or 
already synthesized ATP or to prevent its use for usual and necessary 
cellular metabolic reactions constitutes an AAD. Thus, possible AAD 
include, but are not limited to, O/P uncoupling agents which waste the 
energy of potentially synthesizable ATP, intracellular introduction of 
inappropriate foreign ATPases, substances or means which inappropriately 
increase the activity of natural cellular ATPases, chemical agents that 
cause direct, generalized wasting-hydrolysis of ATP within the cell, 
agents that selectively bind to and energetically inactivate ATP, and 
molecular species which generally competitively inhibit existing ATP 
participation in normal metabolic reactions. 
In FIG. 3, the AAD is shown as acting at the RC level to wastefully inhibit 
ATP synthesis (as with the UA) and at the level of the already-made ATP 
(as with the TH). The various AAD may be used singly, or in combination in 
order to maximize overall effectiveness while maintaining a relatively low 
level of each particular AAD. The therapeutical result is the depression 
of the ATP.sub.A (ATP.sub.A .dwnarw.) to the lethal level, ATP.sub.A 
.ltoreq.ATP.sub.L. This condition of death by energy starvation is 
depicted in FIG. 3 by the upper terminal branch of the diagram. 
The third major provision of the most preferred embodiment of the present 
therapy system is the administration of a lactate export blocking agent 
(LEB) concurrently with the DNR-FAB-AAB-AAD combination of metabolic 
effectors. The LEB acts to effectively inhibit the export of lactate from 
the cancer cells, with the consequence that with the AAD of the present 
therapy system the ensuing buildup of lactic acid within the rapidly 
glycolyzing cell ultimately results in the depression of the intracellular 
pH to a lethal level pH.sub.L. As depicted in the lower terminal branch of 
FIG. 3, the AAD-depressed ATP.sub.A level causes a decrease in the 
intracellular concentration of ATP (decreased ATP pool, suora) which then 
stimulates an increase in the GLY by stimulation of increased 
phosphofructokinase (the rate-limiting enzyme of the EMP) activity in the 
Embden-Meyerhof pathway. This results in a commensurate increase in 
LAC.sub.p. In the presence of the LEB, the maximum LAC.sub.E is 
effectively lowered due to inactivation of part of the available export 
capacity. When, through imposition and maintenance of adequate levels of 
AAD and LEB, LAC.sub.p exceeds the maximum LAC.sub.E possible, LAC 
concentration continuously increases in the cancer cells and the 
intracellular acidity ultimately reaches a lethal level (pH=pH.sub.L). The 
action of the LEB strongly decreases the maximum possible LAC.sub.E by 
binding to and inactivating a portion of the lactate-exporting molecular 
moieties in the cell membrane [Spencer, T. L. et al. (1976), supra; Belt, 
J. A. et al. (1979), supra], while the high GLY stimulated by the AAD 
depression of the ATP.sub.A greatly increases the LAC.sub.P ; ultimately 
LAC.sub.p &gt;LAC.sub.E maintains and lethal acidity buildup ensues in the 
cancer cells. Adequate levels of LEB ensure that LAC.sub.p will become 
greater than the pegged LAC.sub.E at GLY levels before the maximum 
operational GLY level is reached, and hence that the cancer cells will die 
of a lethal pH depression. 
The importance of the ATP.sub.A decrease, obtainable with the AAD of the 
concurrently administered DNR-FAB-AAB-AAD combination of the present 
invention, is paramount in securing the LEB effectiveness. The ATP.sub.A 
can be continuously decreased with adequate AAD increase, to exert an 
increasingly stronger GLY stimulation so as to maintain the increased GLY 
against the GLY-increase-limiting effect of the decreasing intracellular 
pH per se, so that the intracellular acidity continues to increase in the 
presence of the LEB. The decreasing intracellular pH otherwise exerts an 
increasingly strong inhibiting effect on enzymes of the EMP as the pH 
decreases below the normal intracellular pH level of .about.7.0, with a 
consequent decrease in the maximum GLY level attainable as the pH 
decreases. 
In general, it is not possible to achieve a full 100% blockage of the 
lactate export capacity of cancer cells with a LEB, and hence not possible 
to achieve a pH.sub.L with a LEB alone. Also, the concentration of LEB 
required to effect a given percentage blockage of the initial maximum 
export capacity (i.e., that without any LEB) increases very rapidly as the 
percentage blockage is increased. For example, the average LEB 
concentration increase per percent-unit of lactate export blockage in 
going from 80% to 95% blockage is 10-fold greater than that required in 
going from 40% to 80% blockage. The low ATP.sub.A attainable by the 
DNR-FAB-AAB-AAD (or AAD by itself) of the present therapy system therefore 
acts to permit and ensure a lethal level of effectiveness of the LEB, 
which otherwise would not be attainable at clinically practicable levels 
of LEB. .The high GLY and LAC.sub.p fostered by the AAD-mediated ATP.sub.A 
decrease thus ensures saturation of the LAC export rate capacity (i.e., 
LAC.sub.p &gt;LAC.sub.E) of the cancer cells at moderate LEB levels much 
below the clinically unattainable 100% blockage required to effect 
complete saturation with the LEB alone. Lethal pH levels can thus be 
attained with relatively low levels of LEB administration, which may be 
clinically quite beneficial with certain LEB agents, and use of LEB which 
cannot achieve high levels of transport blockage becomes possible. 
Alternately, the use of the LEB markedly reduces the degree to which the 
ATP.sub.A would have to be depressed, to otherwise produce lethality by 
ATP.sub.A .ltoreq.ATP.sub.L (energy starvation), and hence considerably 
lowers the overall body metabolic rates (due to ATP wasting in normal 
cells) which would otherwise exist during treatment. These important 
synergistic interactions are summarized in FIG. 3 in the lower terminal 
branch of the diagram. The ATP.sub.A causes the GLY to increase, giving a 
higher LAC.sub.p and LAC.sub.E. With administration of the LEB, the 
maximum LAC.sub.E possible becomes pegged at a low level, whence with 
continuing LAC production at an elevated rate the intracellular pH 
ultimately decreases to a lethal level pH.sub.L. 
An example of a most preferred LEB which has great clinical efficacy when 
used in the present therapy system is the naturally occurring plan 
flavonoid quercetin (3,5,7,3',4'-Pentahydroxyflavone). The first 
comprehensive study of lactate export inhibition in a cancer cell form in 
vitro utilized quercetin [Spencer, T. L. et al.(1976), supra]. 
Subsequently, many bioflavonoids have been shown in vitro to be effective 
inhibitors of lactate export in malignant cells [Belt, J. A. et al. 
(1979), supra]; however, they have not previously been shown to be capable 
per se of effecting the death of malignant cells in vitro or in vivo. 
These coordinated and advantageously synergistic actions of the primary 
metabolic effectors (AAD, DNR, FAB, AAB and LEB) are summarized 
schematically in FIG. 4 in terms of cancer cell ATP production and wasting 
rates (e.g., .mu.mol ATP/min/Kg cells). Level 1 is the rate 
(ATP.sub.G.sbsb.i) at which the cancer cell is producing ATP via 
glycolysis initially, prior to therapeutical intervention. Level 2 is the 
initial total rate (ATP.sub.A.sbsb.i) at which ATP is available for use by 
the cell for its ongoing metabolic requirements. ATP.sub.A.sbsb.i is the 
sum of the initial glycolytic ATP production rate ATP.sub.G.sbsb.i and the 
initial O/P ATP production rate via the CAC-RC oxidative pathway, 
ATP.sub.O.sbsb.i. ATP.sub.A.sbsb.i is equal to ATP.sub.R.sbsb.i, the 
initial overall rate at which ATP is being metabolically used up by the 
cell. Upon administration of the AAD in increasing dosage (mg/Kg), or 
activity level, the level of ATP.sub.0 will increase (.DELTA.ATP.sub.0) 
commensurately, due to a slight transient decrease in ATP.sub.A (below 
ATP.sub.A.sbsb.i and ATP.sub.R.sbsb.i) and to the associated decrease in 
[ATP], the concentration of ATP in the cell, to precisely compensate for 
the rate ATP.sub.W at which ATP is being wasted by the AAD. Without the 
DNR+FAB+AAB (collectively denoted as "DFA" in FIG. 4), the total ATP 
production rate ATPP would rise to level 4 (ATP.sub.p.sbsb.max sDFA) as 
the AAD dosage level is continuously increased, where it pegs (becomes 
maximized) due to a natural limit on the rate of availability of FA and AA 
for the CAC. With the administration of the DNR+FAB+AAB, however, 
ATP.sub.p can rise only to level 3 (ATP.sub.p.sbsb.max cDFA) before 
becoming pegged due to a more limited rate of FA and AA availability for 
the cancer cell CAC. Thus, administration of the DNR+FAB+AAB significantly 
lowers the maximum rate at which the cancer cell can produce additional 
compensating ATP (.DELTA.ATP.sub.0) by oxidative-phosphorylation as the 
AAD dosage is continually increased. 
When ATP.sub.p reaches level 3 with increasing AAD administration, a 
further increase in AAD results in a transient decrease of ATP.sub.A below 
ATP.sub.A.sbsb.i (and ATP.sub.R.sbsb.i) and of [ATP] below [ATP].sub.i. 
This further decrease in [ATP] then drives phosphofructokinase (PFK), the 
rate-limiting enzyme of the EMP, to a higher level of activity and GLY and 
.DELTA.ATP.sub.G increase steadily to compensate for the increased 
ATP.sub.W wasting as the AAD is increased. All during this overall AAD 
increase, [ATP] remains slightly less than [ATP].sub.i, by an amount that 
is just sufficient to replace the ATP.sub.W loss by stimulating an 
increased rate of ATP production, first by the ATP.sub.O increase 
.DELTA.ATP.sub.O (until its peg is reached) and then by increased GLY, 
.DELTA.ATP.sub.G. Without administration of the LEB, at a sufficiently 
high level of AAD administration GLY will ultimately peg (i.e., the EMP 
will reach its maximum operational capacity), whence further increase in 
AAD will force ATP.sub.A to decrease strongly (below ATP.sub.A.sbsb.i), 
since both .DELTA.ATP.sub.O and .DELTA.ATP.sub.G are now pegged, until the 
lethal energy starvation level ATP.sub.A ATP.sub.L =is reached. In the 
presence of an adequate level of LEB, however, imposing a substantial 
percentage blockage of the cell's normal maximum lactate export capacity, 
the high LAC.sub.p of the greatly increased GLY soon exceeds the maximum 
possible LAC.sub.E as the AAD is increased, whence the cellular pH 
decreases to a lethal level, pH.sub.L. Consequently, with the LEB the 
cancer cell dies of lethal acidity substantially before the ATP.sub. L 
starvation level can be reached. 
The total rate of ATP wasting by the AAD required to produce lethality 
without the LEB (ATP.sub.W for ATP.sub.L) and with the LEB (ATP.sub.W for 
pH.sub.L) are denoted in FIG. 4, along with the associated increases in 
the glycolysis-ATP rate .DELTA.ATP.sub.G which must be overcome. The 
significant decrease in the overall level of ATP.sub.W generated by the 
AAD required to produce lethality with the coadministered DNR-FAB-AAB-LEB 
combination of metabolic effectors versus that without the LEB (and with 
or without the DNR-FAB-AAB) is evident. Moreover, since the overall 
ATP.sub.W level of ATP wasting is also experienced by the normal cells, 
with a commensurate rise in their CAC-RC to provide glucose-derived 
compensating ATP (to keep their ATP.sub.A essentially equal to their 
ATP.sub.A.sbsb.i and to their ATP.sub.R.sbsb.i), the pronounced decrease 
in required AAD effected by the coadministered DNR-FAB-AAB-LEB combination 
also results in a significant reduction in the overall whole body resting 
metabolic rate (i.e., O.sub.2 consumption rate) increase during treatment. 
As the initial .DELTA.ATP.sub.O increase takes place, a small increase in 
.DELTA.ATP.sub.G also concurrently occurs because of the small decrease in 
[ATP], but this is included in the overall .DELTA.ATP.sub.G in FIG. 4. 
ATP.sub.R remains equal to ATP.sub.R.sbsb.i during the rise of ATP.sub.W 
to its maximum (i.e., until cell death), provided the AAD action is 
imposed rapidly enough. 
In the .unlikely event that the increase in .DELTA.ATP.sub.G (i.e., in 
.DELTA.GLY) becomes pegged in a cancer cell before the intracellular 
pH.sub.L is reached, death by lethal acidity buildup will not occur. Such 
pegging of .DELTA.GLY could conceivably occur in some cells, since GLY is 
inhibited by lower pH levels [Spencer at al. (1976), supra: Belt, J. A. et 
al. (1979), supra]. However, a pegging of GLY in the present therapy 
system would simply mean that the overall .DELTA.ATP.sub.G that the 
ATP.sub.W had to overcome was less, whence the ATP.sub.L (lethal energy 
starvation) level could be reached sooner (i.e., at a lesser level of AAD 
administration). In effect, such a pH-imposed peg of .DELTA.GLY 
constitutes a selective blockage of the EMP specifically in the cancer 
cells and hence permits an easier attainment of the ATP.sub.L level with 
the AAD. Interestingly, in such a case the LEB actually serves to enhance 
cancer cell death by energy starvation, rather than by lethal acidity 
(pH.sub.L). Clinically, the important point is that with the present 
therapy system, cancer cell death is insured, whether .DELTA.GLY becomes 
pegged or not with the LEB. 
While the foregoing therapeutic principles described herein are clearly 
applicable to mammals generally, the treatment regimen as elucidated in 
detail hereinafter ("Illustrative Therapy System for Human Patients") is 
of specific applicability to humans and other mammals with comparable 
active and resting metabolic rate ranges--i.e., other primates. Specific 
adaptation of this invention to other mammals, e.g., with significantly 
higher or lower active and resting metabolic rate ranges is within the 
scope of this invention and can, using the principles herein described, be 
effected by those skilled in the requisite technology without departing 
from the invention. It is indeed contemplated that the therapy of the 
invention, with suitable adaptation to take account of the active and 
resting metabolism of the animal to be treated such as to maintain daily 
caloric balance, will be particularly useful in the treatment of malignant 
neoplasms in valuable agricultural animals, pets, zoo animals, race horses 
and other pedigreed stock, et cetera. 
Defined Nutritional Regimen (DNR) 
The essential features of the DNR of the present invention, independent of 
the overall therapeutical regimen thereof which is utilized, are the 
provision of (a) an absolute minimum of fat, which the cancer cells can 
use for ATP-energy production, so as to supply substantially only the 
minimal levels of the essential fatty acids, (b) a minimum of protein, 
which the cancer cells can use for ATP-energy production and for mitogenic 
anabolism, albeit an amount which is adequate on the average to maintain 
the whole-body nitrogen balance without excess during the overall 
treatment period, and (c) an allowance of carbohydrate which, after 
subtraction of the total fat and protein caloric contributions, provides 
glucose sufficient to furnish the remaining daily calories required to 
satisfy the total daily caloric requirements of the body. The amount of 
DNR given should avoid any substantial excess, since excess glucose would 
be converted to fatty acids which would then be readily available to the 
cancer cells for ATP-energy production in the absence of adequate FAB; 
malignant cells have been demonstrated to possess full capability for 
converting glucose to fatty acids [Abraham, S. et al., Proc. Am. Assoc. 
Cancer Res. 2, 89 (1956); Begg, R. W. et al., Fed, Proc. 15, 216 (1956); 
Medes, G. et al., Cancer Res. 13, 27 (1953)]. 
The total daily caloric requirement (Kcal/d) of the individual patient may 
be determined simply by increasing the caloric amount of the DNR to a 
level which prevents a successive daily loss or gain of body weight. 
Alternately, the daily caloric requirement can be determined precisely by 
performing an actual measurement of the resting metabolic rate (i.e., 
O.sub.2 consumption rate), converting this measurement value to its 
caloric equivalent for the DNR being administered, and adding in an 
appropriate caloric allowance for the daily activity level of the patient. 
(U.S. Pat. No. 4,724,234 presents a detailed discussion of metabolic rate 
measurements for precise DNR caloric calculations.) Actual metabolic rate 
measurements are preferred when using UA as AAD in the present invention 
because of their pronounced capability to elevate body metabolic rate. 
In Phase I of the preferred treatment protocol of the present therapy 
system (see "Illustrative Therapy System for Human Patients", infra), the 
essential fatty acids, protein, and carbohydrate components of the DNR are 
derived from essentially pure sources or sources of known analysis, and 
the DNR is administered in the form of liquid-suspension cocktails at 
periodic intervals over the day. The preferred component sources are: 
(1) for essential fatty acids: linoleic and linolenic acids at 1% of the 
patient's normal daily caloric requirements from sources such as primrose 
oil, or a mixture of safflower and linseed oils, 
(2) for protein: casein or egg protein, and 
(3) for carbohydrate: a mixture of pure dextrose, sucrose, and starch. The 
protein source used should provide a high quality amino acid complement. 
That is, the relative proportions of the amino acids should be those 
corresponding to average human protein composition; otherwise amino acids 
which are below their human proportionate equivalent will result in the 
inability of the anabolic use of the other amino acids (which will be in 
proportionate excess), whence they will become available as oxidative 
energy sources for the cancer cells. Non-nutritive bran (nominally 0.45 
g/Kg of body weight) may be added to the DNR to provide fiber and bulk, 
along with a vitamin and mineral mix, prior to blending. The vitamin and 
mineral allowance also contains KCl (65 mg/Kg) and NaCl (60 mg/Kg) since 
the purified preferred sources supply very little K and Na, along with at 
least twice the Recommended Daily Allowance (RDA) of all water-soluble and 
lipid-soluble vitamins, and appropriate levels of Ca, P, Mg, Mn, I, and 
Se, and choline. 
In Phase II of the preferred treatment protocol, the DNR is provided in 
specific solid-food menus of natural food elements of defined nutrient 
content formulated so as to give the nitrogen-balance level of high 
quality protein, and as minimal an amount of fat as possible by the choice 
of low-fat food elements. The required carbohydrate allowance is composed 
of that occurring in the protein-supplying natural food elements, plus 
supplementation from substantially total-carbohydrate sources (candies, 
custards, and flavored carbohydrate beverages) to satisfy the total 
therapeutical caloric level necessary to an ambulatory patient or 
outpatient. Supplementary non-nutritive bran, if desired, and vitamins and 
minerals at the minimum RDA level or higher, are also provided in the 
completely specified DNR for Phase II of the preferred protocol. 
Although the oral route is preferred for administration of the DNR, the use 
of total or partial parenteral alimentation procedures to administer 
substantially the nutrient equivalent of the DNR in a form suitable for 
infusion can readily be used when clinical conditions so demand. In such 
cases, administration of amino acids in pure and balanced form is of 
course required. An example is the case where, because of a malignant 
growth blocking the esophagus, a patient cannot swallow even semi-solid 
foods or liquids at the start of the therapy. Once the tumor mass has been 
regressed by the therapy, and swallowing of the DNR cocktails or 
tube-feeding is possible again, the preferred DNR cocktail ingestion 
procedure can resume. Additionally, total or partial parenteral 
administration can be used for particular elements of the DNR and/or 
particular vitamins and minerals which cannot be absorbed adequately when 
taken by the oral route in special patients. 
When using relatively high dosages of or particularly potent AAD (such as 
UA, for example), the resting metabolic rate may temporarily elevate to 
levels above that which can be calorically balanced with the DNR. For 
short periods (i.e., 24 hours), this condition poses no problems since the 
most metabolically active normal tissue, viz., muscle, readily utilizes 
its internal creatine phosphate store to produce ATP, a store which, like 
liver glycogen, is particularly high from the DNR administered during 
periods of lower (i.e., calorically balanced) metabolic rates. For longer 
periods, supplementation with glucose infusion can be used. Under such 
conditions of temporary caloric intake deficiency, it is particularly 
desirable to administer a FAB in adequate dosage to prevent energy 
availability from an otherwise potentially gross (and oncolytically 
detrimental) rise in plasma free fatty acids from mobilized body fat 
depots. 
Fatty Acid Blocking Agents (FAB) 
The primary purpose of the FAB is to significantly inhibit energy 
production from endogenously derived body FA in the cancer cells. FAB may 
act at one or more of several metabolic levels, and one or more FAB may be 
used in combination in the present therapy system. Examples of some forms 
of FAB are as follows: 
(1) FA Mobilization Inhibitors (FAB which act by inhibiting mobilization of 
free fatty acids from body adipose stores) include but are not limited to 
insulin (e.g., 5 to 45 I.U. of lente insulin per day, intramuscular 
injection) and epinephrine .beta.-receptor blockers (e.g., Inderal). 
(2) FA Transport Inhibitors (FAB which act by inhibiting the transport of 
FA into cells or into cellular mitochondria) include but are not limited 
to 2-tetradecylglycidic acid, methyl 2-tetradecylglycidate, malonyl CoA, 
D-acetylcarnitine, D-carnitine, deoxycarnitine, deoxynorcarnitine, 
L-carnitine, D-palmitoylcarnitine, D-decanoylcarnitine, crontonyl CoA, 
.DELTA.2,3-hexadecenoyl CoA, p-chloromercuribenzoic acid and 
N-ethylmalemide. 
(3) FA Metabolism Inhibitors (FAB which act by inhibiting specific 
enzyme-mediated reactions in the .beta.-oxidation of FA for energy 
purposes) include but are not limited to orotic acid, dichloroacetic acid, 
4-pentenoic acid, .alpha.-amanitin, valproic acid, bromstearic acid, 
2-bromooctanoic acid, hydrazine monohydrate, 1-phenyl-3-pyrazolidone, 
phenylpyruvic acid, .alpha.-ketoisocaproic acid, 
methylenecyclopropylacetic acid and biguanides. 
The foregoing is intended to be a representative but not exhaustive listing 
of FAB agents which can be used in practicing the present invention, 
commensurate with their clinical tolerability at effective dosage levels. 
Any one or any combination of such agents may be employed as the FAB of 
the present invention, commensurate with the tolerability of their in vivo 
use. 
Provision of FAB to inhibit energy production from free fatty acids in 
cancer cells is particularly desirable in the present therapy system due 
to the ready and copious availability of fatty acids mobilizable from body 
stores when needed, and particularly under conditions of stress. Without 
such endogenous FA-availability restriction, levels of the AAD required to 
produce an adequately low ATP.sub.A for effecting cancer cell death by 
either energy starvation (ATP.sub.L) or lethal pH depression (pH.sub.L) 
with an LEB may not always be possible to impose clinically, at least not 
without undesirably high body metabolic rate elevations associated with 
the compensation for the AAD-wasted ATP by normal cells. 
Amino Acid Blocking Agents (AAB) 
The primary purpose of the AAB is to inhibit the use of 
endogenously-derived AA for energy production in the cancer cells. This 
inhibition of AA use is particularly desirable when endogenous FA use is 
effectively restricted, since the alternate oxidation of AA by the cancer 
cells could in principle provide in some cases an adequate rate of 
oxidative ATP production to preclude achieving cancer cell death by energy 
starvation or lethal pH. In general, it is the condition of an excessive 
plasma concentration of AA that is to be controlled, since AA from dietary 
proteins are normally rapidly taken up and utilized by the normal cells of 
the body. Elevated patient plasma concentrations of AA derive primarily 
from a chronic elevation of plasma cortisol, usually because of a 
continuing condition of physiological and/or psychological stress in the 
cancer patient. Consequently, the most effective AAB currently clinically 
available act indirectly by reducing the cortisol concentration to a more 
normal state, both in magnitude and duration of the elevation. Examples of 
some currently available forms of AAB are as follows: 
(1) Agents which reduce the chronically elevated plasma cortisol levels by 
directly inhibiting cortisol synthesis in the adrenal cortex, including 
but not limited to aminoglutethimide 
(3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione). 
(2) Agents which enhance reduction of chronically elevated plasma cortisol 
levels by degradative removal in the liver, including but not limited to 
thyroid hormone (T.sub.4 and T.sub.3). 
(3) Agents which reduce plasma cortisol levels by inhibiting excessive 
stimulation of the adrenal cortex by pituitary adrenocorticotropic hormone 
(ATCH), including but not limited to synthetic cortisol analogs and cyclic 
AMP inhibitors. 
(4) Procedures which reduce chronically elevated plasma cortisol levels by 
inhibiting or normalizing excessive hypothalamic stimulation of 
hypophyseal ACTH release, including but not limited to stress-relieving 
psychotherapy. 
ATP-Availability Depressor Agents (AAD) 
The basic purpose of the AAD, alone or in combination with other metabolic 
effectors, in the present therapy system is to effect a reduction, 
selectively in the cancer cells, of the maximum rate at which ATP is 
available for supporting essential metabolic energy requirements. The AAD 
depresses the ATP availability rate ATP.sub.A of the cancer cells to a 
level which permits attainment of a state of lethal cancer cell starvation 
(ATP.sub.A =ATP.sub.L), or lethal pH depression (pH=pH.sub.L) when 
utilized with a LEB. Examples of some of the forms of AAD are as follows: 
(1) Agents which inhibit the oxidative ATP production rate by uncoupling 
oxidation and phosphorylation in the RC: O/P uncoupling agents, UA, 
including but not limited to 4-hydroxy-3,5-diiodobenzonitrile; 
benzotriazoles, such as 5-nitrobenzotriazole, 
5-chloro-4-nitrobenzotriazole, or tetrachlorobenzotriazole; 
benzylidenemalononitriles, such as 4-hydroxybenzylidenemalononitrile 
[4-OH-BMN], 3,5-ditertbutyl-4-hydroxybenzylidenemalononitrile, 
3,5-ditertbutyl-4-acetoxybenzylidenemalononitrile, or 
.alpha.-cyano-3,5-tertbutyl-4-hydroxycinnamic acid methyl ester; 
1,3,6,8-tetranitrocarbazole, 2,6-dihydroxyl,1,1,7,7,7-hexafluoro-2,6-bis 
(trifluoromethyl)-heptanone-4-[bis(hexafluororoacetonyl)acetone]; free 
fatty acids, such as long chain aliphatic monocarboxylic acids, 
n-tetradecanoic acid [myristic acid], or cis-9-octadecenoic acid [oleic 
acid]; phenols, such as 4-chlorophenol, 2,4,6-trichlorophenol [TCP], 
2,4,6-tribromophenol, pentachlorophenol [PCP], 4-nitrophenol, 
2,4-dinitrophenol [DNP], 2,6-dinitrophenol [2,6-DNP], 
4-isobutyl-2,6-dinitrophenol, 4-isooctyl-2,6-dinitrophenol, 
4,6-dinitrocresol, or 2-azido-4-nitrophenol; phenylanthranilic acids, such 
as N-phenylanthranilic acid, N-(3-nitrophenyl)anthranilic acid, 
N-(2,3-dimethylphenyl)anthranilic acid [mefenamic acid], 
N-(3-chlorophenyl)anthranilic acid, or 
N-(3-trifluoromethylphenyl)anthranilic acid [flufenamic acid]; 
2-(phenylhydrazono)nitriles, such as carbonyl cyanide phenylhydrazone 
(phenylhydrazonomalononitrile) [CCP], carbonyl cyanide 
3-chlorophenylhydrazone [m-Cl-CCP;CCCP], carbonyl cyanide 
4-trifluoromethoxyphenylhydrazone [p-CF.sub.3 O-CCP;FCCP], carbonyl 
cyanide 4-(6'-methyl-2'-benzothiazyl)phenylhydrazone [BT-CCP], the methyl 
ester of phenylhydrazonocyanoacetic acid, the methyl ester of 
(3-chlorophenylhydrazono)cyanoacetic acid, 
2-(3'-chloro-phenylhydrazono)-3-oxobutyronitrile, 
2-(2',4-dinitrophenylhydrazono)-3-oxo-4,4-dimethylvaleronitrile, or 
2-[3',5-bis(trifluoromethyl) 
phenylhydrazono]-3-oxo-4,4-dimethylvaleronitrile; salicylanilides such as 
salicylanilide, 2',5-dichloro-4'-nitrosalicylanilide [S-3], 
4',5-dichloro-3-(p-chlorophenyl)salicylanilide [S-6], 
2',5-dichloro-3-(p-chlorophenyl)-5'-nitrosalicylanilide [S-9], 
2',5-dichloro-3-tert-butyl-4'-nitrosalicylanilide [S-13], 
3,5-dichlorosalicylanilide, 3,5-dichloro-4'-methylsalicylanilide, 
3,5-dichloro-4'-nitrosalicylanilide, or 3,4',5-trichlorosalicylanilide 
[DCC]; tribromoimidazole [TBI]; trifluoromethylbenzimidazole, such as 
2-trifluoromethylbenzimidazole [TFB], 5-chlorotrifluoromethylbenzimidazole 
[CTFB], 4,5-dichlorotrifluoromethylbenzimidazole, 
4,7-dichlorotrifluoromethylbenzimidazole, 
4,5,6-trichlorotrifluoromethylbenzimidazole, 
4,5,6,7-tetrachlorotrifluoromethylbenzimidazole (TTFB], 
4-(2-chlorophenylhydrazono)-3-methyl-5-isoxazolone, 
3-acetyl-5-(4-fluorobenzylidene)-2,5-dihydro-4-hydroxy-2-oxothiophene, 
2-amino-1,1,3-tricyano-1-propene, n-decylamine, anilinothiophenes, such as 
2-(2,6-dimethylanilino)-3,4-dinitro-5-chlorothiophene [DDCT], or 
2-(4-chloroanilino)-3,4-dinitro-5-bromothiophene [BDCT], arsenate ion, 
arsenite ion, cadmium ion, 2-chloro-5-nitrobenzyldidenemalononitrile, 
decachloro-1,2-carborane [decachlorobarene], desaspidin, 
diethylstilbestrol [DES], gramicidin D, merphalan (sarcolysine), 
thyroxine, tetraphenylboron ion [TPB], trialkyltin ion, tributyltin ion, 
and valinomycin. 
As discussed previously, supra, for appropriate clinical use in the present 
therapy system, an O/P uncoupling agent must not only be capable of 
producing an adequate degree of uncoupling action to achieve desired 
therapeutic levels of oncolysis, but must also be substantially free of 
any detrimental, toxic, or otherwise significantly undesirable side 
effects, and must also be physiologically tolerable by the patient in 
order to be used in the therapy treatment of this invention. 
High pK.sub.a Uncoupling Agents 
Most UA, particularly those of the so-called "classical" group [Heytler, P. 
G. Inhibitors of Mitochondrial Functions (p.203) Pergamon Press, New York 
(1981)] are acids which dissociate, or ionize, in solution. As is well 
known pharmacodynamically, the total concentration of such agents in a 
cell (i.e., the concentration of the dissociated anionic moiety plus the 
concentration of the undissociated molecule) is dependent upon the pK of 
the UA molecule and the extracellular pH and intracellular pH.sub.L of the 
cell, for a given extracellular total UA concentration. (The pK.sub.a is 
the negative of the logarithm of the acidic dissociation constant Ka of 
the molecule.) For a given pK.sub.a UA, the total concentration of UA in 
the cell decreases as the intracellular pH decreases, in accord with the 
Henderson-Hasselbalch relation [e.g., see Goodman, L. S. et al. (Ed.) The 
Pharmacological Basis of Theraoeutics, 5th Ed., Ch. 1, Macmillan Pub. Co., 
New York (1975)]. The effectiveness of a given intracellular pH change in 
reducing the total UA concentration in the cell depends very much on the 
pK.sub.a ; UA with smaller pK.sub.a constants are much more susceptible to 
being moved out of the cell (i.e., decrease in total UA concentration) as 
the intracellular pH decreases than UA with relatively high pK.sub.a 
values (e.g., pK.sub.a .gtoreq.7). 
For example, a cancer cell that has a given initial total concentration of 
an UA with a pK.sub.a =4.0 and an initial intracellular pH=7.0 will have 
that concentration reduced by 89.9% if the intracellular pH decreases to 
6.0 due to acidity buildup in the cell. The desirable uncoupling action of 
the UA will thus be reduced steadily in the cancer cell as it becomes 
increasingly acid, until at pH=6.0 only about 10% of the initial 
uncoupling (i.e., AAD) activity remains. Since the UA concentration 
variation is logarithmically related to the pH change, even small 
decreases in intracellular pH can produce relatively large changes in UA 
concentration, and hence in O/P uncoupling activity. Thus, a cancer cell 
that has a given initial total concentration of an UA with a pK.sub.a =4.0 
and an intracellular pH=7.0 will have that concentration reduced 50% if 
the intracellular pH decreases by only 0.3 of a pH unit. The uncoupling 
activity in the cancer cell would thus be reduced by 50% by the relatively 
small pH change in going from pH=7.0 to pH=6.7, for an UA with a pK.sub.a 
=4.0. This means that much or most of the O/P uncoupling effectiveness in 
the cancer cell, with a UA having a pK.sub.a =4 used as the AAD, would be 
lost as the cell becomes progressively more acid, as is particularly the 
case when the UA (as the AAD) is used in combination with a LEB. This loss 
of uncoupling activity acts in turn to decrease the pH decline per se, so 
that a point may ultimately be reached by the cancer cell when no further 
decrease in pH can occur, whence the desired pH.sub.L cannot be reached, 
even with both the UA and the LEB present. The result of using a low 
pK.sub.a UA as the AAD, therefore, could be in some cases that the cancer 
cells experience only a small fraction of the uncoupling activity 
simultaneously experienced by the normal cells of the body, which do not 
become acid. The resultant clinical situation would then be one wherein 
the body is at the maximum tolerable metabolic rate permissible with the 
low pK.sub.a UA, but the cancer cells simultaneously are not experiencing 
enough uncoupling to reach the pH.sub.L level, whence cancer cell death 
does not occur, although cancer cell proliferation may be arrested. As has 
been experienced clinically, the same situation might maintain also in 
cases where a LEB is not utilized, but the cancer cells still become 
sufficiently acid to peg the maximum uncoupling activity that is 
attainable, whence ATP.sub.A ATP.sub.L =(death by energy starvation) 
cannot be attained. These adverse potentialities are entirely precluded by 
use of acidicly dissociable UA with relatively large pK.sub.a values, 
substantially pK.sub.a .gtoreq.7. At pK.sub.a values above about 7, the 
sensitivity of the intracellular UA concentration to physiologically 
expectable intracellular pH changes (i.e., 5.5.ltoreq.pH.ltoreq.7.5) 
becomes increasingly smaller as the pK.sub.a increases, reaching 
practically zero at pK.sub.a =9.0 and above. 
Consequently, regarding the use of ionically dissociable UA as AAD in the 
present invention, most especially when they are used in combination with 
the LEB thereof to effect a lethal pH depression, it is desirable, 
advantageous, and preferred to utilize those acidicly dissociable UA which 
have a pK.sub.a substantially in the range of pK.sub.a .gtoreq.7. More 
generally, in the case of any acidicly or ionically dissociable molecule 
used as an AAD under the present invention, it is preferred that such 
molecule have a pK.sub.a substantially in the range pK.sub.a .gtoreq.7. 
Most generally, in the case of any substance, means or procedure used as 
an AAD under the present invention, it is preferred that such substance, 
means or procedure be substantially insensitive, in respect to its 
ATP-availability depressing action, to changes in the intracellular pH, in 
order to obtain maximal oncolytic efficacy. 
Examples of high pK.sub.a uncoupling agents, together with their respective 
pK.sub.a values, include but are not limited to the following: 
4-nitrophenol (7.01); 4-chlorophenol (9.18), phenylhydrazonocyanoacetic 
acid, methyl ester (8.40); (3-chlorophenylhydrazono) cyanoacetic acid, 
methyl ester (7.70); 5-chlorotrifluoromethyl benzimidazole (8.9). 
(2) Agents which result in wasting (hydrolysis) of ATP that is already 
synthesized include but are not limited to 
(a) Inappropriate stimulation of endogenous cellular ATPase activity: 
Thyroid hormone (see definition of TH, infra); Protein 
restriction/restoration cycling (see Example 14, infra). 
(b) Exogenously supplied enzymic ATPases and Phosphohydrolases: ASFV 
ATPase; Azotobacter adenylate kinase; Molybdenum-Iron Protein (Klebsiella 
pneumoniae); recA Protein (E. coli). 
(c) Exogenously supplied nonenzymic ATPases and chemical hydrolyzers: 
Perchloric acid. 
Thyroid Hormone 
Thyroid hormone (TH), for use as an AAD and/or AAB of the present 
invention, is defined as comprising T.sub.4 (thyroxine) and/or T.sub.3 
(triiodothyronine), in any clinically appropriate form and proportion, and 
from any clinically appropriate source. It is generally held, 
pharmacologically, that the active form of thyroid hormone is T.sub.3, and 
that the T.sub.4 provided by the thyroid gland is ultimately converted to 
the active T.sub.3 form. Consequently, in the present therapy, TH may be 
T.sub.4 and/or T.sub.3, or appropriate sources thereof, such as 
thyroglobulin or dessicated thyroid gland powder. For TH dosing purposes, 
the pharmacological convention of relating T.sub.4, T.sub.3, and T.sub.4 
+T.sub.3 metabolic-effectiveness equivalents to that of 1.0 grain of 
dessicated thyroid gland powder is followed herein. One grain of 
dessicated thyroid gland powder contains 50 .mu.g of T.sub.4 and 12.5 
.mu.g of T.sub.3, and in metabolic effectiveness 1.0 .mu.g of T.sub.3 is 
equivalent to 4.0 .mu.g of T.sub.4. 
(3) Agents which inhibit ATP participation in cellular energy transfer 
metabolic reactions: 
(a) Metabolically competitive analogs of ATP including but not limited to: 
Adenylyl imidophosphate; adenylyl methylenediphosphate; 2-chloroadenosine; 
adenosine 5'-ethylcarboxamide; 1-methylisoguanosine; adenosine 
tetraphosphate; 3'-arylazido-ATP. 
(b) Agents which foster abortive energy transfer in ATP reactions including 
but not limited to: Phenylalanyl-tRNA-synthetase+Phenylalanine+Zn.sup.++. 
(c) Agents which bind to and energetically inactivate ATP including but not 
limited to: Chelate formation with Pseudomonas Membrane Protein. 
In general, it is advantageous and most preferred in the clinical practice 
of the present therapy system to include for use as the AAD at least one 
agent which wastefully hydrolyzes or energetically inactivates 
already-made ATP (as in (2) ane (3) above), and which additionally is 
insensitive to intracellular pH when the LEB is used with the AAD. The 
reason for this inclusion is that such AAD agents are effective in 
depressing ATP.sub.A deriving from ATP made via O/P and glycolysis, 
whereas UA (as in (1) above) can depress ATP.sub.A only to the extent of 
ATP deriving from O/P alone. Consequently, UA alone could not appreciably 
depress ATP.sub.A, for example, in cancer cells whose ATP production was 
derived in major proportion from glycolysis per se, whereas wasteful 
hydrolyzers and inactivators of already-made ATP could readily effect the 
desired ATP.sub.A depression in such cells, as well as in cells subsisting 
primarily on O/P-derived ATP prior to therapeutic intervention. 
Utilization of a combination of a high pK.sub.a UA with an ATP-hydrolyzing 
agent and/or ATP-inactivating agent as the AAD has the clinical benefit of 
providing maximum overall AAD effectiveness while reducing the level of 
administration of both agents, compared to that required when either agent 
is used alone as the AAD. 
Lactate Export Blocking Agents (LEB) 
The purpose of the LEB in the present therapy system is to limit the 
maximum rate of export of lactic acid from the cancer cells, to such an 
extent that the AAD-mediated increase in lactate production rate LAC.sub.p 
can lead to a buildup of lactate in the cancer cells sufficient to produce 
a lethal intracellular pH. Although some early studies indicated the 
existence of lactate export inhibition properties of certain agents 
[Harold, F. M. et al., J. Bacteriol. 117 1141 (1974); Halestrap, A. P. et 
al., Biochem. J. 148, 97 (1975); Henderson, A. H. et al., Am J. Physiol. 
217 1752 (1969); Lamers, J. M. et al., Biophys. Acta 394, 31 (1975); 
Watts, D. J. et al., Biochem. J. 104 51P (1967)], the first comprehensive 
study of a cancer cell form with a blocking agent was performed in vitro 
with the bioflavonoid quercetin [Spencer, T. L. et al., Biochem. J. 154, 
405 (1976)]. Examples of some forms of LEB include but are not limited to 
the following: 
(a) (1) General chemical substances demonstrating LAC.sub.E inhibition in 
cancer cells: 4,4'-bis(isothiocyano)-2,2'-stilbenedisulfonate; 
isobutylcarbonyl lactyl anhydride; .alpha.-cyano-4-hydroxycinnamate; 
.alpha.-cyano-3-hydroxycinnamate, DL-p-hydroxy-phenyl-lactate and 
mersalyl. 
(b) Bioflavonoids demonstrating LAC.sub.E inhibition in cancer cells: 
5,7,4'-Trihydroxyflavone (apigenin); 3,7,3',4'-quadrahydroxyflavone 
(fisetin); 3,5,7,2',4'-pentahydroxyflavone (morin); 
3,5,7,3',4'-pentahydroxyflavone (quercetin); 
5,7,4'-trihydroxy-3,6-OCH.sub.3 -flavone (K3); 
5,7,3'-trihydroxy-3,6,4'-OCH.sub.3 -flavone. 
The naturally occurring plant bioflavonoids, common in many food products, 
are a preferred class of LEB for use in the present therapeutical system. 
The bioflavonoid quercetin (3,5,7,3',4'-pentahydroxyflavone) is currently 
the most preferred LEB for use in the present therapy system, being the 
most effective (on a weight basis) of the bioflavonoids in regard to 
producing lactate export inhibition in cancer cells, as well as having a 
clinically demonstrated absence in the present therapy system of toxicity 
and untoward side effects at therapeutically effective doses in human 
cancer patients (see, e.g., Examples through 4, infra). Quercetin exerts 
its inhibitory action by binding to and deactivating the molecular 
moieties specifically responsible for the transport of lactate through the 
pericellular membrane [Spencer, T. L. et al. (1976), supra]. Moreover, 
quercetin has been demonstrated to exert a remarkable inhibitory influence 
in blocking mammalian malignant neoplasm promotion by a variety of 
carcinogenic agents [e.g., Kato, K. et al., J. Toxicol. Sci. 9, 319 
(1984); Kato, K. et al., Ecotoxicol. Environ. Safety 10, 63 (1985); Kato, 
K. et al., Carcinooenesis 4 1301 (1983); Levy, J. et al., Biochem. 
Biophys. Res. Commun. 123, 1227 (1984); Nishino, H. et al. Oncology 41, 
120 (1984); Nishino, H. Gann 75, 113 (1984); Hirose, M., Cancer Lett. 21, 
23 (1983)]. It has also been shown to possess a potential antimetastatic 
action in mammals [e.g., Ishikawa, M., Int. J. Cancer 15, 338 (1987)]. 
Combinations of the Metabolic Effectors 
The most fundamental metabolic effector of the present invention is the 
AAD, most preferably AAD substantially insensitive to therapeutically 
induced intracellular pH decreases in the cancer cells. At adequate levels 
of administration, the AAD alone is capable of effecting very significant 
rates and extents of oncolysis (see, e.g., Example 14, infra), albeit with 
quite high concomitant elevation of the patient whole-body resting 
metabolic rate. The AAD-alone regimen effects cancer cell death by 
depressing the ATP.sub.A to the lethal ATP.sub.L level, i.e., by imposing 
energy starvation. The LEB is the second most fundamental metabolic 
effector but, as emphasized previously herein, must be used in combination 
with the AAD in all cases to be therapeutically effective. With the 
AAD-LEB combination oer se. cancer cell death is effected by a buildup in 
intracellular acidity to a point where a lethal pH.sub.L level is reached 
(see Examples 3 and 4, infra). With the AAD-LEB regimen, the required 
level of AAD to achieve cancer cell death is decreased relative to the 
AAD-alone regimen, but may still be appreciable, particularly if the 
cancer cells have a very high O P-ATP production rate capability that must 
be overcome by the AAD, whence the patient wholebody resting metabo)ic 
rate elevation may still be quite high during treatment. Addition of the 
metabolic effectors DNR and/or FAB and/or AAB to the AAD regimen serves to 
decrease the maximum rate at which NADH can be supplied to the RC of the 
cancer cells (by limiting FA and AA availability for the CAC), and hence 
commensurately decreases the level of AAD action required to effect 
oncolysis. This lowered AAD requirement is quite beneficial clinically in 
that a commensurately lower patient whole-body resting metabolic rate then 
exists at the AAD level where very significant oncolysis maintains. Thus, 
while very significant oncolysis can be effected with the AAD-alone 
regimen and with the AAD-LEB regimen with adequately strong AAD, each 
regimen can be significantly clinically benefited in terms of permitting a 
lowered patient whole-body resting metabolic rate elevation by 
coadministering with them one or more of the DNR, FAB and AAD metabolic 
effectors. Moreover, they permit attainment of very significant oncolysis 
clinically with relatively "weak". AAD which otherwise might not be able 
to depress ATP.sub.A adequately at their clinically maximal administration 
levels. Maximal benefit in this respect is of course obtained by 
coadministration of the full DNR-FAB-AAB combination in each case. 
Consequently, the most preferred clinical regimen of the present therapy 
system is the coadministration of all five metabolic effectors in the 
combination AAD-LEB-DNR-FAB-AAB. 
Most Preferred Embodiment 
Although the AAD-alone or the AAD-LEB alone at adequate strength are per se 
capable of effecting pronounced oncolysis, it is most preferred to utilize 
the concurrent administration of AAD, LEB, DNR, FAB and AAB. 
Although the concurrent administration of the overall combination of all 
five of the basic metabolic effectors AAD-LEB-DNR-FAB-AAB is considered 
the most preferred embodiment of the present therapy system for clinical 
purposes, it must be clearly emphasized that the AAD-alone or the AAD-LEB 
alone at adequate strength are per se fully capable of effecting 
pronounced oncolysis. However, the concurrent administration of the DNR, 
FAB and AAB, singly or in combinations, with the AAD or with the AAD-LEB 
serves to lower the rate of availability of NADH to the RC in the cancer 
cells, and hence to lower the maximum rate at which ATP can be produced 
via the RC. Consequently, with the coadministration of the DNR and/or FAB 
and/or AAB with the AAD or with the AAD-LEB, the amount of AAD action 
required to achieve cancer cell death by ATP.sub.L or pH.sub.L, 
respectively, is significantly lowered. This lowering of the required AAD 
is of appreciable clinical advantage, since with a lower AAD level the 
patient experiences a commensurately lower whole-body resting metabolic 
rate elevation during treatment. Additionally, with the coadministration 
of the DNR and/or FAB and/or AAB, very significant oncolysis can be 
achieved with AAD that have relatively weak maximal depressor action 
levels, levels that may be inadequate to effect oncolysis when the AAD or 
AAD-LEB are used alone. Moreover, very significant oncolysis can be 
achieved at much lower AAD levels in cancer patients having particularly 
elevated plasma-free fatty acid and amino acid levels due to 
disease-fostered stress, when the DNR-FAB-AAB is coadministered with the 
AAD or the AAD-LEB. Thus, although the primary metabolic effectors AAD and 
AAD-LEB can be used alone at adequately strong levels to effect 
significant oncolysis, their efficacy is successively enhanced and the 
whole-body metabolic rate elevation lowered by the coadministration of one 
or more of the "adjuvant" metabolic effectors DNR, FAB and AAB. 
ILLUSTRATIVE THERAPY SYSTEM FOR HUMAN PATIENTS 
The following clinical protocol represents a typical administration regimen 
for implementing the therapy system of the present invention for human 
cancer patients. Moreover, it constitutes a most preferred embodiment of 
the present therapy system, one that is particularly suitable for 
(otherwise) terminal cancer patients for which other treatment modalities 
have failed. This particular regimen and its combination of specific 
therapeutical metabolic effectors is exceptionally simple to administer 
and is free of untoward side effects, allowing it to be utilized with far 
advanced patients having severe debilitation from their disease and from 
prior treatment with such modalities as mitoxin chemotherapy and 
radiotherapy. 
The regimen is composed of two clinical phases, administered sequentially. 
Phase I consists of the administration of the therapy system at a hospital 
or clinic on an in-patient basis. The duration of Phase I generally ranges 
from two to four weeks. Upon completion of Phase I, the patient enters 
Phase II, which consists of a continuation of the same therapy regimen but 
on an out-patient basis. The duration of Phase II is variable, depending 
upon the rate of patient responsiveness; treatment is continued as long as 
the malignant condition is being effectively regressed or controlled. 
Phase I 
In Phase I, the patient enters the hospital and first receives a thorough 
physical examination along with complete laboratory tests (i.e., "SMAC-24" 
or equivalent, with hematology, blood chemistry, enzymology, serology and 
urinalysis) to rule out the existence of any prohibitively 
contraindicatory condition or conditions. The therapy is then initiated as 
soon as the laboratory test results are available and evaluated. The 
following therapeutical metabolic effectors are administered: 
(1) DNR: The patient's resting metabolic rate (10.sub.2 /d) is measured at 
the start of the therapy, and this result is adjusted for physical 
activity (e.g., by increasing the resting metabolic rate value by 10% to 
5%, depending upon the level of activity of the particular patient), to 
establish the active metabolic rate. The effective metabolic rate is then 
determined as one-half of the sum of the resting metabolic rate and the 
active metabolic rate. The total lO.sub.2 /d of the effective metabolic 
rate is converted to its equivalent in Kcal/d of carbohydrate (powder) by 
multiplying by 5.426 Kcal/d g/d per Kcal/d. One percent of the 
carbohydrate caloric value is provided as essential fatty acids (0.108 g 
of essential fatty acids per Kcal). Protein (e.g., casein or egg protein 
powder) is provided, nominally, at a level of 15 to 20 g/d per 70 Kg of 
body weight. These ingredients are blended into a suspension along with an 
appropriate level of vitamins and minerals (as previously described). The 
DNR is then dispensed to the patient in several nutrient cocktails at 
intervals over the day. When required, the equivalent DNR can be partially 
or wholly furnished in appropriate intravenous form parenterally. The 
effective metabolic rate is determined periodically (daily or weekly) 
thereafter, and the result used to adjust the DNR to the measured caloric 
level, to appropriately accommodate such changes in the metabolic rate as 
may occur during the treatment period of Phase I. 
(2) FAB: The FAB in this therapeutical protocol is lente insulin (18-20 hr 
duration) and is administered by intramuscular injection once per day (at 
approximately 9:00 AM) at a dose of 10 to 20 I.U., nominally. Prior to 
such insulin administration, the blood glucose level is determined by use 
of a drop of blood and conventional glucose test strips available for that 
purpose. Blood glucose levels may similarly be checked whenever desired. 
In general, with appropriate DNR levels or glucose intake, blood glucose 
concentration remains normal or slightly elevated in this insulin dose 
range. Insulin is, clinically, a particularly good FAB. Not only does it 
very effectively block FA mobilization from body adipose-cell stores, it 
also simultaneously aids in insuring a rapid rate of glucose transport 
into normal cells for energy use, and into cancer cells for maximizing the 
.DELTA.GLY (for achieving maximal lethality with the LEB). 
(3) AAB: In this therapy protocol, the AAB and the AAD are the same, namely 
thyroid hormone; see "AAD" below. 
(4) AAD: The AAD in this therapy protocol is thyroid hormone. TH is 
administered in tablet form nominally at a dose rate of 1.0 to 3.0 
equivalent grains (see definition of TH, supra) per day given orally at 
8:00 AM. With higher doses of TH, significant increases in the resting 
metabolic rate may occur, whence appropriate adjustment of the DNR caloric 
input is required. 
(5) LEB: The LEB in this therapy protocol is the bioflavonoid quercetin, 
provided in the dihydrate form. The additional potential antimetastatic 
and anticarcinogenic properties of quercetin have been cited previously 
herein. Quercetin is administered orally in capsule form, twice daily (at 
approximately 8:00 AM and 8:00 PM) at a nominal dosage level of 2.0 to 3.0 
mg per Kg of body weight per capsule, of the pure (anhydrous) material. 
The maximum dosage of quercetin may be increased, if required. Quercetin 
is generally poorly absorbed in the intestinal tract, and elevated dosages 
may be necessary in particular cases to ensure attainment of adequate 
plasma levels. 
During Phase I, the DNR, FAB (lente insulin), AAD and AAB (thyroid 
hormone), and LEB (quercetin) are concurrently administered each day at 
their prescribed times and doses. The first DNR nutrient cocktails are 
given at 8:00 AM each day and thyroid hormone tablets are given 
concomitantly. The insulin injection is given one hour later, to allow 
time for glucose assimilation prior to the insulin administration. Blood 
glucose measurements, using simple chemical test strips and a drop of 
blood, are made each morning to insure that the glucose level is adequate, 
prior to the insulin administration. The body weight is measured daily to 
insure maintenance of steady weight by increasing or decreasing the daily 
caloric intake of the DNR. Additionally, the effective metabolic rate may 
be determined periodically to establish the precise DNR caloric intake 
requirements under the actual treatment conditions. Laboratory tests, as 
previously described, are done weekly, to monitor the hemapoietic, 
electrolyte and enzymic parameters. The adequacy of plasma-free fatty acid 
depression by the insulin (FAB) can be monitored by use of the plasma 
creatine phosphokinase (CPK) concentration, if desired. Levels 5% to 10% 
above the normal CPK range maximum are indicative of effective free fatty 
acid availability control. The patient may engage in a normal level of 
activities, but should not over-exert during this period, particularly 
when the metabolic rate is somewhat elevated. I all is going well with the 
patient in three to four weeks, the patient proceeds to Phase II 
(outpatient phase). 
Phase II 
In Phase II, the outpatient phase, the patient remains on precisely the 
same therapeutical protocol as in Phase I. However, for variety, the 
carbohydrate, protein, and essential fatty acids of the DNR may be 
supplied by regular food items rather than by the dehydrated carbohydrate 
and protein powders and oils served in suspension form. The food diet may 
be supplemented with the Phase I type of DNR nutrient cocktails if 
desired. The patient returns to the clinic or hospital at periodic 
intervals (every two to three weeks initially) for physical checkups, 
laboratory tests, and tumor-status evaluations. The patient is continued 
in Phase II until clinically free of their specific malignancy or for so 
long as the malignancy remains under control. Concurrently, the patient 
proceeds with his normal lifestyle and activities. 
The foregoing illustration of a typical but specific clinical protocol 
according to the most preferred embodiment of the present invention 
demonstrates the essential features thereof and the simplicity of its 
administration. However, it is understood that the phasing and duration of 
treatment periods therein are arbitrary, depending on the particular 
patient and the specific clinical status and condition. Thus, in 
particular cases, Phase II may constitute the entire treatment program, 
Phase I being unnecessary. Similarly, the treatment may be interrupted for 
intervals at any point. Additionally, as emphasized previously herein in 
the section "Combinations of Metabolic Effectors," supra, in particular 
cases only the AAD-alone or the AAD-LED combination alone, or either of 
these regimens in combination with one or more of the DNR, FAB and AAB 
metabolic effectors, may be administered. 
The present therapy system may readily be given concurrently, to 
appreciable clinical advantage in certain cases, with other cancer 
treatment modalities presently practiced. For example, full administration 
of the present therapy system concurrently with a protocol of mitoxin 
chemotherapy adds a third individual mode of cancer cell destruction, 
while allowing a pronounced reduction in the toxic and debilitating 
side-effects of the mitoxin modality by permitting use of smaller doses of 
the mitoxic drugs. A similarly efficacious result can be obtained from the 
use of the present therapy system concurrently with oncological 
radiotherapy, immunotherapy or hyperthermotherapy, in appropriate cases. 
Moreover, in appropriate cases the present therapy system, as has been 
demonstrated clinically, can be used to reduce advanced but localized 
malignant lesions to a size and extent that oncological surgery, including 
laser surgery and cryosurgery, may be advantageously used, thereby 
effecting a rapid and complete final removal of a previously inoperable 
lesion. 
In general, the dosage level of each metabolic effector in the present 
therapy system lies between the minimum required to effect oncolysis and 
the maximum at which it causes untoward or toxic side-effects in the 
particular patient. 
It should be further noted that, while the foregoing therapeutic principles 
described herein are directly applicable to humans and other mammals with 
comparable resting metabolic rate levels, i.e., other primates, specific 
adaptation of this invention to mammals (and indeed other vertebrates) 
with significantly higher or lower resting metabolic rates is within the 
scope of this invention. It can, using the principles herein described, be 
effected by those skilled in the requisite technology without departing 
from the invention. It is indeed contemplated that the therapy system of 
the invention, with suitable adaptation to take account of the resting 
metabolic rate of the animal to be treated, such as to maintain daily 
caloric balance, will be particularly useful in the treatment of malignant 
neoplasms and conditions in valuable agricultural animals, pets, zoo 
animals, race horses, other pedigreed stock, and the like. 
EXAMPLES OF CLINICAL EFFECTIVENESS OF METABOLIC EFFECTOR MALIGNANCY THERAPY 
ACCORDING TO THIS INVENTION 
In Examples 1 and 2, infra, patients with totally different cancer types 
(i.e., different malignant cell phenotypes and body tumor sites) were 
identically treated according to Phase I and Phase II of the "Illustrative 
Therapy System for Human Patients" of the detailed description, supra, 
comprising the most preferred embodiment of the present invention. In 
these patient cases, the specific metabolic effectors used were: DNR, FAB 
(lente insulin), AAB (thyroid hormone), AAD (thyroid hormone), and LEB 
(quercetin). In these example cases, the AAD and AAB were co-supplied by 
the same agent, thyroid hormone. The results of these two cases 
demonstrate the pronounced oncolytic effectiveness of the present 
invention when all five basic metabolic effectors are used concurrently in 
synergistic combination, and when the AAD employed is insensitive to 
intracellular pH changes. 
EXAMPLE 1 
Example Case No. 1: 
Female, 57 years old. 
Diagnosis: 
Recurrent infiltrating ductal cell carcinoma of the breast; terminal 
inflammatory stage. 
Basis of Diaonosis: 
Multiple specimens and histological analyses from excised malignant tumor 
of right breast. 
Therapy Prior to Present Treatment: 
Surgery (tumorectomy), extensive radiotherapy (4000 rads), and intensive 
mitoxin chemotherapy (Cytoxan). Patient had been asymptomatic for nearly 
three years, following initial treatment. 
Tumor Status at Start of Present Treatment: 
Right breast significantly swollen and enlarged; rigid, immobile, and 
painful. Breast has numerous pinkish indurated tumor nodules protruding 
slightly above skin surface, more frequent in number towards the areola. 
Areola and periareola area of breast contains many dark tumor nodules; 
areola is practically covered by thick, merging cancer nodules. Nipple is 
three-fourths retracted into breast. Breast exhibits marked hyperthermia 
(temperature elevation) relative to normal left breast. Intense, indurated 
inflammation area exists in band around breast extending back three inches 
from edge of areola. A broad area of highly inflammatory involvement 
extends from the breast over the right thorax, up to right axilla. Left 
breast is unaffected. A large (5 cm diameter), hard, firmly fixed mass is 
located in the right axilla; patient cannot lift arm upward from side or 
lower it completely to side because of axillary tumor involvement. Patient 
is very apprehensive, but in good general physical condition. Body weight 
is essentially normal for sex and height. Elevated serum cortisol level of 
20 .mu.g/dl typical of advanced, highly stressed cancer patients. 
Treatment Conditions (Phase I): 
DNR: Nutrient cocktails 
FAB: Lente insulin (10 I.U./d) 
AAB: (co-provided by the AAD) 
AAD: Thyroid hormone: Thyrolar 1, Armour (2.0 tablets/d) 
LEB: Quercetin (1.5 mg/Kg twice per day) 
Response to Treatment (Phase I): 
Day 10 (Day number denotes number of days since beginning of treatment of 
patient with present protocol): Extensive elevation and induration of 
inflammation areas on right thorax and on right breast greatly diminished 
throughout; skin approaching normal appearance. Previous nodules on breast 
are disappearing; no new nodules have formed. Large dark nodules in and 
around areola are strongly suppurating a pale yellow fluid around edges of 
nodules; the smaller dark nodules appear to be drying out and forming 
blackish crusts or scabs. Axillar mass is softer to palpation, somewhat 
smaller, still fixed but not as firmly as initially. Hyperthermia of right 
breast still considerable. Resting metabolic rate over past 10 days has 
averaged 1.4 times the patient's standard basal metabolic rate (i.e., Mayo 
standard basal metabolic rate for her height, weight, sex and age; see 
U.S. Pat. No. 4,724,234). All laboratory results (i.e., SMAK-24 and 
urinalysis) normal; cortisol level 12 .mu.g/dl, having decreased from the 
20 .mu.g/dl level at start of therapy. Weight has increased slightly since 
Day 1. Patient feels fine; free of any side effects; takes daily walks. 
All tumor progression arrested; generalized, significant tumor regression 
in progress. 
Day 20: Induration and elevation of former inflammation area on right 
thorax completely gone; skin is flat, smooth and dry, with brownish 
pigmentation. Periareola inflammation area now flat, smooth, but still 
reddish (inflamed). All previous tumor nodules on right breast have 
disappeared; no new nodules have formed since Day 1. Several of the 
smaller areola and periareola "scabs" have fallen off; skin beneath 
appears perfectly normal when viewed under magnification. Larger areola 
crusts (scabs) are still suppurating; scabs are very hard and firmly 
adhered to skin surface. Attending medical oncologist feels that "scabs" 
are dead or dying surface cancerous nodules and will all eventually dry 
out and fall off when oncolysis is complete. Axillar mass greatly 
diminished in size; now 2 cm in diameter, a 70.3% reduction in the 
original tumor mass; now free of chest wall and fully movable; soft. 
Patient's arm is fully mobile again; can lift right arm over head and hold 
it flat by side without any difficulty. Hyperthermia of right breast is 
hardly discernable by touch. Breast is much less swollen; is soft and 
movable, no longer rigid; not as painful, but remains tender. The resting 
metabolic rate has averaged approximately 2.0 times the standard basal 
metabolic rate over the preceding 10 days. All laboratory results are 
normal; cortisol level still lower, down to 8 .mu.g/dl. Weight has 
remained constant during past 10 days. Oncologist says patient in 
excellent condition physiologically and psychologically. All tumor 
progression fully arrested, and patient appears clinically free of tumor 
except for large areola scabs where continuing suppuration indicates still 
ongoing tumor lysis. 
Day 30: Area of periareola inflammation now gone; skin is flat, smooth, and 
dry; characteristic brownish pigmentation remains. No new tumor nodules 
have appeared since Day 1. Many more of the blackish scabs in the areola 
and periareola region of the right breast have fallen, leaving normal skin 
underneath. Interestingly, there are no depressions or scars left in the 
region where the tumor nodules have been. Microscopically, the fallen 
scabs appear to be hard, black shells which covered the local surface 
tumor masses during oncolysis. Although several scabs remain, only the two 
larger ones covering the site of the tumorectomy incision have suppuration 
from time to time, indicative of continuing oncolysis. Breast is fully 
normal, soft, movable, nonpainful. Previously retracted nipple has 
egressed out of breast and is now fully normal in size and disposition. No 
discernable hyperthermia of right breast relative to normal left breast. 
Axillar mass has decreased further in size, and has resolved into two 
distinct, palpable lymph nodes. The resting metabolic rate over the past 
10 days has averaged 2.0 times basal. All laboratory results normal; 
cortisol 8.5 .mu.g/dl. Body weight has remained constant. Overall 
condition of patient remains excellent. Patient continues to take daily 
walks and is normally active for her age. 
Day 40: Nothing has changed significantly from Day 30. A few more dark 
scabs have fallen from the areola and periareola area of the breast. The 
two large scabs covering the initial incision continue to have slight 
suppuration around their margins, but appear to be dryer and harder. 
Interestingly, the overall regression pattern appears as one in which 
oncolysis begins simultaneously throughout all of the tumor region, but in 
which the first recurrent masses (i.e., along the initial tumorectomy 
incision) take the longest time to eradicate, this despite the fact that 
the now-normalized axillar mass was initially many-fold larger than the 
combined peri-incisional surface masses. Laboratory results are normal and 
weight has remained constant. Patient remains in excellent condition and 
is asymptomatic. 
Day 47: Patient leaves hospital to enter the outpatient treatment stage of 
Phase II. In Phase II, the patient will resume her normal lifestyle 
activities but will report back to the attending oncologist at frequent 
intervals for laboratory tests and physical examinations. The medication 
schedule will remain exactly the same as in Phase I. The DNR will remain 
calorically the same, but will be from regular food items, rather than 
from the Phase I nutrient cocktail suspensions. 
Response to Treatment (Phase II): 
Day 75: Patient has been on out-patient regimen for 28 days. Treatment 
protocol has remained exactly the same as in Phase I, except the DNR 
carbohydrate, protein, and essential fatty acids are provided by normal 
food items, for palative reasons. Patient's disease remains fully 
arrested; oncologist reports patient clinically free of discernable tumor 
activity. All previous inflammation areas are flat and smooth. The two 
largest scabs at the initial incision site have come off, revealing fully 
normal skin underneath; the initial incision scar in the areola which they 
covered is now fully visible. Only a relatively few scabs remain, mostly 
in the periareola area. These exhibit no suppuration and appear hard and 
dry. Patient's blood and urine parameters have remained normal and weight 
constant. Patient has continued usual household activities and lifestyle 
with no problems; is in excellent condition. 
Day 109: Five days after previous examination on Day 75, patient became 
severely ill with influenza during a vacation trip, and went off the 
therapy regimen for 14 days. After nine days of being off the regimen and 
during the height of stress of her illness, two small scabs remaining in 
the periareola region came off and the red areas beneath began to enlarge 
and become peripherally inflamed. Following a return to the therapy 
protocol on Day 94, the inflammation gradually disappeared and the areas 
became covered over with exactly the same form of blackish scab as seen 
with lesions in the initial days of the treatment in Phase I; moderate 
suppuration ensued. These scabs were still present on Day 109, but were 
free of suppuration, hard, and dry. The patient lost several pounds of 
weight during the period of her illness, due to lack of food intake. 
Otherwise, she was in good health after the influenza episode. 
Day 183 (six months): Patient was seen by attending oncologist at 
approximately tri-weekly intervals after Day 75. She has remained in good 
health and gained back most of the weight lost during her influenza 
illness. Her malignant disease remains fully arrested. Most of scabs have 
fallen, leaving normal skin underneath. Several scabs still remain, but 
appear hard and dry. Detailed examination by attending oncologist reveals 
no evidence of metastases. (It is germane to note here that another female 
patient with recurrent breast cancer, presenting to the oncologist at the 
same time as the present example patient, but in a less advanced disease 
state, was placed on intensive mitoxin chemotherapy. That patient 
succumbed approximately three months after resumption of mitoxin 
chemotherapy.) Present patient's blood and urinary parameters have 
remained normal, including estrogen level. Cortisol remains at a low 
level. Patient is in good psychological condition and continues an active 
lifestyle while remaining on the Phase II therapy regimen. 
EXAMPLE 2 
Example Case No. 2: 
Female, 48 years old. 
Diagnosis: 
Far advanced basal cell carcinoma of the left face (naso-orbital-cheek 
area) of 11/2 years duration; tumor invading nose, cheek, and left eye; 
large (1.5 cm diameter) central ulcerated crater. 
Basis of Diagnosis: 
Histological analyses of three biopsy specimens taken from the upper 
margins and floor of the open ulcer; all specimens demonstrated malignant 
keratinocytes (basal cells) disposed in numerous nests in dense fibrous 
stoma, and in pseudo-glandular arrangements. 
Therapy Prior to Present Treatment: 
Topical ointments and antibiotics supplied by dermatologist over 11/2-year 
period, with no effect on lesion progression. 
Tumor Status at Start of Present Therapy: 
Tumor consists of a single, continuous mass extending laterally from the 
midline of the nose to the left for 4.25 cm and vertically from the left 
eyelid downward 4.0 cm. A deep, open, ulcerated cavity of approximately 
1.5 cm diameter is centered over the point where the small initial 
"pimple" arose 11/2 years ago. A very hard, rigid, fixed, continuous tumor 
mass, with well-defined margins as determined by palpation, extends under 
the ulcer and subcutaneously laterally and vertically as described. Skin 
immediately surrounding ulcer is intensely inflamed for a distance of 0.5 
cm; no suppuration or drainage from ulcer currently being experienced by 
patient. Floor of ulcer bright red, except for black thrombus spots where 
biopsies were taken seven days previously. The tumor area is raised 
approximately 0.5 cm above the normal surface of the face, being 
particularly raised in the region near the eye and causing significant 
obscuration of the visual field when reading. Conjunctiva of left eye 
inflamed and irritated, but no obvious tumor invasion of eye orbit yet 
present. Left nostril is essentially completely closed internally from 
lateral compression by tumor mass. Xerographic x-ray study indicates tumor 
has not yet invaded any b one structures. Patient infrequently experiences 
slight pain in the ulcer region. Patient was referred to a plastic surgeon 
for treatment, but surgery was ruled out because of extensiveness of 
lesion and its location (eye, nose involvement); radiotherapy and topical 
mitoxin chemotherapy also considered untenable treatment modalities in 
view of patient's condition. Patient is in reasonably good general health, 
but is excessively obese (excess body weight above her standard body 
weight for sex and height is 106.4 % of standard body weight). Patient has 
high blood pressure, poor cerebral circulation, moderate hyperglycemia, 
and is under great emotional stress from several causes. 
Treatment Conditions (Phase I): 
DNR: Nutrient cocktails 
FAB: Lente insulin (15 I.U./d) 
AAB: (co-provided by the AAD) 
AAD: Thyroid hormone: Thyrolar 1, Armour (2.0 tablets/d) 
LEB: Quercetin (1.5 mg/Kg twice per day) 
Response to Treatment (Phase I): 
Day 2: (Day number denotes number of days since beginning of treatment of 
patient with present protocol): Pronounced suppuration of pale yellow 
fluid from the ulcer commenced in the late afternoon and continued all 
night. Patient reports experiencing an intense "tingling" sensation 
throughout the entire tumor region. Patient readily consumes total daily 
DNR content, despite its large volume. Afternoon resting metabolic rate is 
1.72 times patient's Mayo standard basal metabolic rate for her sex, age, 
height, and weight. (Hereinafter the resting metabolic rate is indicated 
only by its multiple in terms of the Mayo standard basal metabolic rate.) 
Day 3: Ulcer crater is completely filled with semi-dry, yellowish seric 
material (like dried serum). Resting metabolic rate is now 1.76 times 
standard basal metabolic rate. Patient feels fine. 
Day 5: Pronounced suppuration from ulcer has continued; is especially 
intense in afternoon and night. Tingling sensation at such times 
continues. Afternoon resting metabolic rate is 1.92; morning resting 
metabolic rate is appreciably lower than the afternoon rate, and 
suppuration in the morning proceeds at a much lower rate. Examination 
shows that the skin overlying the whole tumor area is now "angry red" with 
intense inflammation; especially over the area between the ulcer margin 
and the eye. The induration of this area also appears less and the ulcer 
diameter smaller. Laboratory test results (blood parameters and 
urinalysis) all normal, including glucose level. 
Day 7: Resting metabolic rate reached 2.13 yesterday afternoon and was 
accompanied by pronounced afternoon, evening, and night suppuration, along 
with increased intensity of "itching" and "tingling" over entire tumor 
region. Increased intensity of suppuration in afternoon closely correlates 
with increased afternoon elevation in resting metabolic rate level, as 
well as increase in afternoon metabolic rate level from day to day. 
Correspondingly, the intensity of tingling and itching correlates directly 
with the measured resting metabolic rate level. Patient reports that she 
can no longer discern any tumor protrusion into her reading visual field. 
Detailed palpation measurements of tumor size by the attending oncologist 
indicate a pronounced reduction in all dimensions; tumor consistency 
throughout has become appreciably softer. Measurements by oncologist 
indicate a 60% reduction in overall tumor mass (volume) in 61/2 days on 
clinical protocol. Maximum elevation of mass is now less than 0.3 cm at 
any point. These measurements correlate well with the general visual 
assessment of the tumor region indicating that the tumor region has 
shrunken noticeably, including the degree of protrusion above the normal 
surface level of the face. The impression is that the entire tumor mass is 
shrinking back towards the original ulcerative epicenter; the ulcer 
diameter itself has decreased 17% and its margins have become flatter. The 
increased softness in the tumor consistency is indicative of oncolysis 
throughout the tumor mass, as evidenced by the fact that the ulcer crater 
quickly becomes filled with yellow seric fluid upon pressing down upon the 
tumor mass at practically any point. Intranasal examination of the left 
nostril indicates a pronounced decrease in the former constriction by 
tumor-imposed external compression; patient reports she now breathes 
normally through this nostril. Patient doing well generally, but reports 
periods of "shortness of breath" and resultant anxiety when resting 
metabolic rate is significantly elevated (that is, &gt;2.0). Patient 
continues to consume all of daily DNR. 
Day 9: Skin over tumor mass continues to remain inflamed, but inflamed area 
is much smaller than initially, extending out from the ulcer margins. 
Day 14: Intranasal examination of left nostril reveals no palpable 
constriction of air passage by tumor compression. 
Day 16: Afternoon resting metabolic rate has averaged 2.50 over previous 
three days, reaching as high as 2.91. This high resting metabolic rate has 
been accompanied by copious suppuration from the ulcer each afternoon, 
evening and night, and by an accompanying "terrible itching" sensation 
throughout the tumor region. Detailed measurements of tumor dimensions 
made by attending oncologist reveal a 90.4% decrease in overall tumor 
mass, relative to that present on Day 1. 
The ulcer diameter has decreased approximately 39%. Tumor is softer still, 
and left nostril is free of any constriction. Patient remains in good 
condition, but is bothered by periods of shortness of breath when resting 
metabolic rate is particularly elevated and she is active, as in taking 
afternoon walks; this condition is to be expected for an individual with 
such excessive body weight. Results of laboratory tests performed on Day 
12 are all normal; cortisol level is 9.0 .mu.g/dl. 
Day 20: Margin of ulcer is flatter; overall elevation of surface outside of 
ulcer is essentially gone. Conjunctival inflammation has disappeared. 
Day 23: Detailed measurements of tumor dimensions made by attending 
oncologist reveal a 96% decrease in overall tumor mass. The only 
clinically discernable area where tumor may remain is in the area 
adjoining the upper margin of the ulcer; this area is only 1 to 2 mm in 
width. Ulcer has diminished in diameter to 0.6 cm, a 41% decrease; its 
depth has also diminished greatly. Throughout the period of oncolysis the 
pattern of tumor-mass regression has been one of continuous shrinkage of 
the overall mass back towards its originating epicenter (the present ulcer 
crater). Results of laboratory tests made on Day 19 are all normal; 
cortisol level 12 .mu.g/dl. 
Day 24: Patient leaves hospital to enter the out-patient treatment stage of 
Phase II. In Phase II, the patient will resume normal lifestyle activities 
but will report back to the attending oncologist at frequent intervals for 
laboratory tests, physical examinations, and tumor status assessment. The 
medication schedule will remain exactly the same as in Phase I. The DNR 
will remain calorically the same but will be from regular food items, 
rather than from the Phase I nutrient cocktail suspensions. 
Response to Treatment (Phase II): 
Day 52: Patient has been on out-patient regimen for 28 days. Treatment 
protocol has remained essentially the same as in Phase I, except the DNR 
carbohydrate, protein, and essential fatty acids are provided by normal 
food items, for palatability reasons. The patient is judged clinically 
free of active tumor by attending oncologist. Small ulcer remains, but 
margins are smooth and flat. Ulcer depression appears lined with fibrous 
material. No active suppuration despite continued therapy regimen. Results 
of laboratory tests have been normal. Patient has resumed usual housewife 
duties without significant problems. 
Day 98 (three months): Examination reveals only the same small, 
slowly-closing ulcer; no evidence of tumor or tumor activity at clinically 
observable level. Patient is offered option of surgical removal of ulcer 
and closure of lesion site but refuses. Patient continues on present Phase 
II regimen. 
In the following Examples 3 and 4, only the AAD and the LEB of the present 
therapy system were administered. The AAD in each case was a combination 
of a high pK.sub.a UA (CTFB) and a wasteful ATP-hydrolyzer (TH). The LEB 
in each case was quercetin (in the dihydrate form). The dietary intake was 
composed of regular food items, because of the digestive compliance 
limitations of these patients. The results demonstrate the strong and very 
rapid oncolytic action attainable with such an AAD combination of agents 
which are insensitive to intracellular pH conditions and thus are highly 
effective with the LEB at dosage levels which produce only moderate 
elevations in the body resting metabolic rate during therapy, and which 
act separately by inhibiting O/P ATP production and by wasting ATP 
produced by O/P and glycolysis in the cancer cells. 
EXAMPLE 3 
Example Case No. 3: 
Female, 57 years old. 
Diagnosis: 
Poorly differentiated to undifferentiated serous papillary 
cystadenocarcinoma of the ovary, widely metastasized; Stage 3. 
Basis of Diagnosis: 
Histological analyses of multiple specimens from primary and metastatic 
tumors, obtained at exploratory laparotomy, of the ovary, sigmoid colon, 
abdominal wall, liver and diaphragm. 
Therapy Prior to Present Treatment: 
Surgery (four times), multiagent mitoxin chemotherapy (Cisplatinum, 
Adriamycin, Cytoxan, Alkeran), extensive radiotherapy. 
Tumor Status at Start of Present Therapy: 
CAT scan report: "massive retroperitoneal, periportal lymphadenopathy with 
associated obstruction of right ureter and intraabdominally spread ovarian 
carcinoma." In addition, patient had a large (8 cm.times.5 cm) tumor mass 
completely occupying the left supraclavicular fossa and multiple large 
palpable tumors in the lower right abdomen Tumors in both sites hard, 
firmly fixed, and non-painful. Extensive abdominal ascites fluid volume, 
precluding meaningful dimensional palpation of intraabdominal tumor masses 
Pronounced edema in right thigh due to intraabdominal compression of iliac 
artery. Patient very thin, weak, almost totally anorexic with great pain 
and continued episodes of uncontrollable vomiting. 
Treatment Conditions: 
Because of the tenuous condition of the patient and inability to ingest 
adequate food for full caloric balance at elevated metabolic rates, 
treatment with the present therapy was limited to three periods of two 
days each, with approximately seven days between treatments. Only regular 
foods (eggs, milk, cereals, fruits) and the AAD-LEB metabolic effectors 
were used, the AAD being the high pK.sub.a UA 5-chlorotrifluoromethyl 
benzimidazole (CTFB), pK.sub.a =8.9, combined with TH (Thyrolar-1, 
Armour), and the LEB being quercetin. CTFB was given orally at a dosage of 
5 mg/Kg per capsule, one capsule twice daily, and the Thyrolar-1 at a 
dosage of 1.5 tablets per day, each day the CTFB was given. The quercetin 
was given twice daily (8:00 AM and 8:00 PM) at a dosage level of 1.5 mg 
pure quercetin per Kg per capsule, one capsule each time the CTFB was 
administered. The food was supplied at the level of 1369 Kcal/d, but only 
about two-thirds of this caloric level was actually ingested. 
Response to Treatment: 
In the first treatment period, the CTFB was administered for only 11/2 days 
(one capsule AM and PM of the first day, and one capsule AM of the second 
day). On the third day, the abdominal ascites fluid volume had decreased 
significantly, and on the second day following the treatment period the 
patient had lost over 2 Kg of ascitic fluid; the supraclavicular mass had 
become softer and more movable. The patient's resting metabolic rate was 
only 1.3 times her standard Mayo basal metabolic rate during the period. 
Following treatment, the food intake was equivalent to caloric balance. 
The patient lost another 1.5 Kg of ascitic fluid in the ensuing three 
days, and the fluid then began to increase slowly up to the second 
treatment period. In the second treatment period, the CTFB was 
administered for two consecutive days. By the third day following the 
two-day treatment period, the ascites fluid volume had greatly decreased, 
to the extent that the body weight was decreased by approximately 5%. The 
body weight remained essentially constant for several days after this 
initial rapid decrease. The neck tumor mass was softer and more movable, 
and slightly painful. The masses in the lower abdomen, now palpable, 
similarly were of soft consistency and movable, and also had become 
slightly painful upon palpation. The edema in the right leg decreased 
significantly. The frequency and the volume of urination increased. 
Overall pain became less severe, in general. The resting metabolic rate 
immediately following this treatment period rose to 1.5 before subsiding 
slightly. In the third treatment period, the CTFB was administered for 
only 11/2 days, as in the first period. On the third day, the ascites 
fluid volume was further decreased, with the abdomen nearing normal size. 
The neck tumor mass was not only still softer and more movable upon 
palpation, but had decreased significantly in size. The neck mass had 
become very painful to palpation. The abdominal masses were also softer in 
consistency with increased movability, and similarly had become quite 
painful to palpation, as is characteristic following significant induced 
oncolysis. The leg edema had disappeared completely. The patient's resting 
metabolic rate rose to 1.7 during this final treatment period. Throughout 
the therapy, the patient's hematology, blood chemistry, enzymes, serology 
and urinalysis remained normal. The patient's overall weight loss 
(.about.7%) was attributable to a pronounced decrease in the ascitic fluid 
mass. 
EXAMPLE 4 
Example Case No. 4: 
Male, 52 years old. 
Diagnosis: 
Adenocarcinoma of the stomach, with extensive visceral metastases. 
Basis of Diagnosis: 
Initial gastroscopy; histological analyses of multiple biopsy specimens. 
Subsequent laparotomy revealed massive tumor of the gastric body and 
antrum, nearly closing the pilorus; multiple peritoneal metastases; 
metastases in liver and pancreas; abdominal fluid positive for numerous 
malignant ascites cells; case judged surgically untreatable and terminal. 
Therapy Prior to Present Therapy: 
One cycle of combination-drug mitoxin chemotherapy (5-Fluorouracil, 
Adriamycin, Vincristine); patient experienced violent side-effects and 
refused further treatment with mitoxin chemotherapy. 
Tumor Status at Start of Present Therapy: 
Massive tumor (8 cm.times.18 cm) of the stomach, with extensive metastatic 
invasion of all viscera and peritoneal cavity; tumor masses very hard and 
fixed upon palpation; high rate of malignant ascites production. Patient 
experiencing severe pain and edema in right leg as a result of abdominal 
compression restriction of circulation. Patient's body weight upon entry 
(four days prior to treatment) was nearly standard for his sex and height, 
although he previously was grossly overweight before onset of his illness. 
Treatment Conditions: 
The primary clinical objective of administering the present therapy was to 
control the rapidly building ascitic fluid concentration. Patient's body 
weight had increased 7.4% in the four days preceding the start of therapy, 
due to ascitic buildup. Because of the tenuous condition of the patient 
and expected inability to ingest adequate food for caloric balance, 
treatment with the present therapy was limited to two periods of two days 
each, with eight days between treatments. Only the AAD and LEB metabolic 
effectors were used, the AAD being the high pK.sub.a UA 
5-chlorotrifluoromethyl benzimidazole (CTFB), pK.sub.a =8.9, combined with 
TH (Thyrolar-1, Armour), and the LEB being quercetin. CTFB was 
administered orally in capsules at a dosage of 5 mg/Kg/capsule, one 
capsule twice daily, and the Thyrolar-1 at a dosage of 1.5 tablets per 
day. The quercetin was administered at a dosage level of 1.5 mg pure 
quercetin per Kg per capsule; one capsule was given each time a capsule of 
CTFB was given. The food (eggs, milk, cereals, cooked fruits) was supplied 
at the level of 1559 Kcal/d, in mash form. 
Response to Treatment: 
In the first treatment period, the CTFB was administered as follows: two 
capsules, one in AM and one in PM, on first day, and one capsule, AM, on 
second day. On the second day following the treatment period, the 
patient's weight had decreased 1.5% due to decrease in tumoral ascitic 
fluid and by the eighth day post-treatment, by 6.1%. This decrease in 
malignant ascitic activity was accompanied by an appreciable decrease in 
abdominal distention. Edema of the right leg also decreased. The resting 
metabolic rate reached a maximum of only 1.44 on the first day following 
treatment (up from 1.20 before treatment) and the patient was able to 
nearly maintain caloric balance with the food diet at the average 
therapeutical metabolic rate (measured twice daily). In the second 
treatment period, the CTFB was administered twice each day. Following this 
second treatment period, the body weight decreased to the patient's 
standard body weight for his sex and height, evidencing full control by 
the present therapy of the patient's malignant ascites activity, with only 
minimal treatment durations and metabolic rate elevations. Abdominal 
palpation revealed a much softer consistency of visceral masses than upon 
entry. 
In Examples 5 through 12, eight patients were treated with a therapeutical 
regimen according to the present invention wherein only the DNR and AAD 
metabolic effectors were administered. The DNR was adjusted daily to 
ensure caloric balance. The AAD was the O/P uncoupling agent 
2,4-Dinitrophenol (DNP), and was administered once daily in capsule form 
at a nominal dosage level of 1.5 mg/Kg of initial body weight. Patient 
resting metabolic rates were measured twice daily, AM and PM, to provide 
data for DNR caloric determinations and to quantitate the level of 
uncoupling activity (i.e., ATP wasting) being attained. Phase I consisted 
of 12 days of treatment, followed by a rest interval of 7 to 10 days. 
Phase II extended for 12 days of treatment, under daily clinical 
observation. The patients of Examples 5 through 8 were treated in Phase I 
and Phase II; those of Examples 9 through 12 were treated only in Phase 
I. The results of these cases illustrate the powerful oncolytic effect of 
the present therapy system when just the DNR and AAD metabolic effectors 
are used in adequate levels to produce a major decrease in NADH to the 
cancer cell respiratory chain while effecting a major depression of their 
ATP.sub.A by wasting via O/P uncoupling with DNP, a relatively low pKa 
uncoupling agent. 
EXAMPLE 5 
Example Case No. 5: 
Female, 54 years old. 
Diagnosis: 
Adenocarcinoma (clinically colon), far advanced, infiltrating viscera; 
extensive liver metastases. 
Basis of Diagnosis: 
Ultrasound scans with biopsy of protrusive tumor mass; laparotomy with 
multiple histological specimens and analyses. (Tumor inoperable due to 
wide involvement). 
Therapy Prior to Present Treatment: 
None. 
Tumor Status at Start of Present Treatment: 
Huge tumor mass occupying the epi- and mesogastrium region (X-ray), tumor 
compressing lower esophagus to near closure (barium esophagram), stomach 
compressed and displaced to left; left lobe of liver essentially replaced 
by tumor, right lobe with numerous metastases (liver scan); hard, fixed, 
palpable tumor mass measuring 10 cm (vertical).times.7 cm (horizontal) 
protruding superficially from abdomen in region corresponding to left lobe 
of liver. Patient weak, thin, rapidly losing weight, pain and intense 
feeling of pressure in tumor area; able to swallow only liquids, which 
must be taken very slowly; stomach accommodates only small volume before 
feeling of satiation occurs. (Dimension and mass changes given in the 
following Response to Treatment data are for the protruding 10 cm.times.7 
cm abdominal tumor mass.) 
Response to Treatment (Phase I): 
Day 1: Patient starts on DNR; no DNP. Tumor: 10.0 cm. 
Day 2: Patient starts on DNP. 
Day 3: Patient reports she is feeling much better; abdominal pain and 
pressure sensation are definitely decreasing; swallowing is easier. 
Day 6: Oncologist reports tumor is becoming softer in consistency. Tumor: 
8.5 cm; 38% reduction. 
Day 8: Patient reports all pain and pressure sensations have disappeared; 
swallowing fully normal. 
Day 10: Oncologist reports tumor still decreasing in size; has become still 
softer in consistency. 
Day 12: Final day of Phase I treatment. Resting metabolic rate was 3.24 
during the final 16 hours of the period. 
Day 13: Patient in excellent condition; reports feeling fine. Vital signs, 
blood parameters all normal; tumor greatly shrunken, non-protrusive, flat, 
difficult to palpate. No signs whatever of toxemia despite large initial 
tumor mass and rapid rate of tumor lysis on Day 12. Tumor: 6.0 cm; 78.4% 
reduction. 
Day 16: Oncologist reports tumor has continued to shrink despite cessation 
of treatment and return to normal protein level; overall dimension has 
decreased 50%. Tumor: 5.0 cm; 87.5% reduction. 
The oncologist noted the following: X-rays, liver scan, and esophagram 
performed on Day 18 indicated a pronounced decrease in the visceral tumor 
mass and liver metastases, with suggestive regeneration of normal liver 
normal esophageal transport and emptying into stomach. Throughout the 
treatment period, the patient's blood pressure, pulse rate, temperature, 
and blood parameters remained stable and in the normal range. The DNP 
produced the intended transient increase in metabolic rate; no side 
effects other than mild sweating due directly to the DNP, were observed. 
Patient's overall condition has improved greatly. 
Response to Treatment (Phase II): 
Day 1: Patient on DNR and DNP. Pain, with sensation of intense pressure 
within tumor region, swallowing difficult. Tumor: 11.0 cm. 
Day 3: Patient reports swallowing is easier. Oncologist reports tumor 
softer and slightly decreased in size. 
Day 5: Patient reports abdominal pain much diminished. Oncologist reports 
tumor continuing to decrease in size; becoming flatter and less 
protrusive. 
Day 6: Patient reports feeling much better; abdominal pressure sensation 
much decreased as is fullness sensation; no pain in tumor region. 
Oncologist reports tumor now flat, non-protrusive; continuing to decrease 
in size. Tumor: 7.0 cm; 74.2% reduction. 
Day 12: Final day of Phase II treatment. Patient reports feeling fine; 
pressure sensation gone; swallowing normal. Vital signs, blood parameters 
normal. Oncologist reports tumor residue very soft, difficult to palpate. 
Tumor: 6.0 cm; 83.8% reduction. 
Day 13: Blood analyses reveal a significantly elevated level of lactic 
dehydrogenase commensurate with the pronounced tumor lysis observed in the 
palpable tumor; the blood urea nitrogen level is normal. 
The oncologist noted the following: the patient's body weight remained 
stable throughout the treatment period, as did the serum total protein 
level; the red blood cell count increased from 3.9 to 4.1.times.10.sup.6. 
On Day 15, the patient ate normal meals of solid food without encountering 
swallowing or saturation problems of any kind; was in excellent general 
condition. Despite the extensive metastatic involvement of the liver, this 
patient experienced no digestive problems and was able to accommodate and 
assimilate the DNR quite well, even at high caloric intake levels. The 
serum lactic dehydrogenase level on Day 13 was elevated nearly ten-fold, 
indicating the intensity of the tumor lysis of the preceding days. 
Similarly indicative of the pronounced decrease in overall tumor activity 
was the fact that the blood urea nitrogen (BUN) level decreased 78% in 
this semicachexic patient over the "Phase I" treatment period. 
EXAMPLE 6 
Example Case No. 6: 
Male, 57 years old. 
Diagnosis: 
Epidermoid carcinoma of the larynx (left supraglottic fold and false 
cords); metastasized to the left neck. 
Basis of Diagnosis: 
Direct laryngoscopy with multiple biopsies; biopsy of neck metastasis; CT 
scan and Xerographs of larynx and neck. 
Therapy Prior to Present Treatment: 
None. 
Tumor Status at Start of Present Treatment: 
Large tumor of the left supraglottic fold infiltrating the false cords, but 
not crossing the midline; 2 cm diameter, hard, fixed, protruding 
metastasis in the left neck, causing severe steady submaxillar pain due to 
pressure on nerve. Patient unable to eat solid food because of intense 
pain on swallowing, even liquids cause much pain; voice hoarse, moderately 
advanced emphysema of both lungs. (Dimension and mass changes given in the 
following Response to Treatment data are for the protruding 2 cm diameter 
metastasis in the left neck.) 
Response to Treatment (Phase I): 
Day 1: Patient begins on DNR; no DNP. Blood parameters (including serum 
total protein level), liver function tests, urinalysis, and vital signs 
all normal. Patient has difficulty swallowing because of throat pain, also 
suffers from intense pain due to pressure on nerve from neck metastasis. 
Oncologist reports neck tumor hard, fixed, extremely painful. Tumor: 2.0 
cm. 
Day 2: Patient starts with DNP. 
Day 3: Patient reports intense pain in left neck; radiates to left ear. 
Day 6: Patient reports pain in left neck has diminished. 
Day 9: Patient reports pain in left neck has continued to diminish; feels 
that neck tumor is definitely decreasing in size. Oncologist has not 
measured tumor because of pain upon palpation. 
Day 11: Patient's resting metabolic rate increased to 2.97 and remained 
elevated during whole day. 
Day 12: Final day of Phase I treatment. Resting metabolic rate decreased to 
2.57, but remained above 2.0 for the remainder of the day. DNP 
discontinued yesterday. 
Day 13: Patient is greatly improved; reports feeling much better. Vital 
signs all normal. Neck tumor is much less painful upon palpation. 
Oncologist reports neck tumor drastically decreased over two-day period of 
elevated resting metabolic rate (87.5% decrease in total tumor mass); 
tumor much softer in consistency. Tumor: 1.0 cm. 
Day 14: Patient reports pain has essentially disappeared in neck, but 
throat is "sore" at site of primary. Vital signs and blood parameters all 
normal; resting metabolic rate equals 1.0. Patient feels fine; appetite 
very good. 
Day 18: Oncologist reports neck tumor residue slightly mobile, 
non-protrusive, hardly palpable; non-painful. Former hoarseness of voice 
(dysphonia) has greatly diminished. Tumor: 0.8 cm; 93.6% reduction. 
The oncologist noted the following: throughout the treatment period the 
patient's body weight, blood pressure, pulse rate, respiratory rate, 
temperature and blood cytological and chemical parameters remained stable 
and within the normal range. The DNP produced the intended increase in 
metabolic rate; no side effects due directly to the DNP were observed. 
Despite the fact that this patient had moderately advanced emphysema in 
both lungs, the elevation of the resting metabolic rate to as high as 2.97 
produced no symptoms of respiratory insufficiency. 
Response to Treatment (Phase II): 
Day 1: Tumor is hard, fixed, immobile, and very painful on palpation; 
patient is put on DNP (4.5 mg/Kg). Tumor: 4.0 cm. 
Day 5: Neck tumor greatly diminished, as is the pain associated with it; 
burning sensation at site of internal primary, especially upon swallowing. 
Patient feels very good otherwise, takes DNR well. Tumor: 1.0 cm; 98.4% 
reduction. 
Day 6: Voice hoarseness much diminished. 
Day 8: Neck tumor residue hardly palpable; difficult to find; painless. 
Throat soreness at site of internal primary upon swallowing cold liquids, 
but no pain with warm liquids or warm semi-solid food. Laryngoscopy of 
primary site reveals a small, non-bleeding, ulcerative lesion on the left 
supraglottic fold, with surrounding inflammation. Patient feels fine, 
vital signs normal; resting metabolic rate equals 1.27. Tumor: 0.8 cm; 
99.2% reduction. 
Day 11: Voice much clearer; throat pain less upon swallowing. Patient feels 
fine; is very hungry. Tumor: nonpalpable. 
Day 13: Final day of Phase II treatment; DNP discontinued after today. 
Patient is asymptomatic; feels fine; very hungry; only slight pain at 
primary site. Tumor: nonpalpable. 
Day 16: Patient returns to solid food; no pain in throat after first three 
swallows; feels fine. Tumor: nonpalpable. 
The oncologist noted the following: Throughout the treatment period the 
patient's body weight, blood pressure, pulse rate, respiratory rate, 
temperature, and blood cytological and chemical parameters remained 
clinically stable and within the normal range. The DNP produced the 
intended increase in metabolic rate; no side effects whatever due to the 
DNP were observed. 
EXAMPLE 7 
Example Case No. 7: 
Female, 51 years old. 
Diagnosis: 
Lymphocytic lymphoma (nodular, mixed-cell type); retroperitoneal; 
infiltrating; far advanced. 
Basis of Diagnosis: 
Laparotomy with multiple biopsies; CT scans. 
Therapy Prior to Present Treatment: 
Extensive conventional mitoxin chemotherapy; laetrile. 
Tumor Status at Start of Present Treatment: 
Huge retroperitoneal tumor mass with hard, fixed, nonpainful portion 14 cm 
(vertical).times.10 cm (lateral) protruding superficially in the epi- and 
mesogastrium region; protruding mass easily palpable, with well-defined 
margins; central tumor mass displacing viscera outwards and downwards; 
liver, lungs, lymph nodes and marrow negative for metastases; blood free 
of blast cells. Patient extremely thin (cachexic), pale, anemic, tired, 
nervous; blood pressure slightly below normal (110/60); reports strong 
sensation of pressure in tumor region; severe abdominal pain at times; 
lumbar spinal pain, often radiating into legs. (Dimension and mass changes 
given in the following Response to Treatment data are for the 
superficially protruding 14 cm.times.10 cm tumor mass.) 
Response to Treatment (Phase I): 
Day 1: Patient begins on DNR; no DNP. Tumor: 14.0 cm. 
Day 2: Patient begins on DNP; complains of allergy activation (skin rash) 
because of corn-containing food she ate just prior to Day 1; claims 
long-standing allergy to corn products. 
Day 9: Some pain in lower back; patient's resting metabolic rate has 
increased to therapy level (1.68) for first time. Tumor: 14.0 cm. 
Day 11: Patient reports all pain has subsided; all pain medication stopped; 
blood test shows anemia has improved; allergy symptoms completely gone; 
resting metabolic rate equals 1.68. 
Day 12: Final day of Phase I treatment; resting metabolic rate has 
increased to 2.47. 
Day 13: Patient feels much better; all pain has diminished greatly; 
pressure sensation in tumor region has disappeared. Vital signs, blood 
parameters normal. Resting metabolic rate equals 1.0. Hemoglobin has 
increased 16% since starting treatment. Oncologist reports dramatic 
decrease in tumor size in just one day at elevated resting metabolic rate 
(2.47); tumor much softer; no longer protrusive; difficult to palpate. 
Tumor: 8.5 cm; 77.6% reduction. 
Day 14: Patient in excellent state; feels very happy; has much more energy. 
Blood parameters normal except serum total protein level still slightly 
low. Oncologist reports abdominal tumor mass has continued to decrease in 
size; has regressed inward and is very difficult to palpate; dramatic rate 
and extent of tumor reduction verified independently by three different 
oncologists. Tumor: 5.5 cm; 93.9% reduction. 
Day 18: Patient in excellent state; no pain whatever; vital signs all 
normal. Oncologist reports X-rays of abdomen show tumor opacity much 
reduced; viscera seen more clearly. 
Day 20. Patient in excellent condition; good appetite; skin and mucosal 
color much improved; pain-free. Oncologist reports previously protrusive 
residue still decreasing; is much softer; has sunk inward; residue can be 
detected only with deep palpation. 
The oncologist noted the following: Throughout the treatment period the 
patient's body weight, blood pressure, pulse rate, respiratory rate, 
temperature, and blood cytological and chemical parameters remained stable 
and within the normal range. The DNP produced the intended transient 
increase in metabolic rate; no side effects due to the DNP were observed. 
Response to Treatment (Phase II): 
Day 1: Patient with DNR and DNP; strong pressure sensation in central tumor 
site; feels very weak. Tumor: 11.0 cm. 
Day 4: Patient reports diminishing of pressure sensation in tumor site; 
some back pain. Oncologist reports tumor appears to be decreasing in size 
and becoming softer; no measurement given. 
Day 6: Patient reports pain minimal. Vital signs normal, except blood 
pressure which is characteristically low (90/60). 
Day 9: Oncologist reports tumor shape is changing; can now palpate what 
feels like individual lymph nodes; difficult to palpate tumor as it 
appears to be breaking up and flattening out; 8 cm is maximum extent of 
flattened residue. Tumor: 8.0 cm; 61.5% reduction. 
Day 13: Final day of Phase II treatment period; patient reports minimal 
pain; slept well. 
Day 14: Oncologist reports tumor has lost shape and coherency; former mass 
seems to be disintegrating; more mobile; much softer consistency. 
Day 15: Oncologist reports tumor residue very ill-defined and flattened; 
maximum dimension of diffuse residue is 7.5 cm. Patient resumed eating 
regular food without any problem; hemoglobin has increased 24.8% over 
initial level; blood parameters are normal including platelet 
concentration; blood is free of blast cells. 
The oncologist noted the following: Throughout the treatment period the 
patient's body weight, pulse rate, respiratory rate, temperature, and 
blood cytological and chemical parameters remained stable and within the 
normal range; the blood pressure was slightly below normal, as is 
characteristic for this patient. The DNP produced the intended increase in 
metabolic rate; no side-effects due to the DNP were observed. The average 
dosage of DNP over the 13-day treatment period was only 2.0 mg/Kg; the 
average resting metabolic rate was correspondingly low, 1.30. Still, in 
the presence of the relatively low daily protein intake, the tumor 
regressed rapidly and ultimately underwent a generalized disintegration; 
the blood remained entirely free of tumor cells during this 
disintegration. Even with the reduced level of protein in the DNR, the 
hemoglobin increased 24.8%. 
EXAMPLE 8 
Example Case No. 8: 
Male, 59 years old. 
Diagnosis: 
Adenocarcinoma of the prostate (moderately differentiated); infiltrating 
periprostatic soft tissue, lymph nodes, and wall of urinary bladder, 
widely disseminated bone metastases. 
Basis of Diagnosis: 
Cystoscopy with multiple biopsies; right pelvic lymph node dissection with 
histological analyses; transurethral resection with histological analyses; 
nephrogram; bone scans. 
Therapy Prior to Present Treatment: 
Laetrile, Vitamin A, enzymes (IV, orally); hormone therapy; surgery (TURP). 
Tumor Status at Start of Present Treatment: 
Greatly enlarged, rock-hard, malignant prostate; with tumor widely 
infiltrating periprostatic soft tissue, including wall of urinary bladder; 
left kidney semi-occluded due to tumoral obstruction of left ureter at 
point of entrance into bladder; multiple, widely disseminated bone 
metastases in cervical, dorsal, and lumbar spine, right, scapula, both 
iliacs, and both femurs. Patient still in good general condition; no pain, 
good appetite; moderately obese; chronic hypertension; frequent night and 
day urinations due to tumor pressure on bladder; difficulty in urinating; 
urine stream flow greatly reduced; acid phosphatase level nearly twice the 
normal maximum. 
Response to Treatment (Phase I): 
Day 1: Patient starts on DNR; no DNP. Tumor: Acid phosphatase level nearly 
double the normal maximum. 
Day 2: Patient starts on DNP. Patient's resting metabolic rate rises to 
1.4; vital signs normal; very good appetite. 
Day 6: Patient feels fine, resting metabolic rate equals 1.52; blood 
pressure elevated due to characteristic hypertension. Tumor: Night 
urinations have decreased to one; starting and maintaining urine flow 
easier. 
Day 9: Patient feels fine; vital signs normal, except blood pressure still 
elevated; moderate pain in back when lying in bed, disappears in walking. 
Day 11: Patient feels fine; resting metabolic rate equals 1.98, blood 
pressure has decreased with diuretic. 
Day 12: Final day of Phase I treatment; patient reports sweating episode 
during previous night, temperature normal; resting metabolic rate equals 
2.30 today. 
Day 13: Patient reports he feels great; all pain has disappeared; vital 
signs are normal, except elevated blood pressure which continues to 
decrease with diuretic. Tumor: Urine flow significantly improved; stream 
stronger and more steady. 
Day 14: Patient reports he feels great: asymptomatic; blood pressure and 
blood parameters normal, including serum total protein level. Tumor: 
Oncologist reports rectal examination shows prostate size has decreased, 
and consistency is not as hard as originally; acid phosphatase is 
significantly elevated, 5.3 times normal maximum, due to release from 
lysed prostatic cells. 
Days 15-21: Patient continues to feel fine; entirely asymptomatic. Tumor: 
Urination continues to improve despite cessation of treatment and 
resumption of increased protein intake; urination stream steady. 
Day 22: Patient continues asymptomatic; blood pressure under control with 
diuretic. Tumor: Bone scan shows significant reduction of bone metastases; 
oncologist reports excellent response to treatment period. 
The oncologist noted the following: Throughout the treatment period the 
patient's body weight, pulse rate, respiratory rate, temperature, and 
blood cytological and chemical parameters remained stable and within 
normal range; the characteristically elevated blood pressure was 
controlled with the use of a diuretic. The DNP produced the intended 
transient increase in metabolic rate; no side effects due to the DNP per 
se were observed. The patient remains pain-free and in excellent general 
condition. 
Response to Treatment (Phase II): 
Day 1: Patient on DNR and DNP; general condition good; moderate pelvic 
pain. Tumor: Prostate much enlarged and very hard. 
Day 4: Patient reports pelvic pain has ceased entirely; feels fine. Tumor: 
Oncologist reports prostate decreasing in size and becoming softer in 
consistency. 
Day 5: Patient reports greater volume of urine excreted per urination than 
before treatment started; feels fine. Tumor: Patient reports easier to 
commence urine flow; has new sensation that bladder now empties completely 
upon urination. 
Day 8: Patient asymptomatic; vital signs normal; blood pressure holding at 
170/90 with diuretic. Tumor: Oncologist reports prostate is becoming 
flatter, more like normal shape. Patient reports stronger urination 
stream. 
Day 9: Patient asymptomatic; feels fine. Tumor: Oncologist reports prostate 
is flatter and softer. 
Day 13: Final day of Phase II treatment period; DNR administration ceased 
today. Tumor: Oncologist reports prostate still flatter and softer, 
especially on left side; former vesicle tenesmus has disappeared. Patient 
reports still better urine flow, without interruption; night urination 
frequency much less. 
Day 15: Patient in excellent condition; asymptomatic. Tumor: Oncologist 
reports prostate even flatter and softer, with pronounced change on left 
side; non-painful; steady regression toward normal prostate size. 
Hemoglobin level has increased 13.4% over the initial level; classically, 
prostate cancer patients always exhibit anemia. Additionally, the acid 
phosphatase level (classically taken as the most sensitive indicator of 
prostate tumor cell activity) is now completely normal. 
The oncologist noted the following: Throughout the treatment period the 
patient's body weight, pulse rate, respiratory rate, temperature, and 
blood cytological and chemical parameters remained stable and within the 
normal range; the characteristically high blood pressure was controllable 
with diuretics. The DNP produced the intended increase in metabolic rate; 
no side effects due to the DNP were observed. Prostate cancer cells 
generally proliferate only very slowly, and hence possess a relatively low 
level of cellular metabolism; still, the tumor burden of the present 
subject regressed steadily with the present treatment. Equally significant 
is the fact that the patient was also moderately obese, wherein the 
malignant cells were given a strong survival advantage via the 
availability of a nonprotein energy source; yet, the present treatment was 
still able to impose a steady and effective rate of oncolysis. The 
previously elevated acid phosphatase level, the standard indicator of 
prostate tumor activity, became completely normal. Even with the protein 
intake reduced to the equilibrium level, the hemoglobin increased 13.4%. 
The pronounced increase in urine volume that was experienced is indicative 
of a removal of the left urethral tumor obstruction; similarly, the return 
of the sensation of complete emptying of the bladder correlates directly 
with the palpable reduction in the circumurethral tumor/prostate mass. 
EXAMPLE 9 
Example Case No. 9: 
Female, 65 years old. 
Diagnosis: 
Adenocarcinoma of the breast (ductal, infiltrating); widely metastasized. 
Basis of Diagnosis: 
Tumorectomy with histological analyses (on two separate occasions); X-rays; 
(lungs); liver scans; bone scans. 
Therapy Prior to Present Treatment: 
Surgery, extensive conventional (mitoxin) chemotherapy; radiation; 
anti-estrogen drugs. 
Tumor Status at Start of Present Treatment: 
Widely disseminated metastases; protruding superficial tumor mass, hard, 
fixed, 3 cm diameter just below left collarbone; protruding superficial 
tumor, hard, semi-mobile, in surgical scar (1 cm diameter) on left breast; 
metastases in both lungs; multiple bone metastases: skull, spine, pelvis 
(extensive destruction), femurs; extensive liver metastases. Patient is in 
intense pain, primarily pelvic, spinal, and right lower jaw; pain 
intensifies with movement; pancytopenia; arthritis of many years duration; 
stomatitis; history of sporadic hypoglycemia; elevated urine estrogen; 
many emotional problems; vital signs normal. Unable to walk or even get 
out of bed because of pain. 
Response to Treatment: 
Day 1: Patient starts with DNR; no DNP. Patient suffers intense pain, 
especially upon movement; unable to get out of bed or walk. ("cb" denotes 
the superficially protruding tumor mass below the collarbone; "br" denotes 
the tumor mass in the surgical scar on the left breast.) Tumor: 3.0 cm 
(cb), 1.0 cm (br). 
Day 2: Starts with DNP. Patient reports pain at all levels is less, 
although still appreciable. 
Day 4: Patient reports that pain at all levels is greatly diminished; is in 
much better spirits and is more cooperative. 
Day 5: Patient reports that pain at all levels has essentially subsided; is 
walking about with aid of walker; is able to get out of bed by self; is in 
excellent spirits. 
Day 8: Patient remains practically free of pain; walks about easily with 
aid of walker; reports that she is sure tumors under the collarbone and in 
surgical scar are diminishing in size. 
Day 10: Patient reports slight back pain, but is fine otherwise; still 
moving about freely with aid of walker; resting metabolic rate equals 
1.44. 
Day 11: Patient reports perspiring appreciably last night; some shortness 
of breath; vital signs normal; resting metabolic rate equals 1.73. 
Day 12: Final day of treatment period; resting metabolic rate equals 2.19; 
patient remains in bed. 
Day 13: Patient reports feeling tired, but otherwise OK; vital signs 
normal; oncologist reports dramatic shrinkage of observable tumors over 
the past two-day period; residual tumor masses much softer; both only 
slightly protrusive. Tumor: 1.2 cm (cb), 0.4 cm (br); 93.6% regression. 
The oncologist noted the following: Throughout the treatment period the 
patient's body weight, blood pressure, pulse rate, respiratory rate, 
temperature, and blood cytological and chemical parameters remained stable 
and within the normal range. The DNP produced the intended transient 
increase in metabolic rate. No side effects due to the DNP per se were 
observed. This patient had many family and emotional problems and was 
intensely unhappy with hospital confinement and regimentation of diet, 
being unaware of the seriousness of her condition; became most 
uncooperative and undependable in taking the required DNR; was eventually 
released at her insistence. Despite this impediment and the extensive 
metastatic infiltration of the liver, she responded excellently to the 
treatment regimen; her body weight remained stable and her hemoglobin 
increased 16%. A bone scan performed on Day 28 (15 days after the 
completion of the treatment period, and during a time she had been on a 
normal protein intake) revealed a significant improvement in the various 
bone metastases with several of the initial lesions having essentially 
disappeared. Her plasma calcium remained fully normal during her stay at 
the hospital despite the extensive bone metastases; however, she began to 
exhibit increasingly severe hypercalcemin within a short time after 
leaving and resuming her regular diet. 
EXAMPLE 10 
Example Case No. 10: 
Male, 64 years old. 
Diagnosis: 
Carcinoma of the lung (large-cell, undifferentiated), upper lobe, right 
lung. 
Basis of Diagnosis: 
Histological analysis of tumor specimens (two independent analyses); 
X-rays. 
Therapy Prior to Present Treatment: 
Laetrile; dietary. 
Tumor Status at Start of Present Treatment: 
Tumor activity confined to upper lobe of right lung, which X-rays show to 
be completely opacified due to tumor and atelectasis; no metastases 
detectable elsewhere (liver, bone, lymph nodes, viscera). Patient is very 
thin and pale; anemic; suffers a 25% reduction in oxygenation capacity and 
occasional episodes of shortness of breath; has heart murmur with 
extrasystole; tires easily; has periodic episodes of coughing; appetite 
good; no pain; reasonably good general condition; vital signs normal. 
Response to Treatment: 
Day 1: Patient starts on DNR; no DNP. 
Day 2: Patient starts on DNP. 
Day 6: Patient in good condition; feels fatigued upon walking; vital signs 
normal; appetite good. 
Day 11: Patient in excellent condition; much improved color in skin and 
mucosa; red blood cell count has increased; resting metabolic rate rose to 
1.93; no complaint of dyspnea. 
Day 12: Final day of treatment period. DNP has been discontinued; patient 
feeling fine; vital signs normal; resting metabolic rate equals 2.70; 
patient walking about with no complaint of dyspnea. Patient feels fine; 
color improvement very noticeable; vital signs normal. 
Day 14: Patient is in excellent condition. Tumor: Oncologists (two 
independent examinations) report definite indications of increased 
ventilation of right lung; detect new sounds ascribed to ventilatory air 
flow. 
Day 20: Patient in excellent condition; reports a feeling of overall 
well-being. Tumor: Patient is able to take long walks without any 
occurrence of dyspnea; ventilation much improved in right lung. 
The oncologist noted the following: Throughout the treatment period the 
patient's body weight, blood pressure, pulse rate, respiratory rate, 
temperature, and blood cytological and chemical parameters remained stable 
and within the normal range, except for the initial anemia which greatly 
improved. The DNP produced the intended transient increase in metabolic 
rate; no side effects due to the DNP per se were observed. The patient's 
hemoglobin increased 40% during his stay. The ventilation in his right 
lung continued to improve until departure. No specific identification of 
tumor masses per se could be made in any of the post-treatment X-rays, 
which revealed only the same uniform atelectatic opacity of the lobe as 
seen previously. Because of the significant functional improvement, and 
pressing family matters, the patient left for home before commencement of 
the Phase II treatment period. 
EXAMPLE 11 
Example Case No. 11: 
Male, 67 years old. 
Diagnosis: 
Carcinoma of the lung (oat-cell, undifferentiated); tumor located in left 
hilum with extensive diffuse infiltration into surrounding lung tissue. 
Basis of Diagnosis: 
Bronchoscopy with biopsy (at junction of left upper and lower lobes); 
X-rays. 
Therapy Prior to Present Treatment: 
None. 
Tumor Status at Start of Present Treatment: 
Tumor mass centered in the left hilum with extensive diffuse infiltration 
of surrounding tissue; no evidence of liver, bone or brain metastases on 
respective scans; lymph node areas negative except for one suspicious 6 mm 
node in the left base of the neck. Patient is very thin and losing weight 
rapidly because of nervous anorexia; is extremely nervous and under great 
emotional strain because of family pressures upon him; has frequent 
gastritis; has severe spells of violent coughing, which are increasing 
steadily in frequency and duration; suffers shortness of breath; 
occasional retrosternal pain; vital signs normal; blood parameters, liver 
function and urinalysis results normal. 
Response to Treatment: 
Day 1: Patient starts on DNR; no DNP. Tumor: Patient has frequent violent 
coughing spells; uses codeine cough syrup, but with little benefit; 
reports increased retrosternal pain and shortness of breath when excited 
or agitated. 
Day 2: Patient starts on DNP. 
Day 6: Patient reports feeling of improvement and overall well-being, 
despite gastritis induced by emotional upset of family problems. Tumor: 
Patient reports coughing spells less violent. 
Day 7: Resting metabolic rate equals 1.39 today; patient feels fine; no 
dyspnea. Tumor: Patient reports coughing spells milder and much less 
frequent. 
Day 11: Patient in good general condition despite continuing emotional 
upset due to family problems; vital signs normal; resting metabolic rate 
up to 2.03. Tumor: Coughing episodes continue to decrease, in intensity, 
duration, and frequency. Patient experiences no dyspnea, despite elevated 
resting metabolic rate and active walking about. 
Day 12: Final day of treatment period. DNP discontinued yesterday; resting 
metabolic rate equals 1.8 today. 
Day 13: Vital signs all normal; patient feels fine physically. Tumor: 
Patient reports retrosternal pain has disappeared. 
Day 14: Vital signs all normal; blood parameters normal, including serum 
total protein level. Tumor: Patient reports coughing episodes are now 
minimal. 
Day 15: Patient reports feeling of well-being and great improvement; 
appetite has increased. Tumor: Patient reports coughing has completely 
stopped; retrosternal pain is gone; no shortness of breath even with 
active walking; blood urea nitrogen level has decreased relative to 
pretreatment level. 
The oncologist noted the following: Throughout the treatment the patient's 
body weight, blood pressure, pulse rate, respiratory rate, temperature, 
and blood cytological and chemical parameters remained stable and within 
the normal range. The DNP produced the intended transient decrease in 
metabolic rate. No side effects due to the DNP per se were observed. The 
patient left the hospital soon after completion of the Phase I treatment 
period because of continuing family problems, and did not receive the 
Phase II treatment. 
EXAMPLE 12 
Example Case No. 12: 
Female, 57 years old. 
Diagnosis: 
Adenocarcinoma (poorly differentiated; surgically unidentified primarily 
because of far advanced visceral spread); (clinically colon): numerous 
liver and other metastases. 
Basis of Diagnosis: 
Laparotomy with multiple biopsies; X-rays; scans. 
Therapy Prior to Present Treatment: 
Extensive semi-continuous conventional (mitoxin) chemotherapy over a 
prolonged period. 
Tumor Status at Start of Present Therapy: 
Extensive metastatic tumor activity throughout the body; brain, bones, 
viscera, liver (extensive metastases), both lungs, lymph nodes. Patient is 
in late terminal state; in intense general pain (headache, right chest, 
rib cage, abdomen, spine) even though under heavy sedation; has 
hypercalcemia; cannot maintain balance or walk; nausea; very weak; 
anorexic. (Note: Although this patient was clinically considered to be 
fully terminal, it was decided to attempt to administer the Phase I 
treatment to the extent that the DNR intake could continue to be 
reasonably maintained. 
Response to Treatment: 
Day 1: Patient starts on DNR; no DNP. Patient is in intense pain, 
especially headache; very restless; semiconfused; confined to bed; vital 
signs normal; blood parameters normal except moderate hypercalcemia. 
Day 2: Patient taking DNR on schedule; no DNP; still feels very weak. 
Tumor: Headache has decreased in intensity. 
Day 3: Patient is much improved; more alert and communicative; no DNP given 
yet. Tumor: Headache and other pain has diminished greatly; pain 
medication has been reduced to very low level. 
Day 4: Patient in stable state; more cooperative; continues on DNR; starts 
on DNP. Tumor: Pain continues to diminish at all sites. 
Day 5: Patient deemed to be improved sufficiently by oncologist to commence 
with daily palliative radiation treatments of large brain-metastasis 
tomorrow; serum calcium has decreased 11%. Tumor: Headache and other pains 
are essentially gone. 
Day 7: Patient is less restless; slept well; vital signs all normal. 
Patient received first radiation treatment at noon; was very drowsy and 
semi-confused all afternoon. Tumor: Pain has disappeared at all sites; all 
pain medicine is stopped. 
Day 9: Patient reports feeling much better in morning before radiation 
treatments; becomes tired, drowsy, confused, and uncooperative after 
radiation treatments. Tumor: Patient remains pain-free. Patient has been 
free of any clinical signs of hypercalcemia. 
Day 10: Patient better oriented; much less confused; more cooperative; 
vital signs normal; resting metabolic rate has started increasing (1.26). 
No radiation treatment today. Tumor: Patient remains free of pain at all 
sites. 
Day 11: Final day of treatment period; DNP discontinued yesterday. Patient 
greatly improved; is able to carry on coherent conversation with visitors; 
vital signs normal; resting metabolic rate has elevated to 1.99; no 
radiation today. Tumor: Patient continues free of pain. 
Day 12: Patient is very alert and cooperative prior to radiation treatment; 
reports feeling very tired after radiation treatment; sleeps most of the 
afternoon; irritable. Tumor: No pain whatever. 
Day 13. Patient requests discontinuance of daily radiation treatment, as 
she feels much better before treatment and very bad after it; continues to 
improve generally. Tumor: No pain at any level; no signs of hypercalcemia. 
The oncologist noted the following: Throughout the treatment period the 
patient's body weight, blood pressure, pulse rate, respiratory rate, 
temperature, and blood cytological and chemical parameters remained stable 
within the normal range, except for the increasing initial hypercalcemia 
she had at time of entry. The DNP produced the intended transient increase 
in metabolic rate; no side effects attributable to DNP per se were 
observed. The patient was continued on daily radiation treatments by the 
oncologist for another week after her request that they be stopped. Just 
prior to the last radiation treatment (Day 19) the patient slipped in the 
bathroom at night and suffered an orbital hematoma, with apparent 
additional internal bleeding of undetermined origin, and eventually became 
comatose therefrom (Day 24). However, she responded rapidly to an infusion 
of whole blood and improved somewhat, but remained in a state of general 
malaise and unsteadiness. The hypercalcemic state elevated rapidly during 
this period, when she was only minimally on the DNR. She was released (Day 
27) at the request of her family and did not participate in the Phase II 
treatment period. 
The following Example 13 demonstrates the dramatic rate and extent of 
oncolysis that are achievable in human cancer patients with otherwise 
totally refractory malignant neoplasms by use of the present invention. In 
this case the clinical regimen consisted of a Phase I treatment period 
only, of 15-day duration. The patient was administered a DNR-AAB-AAD 
combination of metabolic effectors, wherein the AAD was the O/P uncoupling 
agent 2,4-Dinitrophenol (DNP) and the AAB was aminoglutethimide (AGT). 
However, the patient in effect also had an effective FAB acting, in the 
form of an indigenous enzyme deficiency which precluded .beta.-oxidation 
of endogenous free fatty acids at a significant rate. 
EXAMPLE 13 
Example Case No. 13: 
Female, 46 years old. 
Diagnosis: 
Infiltrating ductal cell carcinoma of left breast; four out of 10 axillary 
lymph nodes positive for carcinoma. 
Basis of Diagnosis: 
Multiple biopsy specimens and histological analyses. 
Therapy Prior to Present Treatment: 
Modified radical mastectomy of left breast, followed by multiagent mitoxin 
chemotherapy (Cytoxan, Methotrexate, 5-Fluorouracil); patient asymptomatic 
for four years before recurrence; multiple subcutaneous erythematous tumor 
nodules recurred along previous mastectomy scar; received intense 
radiotherapy with Cobalt-60, along with combination Adriamycin and 
Vincristine mitoxin chemotherapy; disease continued to progress; patient 
deemed terminal. 
Tumor Status at Start of Present Therapy: 
Numerous isolated areas of subcutaneous tumor covered by erythematous skin 
spread over left chest wall and under left arm; new nodules appearing 
daily and initial lesion sites expanding rapidly; some tumor patches 3 to 
5 cm in extent. Cortisol level 22 .mu.g/dl. 
Response to Treatment: 
Day 1: Patient started on DNR and received AM and PM doses of DNP adequate 
to elevate the resting metabolic rate to 3.0 (times basal) in two days, to 
effect a high level of ATP wastage; daily aminogluethethimide (AGT) 
administration commenced. 
Day 3: Patient's resting metabolic rate rose to and remained at 3.2 (times 
basal) over a 24-hour period yesterday, following which DNP was suspended 
for a period of 4 days; regression of all lesions discernable already on 
Day 3. Patient is consuming all of administered DNR despite high caloric 
level at high therapeutical resting metabolic rates. 
Day 7: Pronounced regression in all tumor areas; all inflammatory areas and 
patches fading; estimated reduction in overall tumor burden approximately 
40%; DNP administration recommenced. 
Day 9: Resting metabolic rate rose to and remained at 3.0 over a 24-hour 
period yesterday. Overall tumor reduction estimated to be 50% on Day 9. 
DNP administration suspended for two days. 
Day 11: DNR administration recommenced. Overall tumor reduction estimated 
to be 70%. 
Day 13: Resting metabolic rate rose to and remained at 3.2 over a 24-hour 
period yesterday. DNR administration suspended. Overall tumor reduction 
estimated to be 90%. 
Day 15: Patient in excellent condition. Attending oncologists report 100% 
reduction of tumors and inflammation areas. 
Day 20: Attending oncologists declare patient to be in complete remission 
and clinically free of discernable cancer. Patient's cortisol level 7 
.mu.g/dl. 
This remarkable result occurred from just three 24-hour duration elevations 
of the resting metabolic rate (to .about.3.0) with the AAD (DNP) within a 
15-day period, and the AAB (AGT), which was administered daily throughout 
the total 15-day period. However, as cited previously, this patient was 
found to possess a substantial deficiency in ability to oxidize fatty 
acids at an appreciable rate, demonstrating the classical symptoms of 
Fatty Acid Oxidation Deficiency Syndrome associated with a genetic 
deficiency of the enzyme carnitine palmitoyl transferase required for 
transport of fatty acids into cellular mitochondria (see e.g., Cumming, W. 
J. K. et al., Journal of the Neurological Sciences 30, 247 (1976)). 
Consequently, she also had, in effect, a very effective (indigenous) FAB 
simultaneously acting with the administered AAD-AAB-DNR. 
The following Example 14 comprises a clinical case in which only the AAD 
metabolic effector was administered to the patient in order to effect 
oncolysis. This example is particularly interesting in that it 
demonstrates the powerful rate and extent of malignant neoplasm regression 
that can be effected with only the AAD of the present therapy system, when 
administered rapidly and in adequate intensity relative to the rate at 
which the cancer cells can generate ATP. It also represents a case where 
the AAD is a "means" or "procedure" (i.e., a nutritionally mediated 
protein intake depression/elevation cycle) rather than a substance or 
agent per se. In this case the AAD utilized the physiologically well-known 
ability of protein intake depression/sudden elevation to temporarily raise 
the body-resting metabolic rate to very appreciable levels 
(&gt;3.times.basal). This phenomenon is ostensibly mediated by a gross 
(inappropriate) stimulation of a wide range of anabolic and other cellular 
ATPases by a sudden pronounced availability of amino acids, following an 
extended period of relative starvation of amino acids. The sudden and 
pronounced increase in the rate of use-up of ATP by the ATPases in the 
cancer cells mediated by the amino acid starvation/restoration cycle far 
exceeds the very limited ATP supply rate capability (ATP.sub.A) under such 
elevated body metabolic rate conditions, whence the cells rapidly succumb 
because of energy starvation (i.e., by ATP.sub.L). In principle, the AAD 
in this example acts through inappropriate stimulation of cellular ATPase 
similarly to thyroid hormone's stimulation of the Na.sup.+ /K.sup.+ 
-dependent membrane ATPases of the Na.sup.+ -pump, but to a much broader 
and more pronounced degree. However, due to the high whole-body resting 
metabolic rates generated, and the imprecision of controllability of their 
maximum level and duration, this procedure is not preferred for general 
use in the present therapy system. 
EXAMPLE 14 
Example Case No. 14: 
Male, 32 years old. 
Diagnosis: 
Malignant melanoma. Metastatic disease following malignant skin mole 
excision two years previously. Disease Stage 3. 
Basis of Diagnosis: 
Initial histological analysis of excised (mole) lesion from right forearm 
below elbow; present needle biopsies and histological analyses of large 
lung metastasis and of large (3.4 cm.times.2.9 cm) tumor mass in lower 
right neck. 
Therapy Prior to Present Treatment: 
Surgical excision only. 
Tumor Status at Start of Present Therapy: 
Large (3.4 cm.times.2.9 cm) hard, firmly fixed, metastatic mass in lower 
right neck region; large metastasis in lower lobe of left lung, with two 
smaller metastases in right lung. Neck and left lung masses proven 
melanoma metastases by direct biopsy and histological analyses. Neck mass 
was protrusive and easily measurable. Patient in reasonably good health, 
but losing weight; neck mass is rapidly increasing in size. 
Response to Treatment: 
For eight days prior to start of therapy (Day 1 is first day of protein 
elevation), patient remains on a regular food (vegetarian) diet, but daily 
protein intake is reduced to 5 g per 70 Kg of body weight or less, by 
elimination of protein-containing food items (e.g., meats, milk, eggs, et 
cetera). No medications of any sort are given. Patient's balanced caloric 
intake is 648 Kcal/d. Resting metabolic rate is 1.01 times Mayo standard 
basal metabolic rate. On the eighth day before Day 1, just prior to 
dietary protein restriction, the following enzyme levels were measured: 
SGOT (aspartate amino-transferase)=117 U/L [Normal range: 0-40]; SGPT 
(alanine aminotransferase) 113 U/L [Normal range: range: 100-240]. 
Day 1: Patient's dietary protein intake increased to 40 g/70 Kg per day; 
otherwise, diet remains the same as for the past eight days. Patient will 
remain on this increased protein intake for the next five days. AM (8:00) 
resting metabolic rate is 1.02 (x basal). PM (4:30) resting metabolic rate 
has risen to 1.70. 
Day 2: AM resting metabolic rate has risen to 2.01; dietary caloric intake 
is increased accordingly, for caloric balance. PM resting metabolic rate 
has increased to 2.40. Patient feels fine. Blood pressure, pulse rate, 
temperature, and respiration rate are normal. 
Day 3: AM resting metabolic rate has increased to 2.71. Dietary caloric 
intake is increased to the equivalent of an overall (effective) metabolic 
rate level of 2.30, which is the maximum the patient can consume orally; 
he is consequently in negative dietary caloric balance at this point. 
Right neck mass (AM) is now quite soft, movable, smaller. PM resting 
metabolic rate has risen still further to 3.21. Patient feels fine. Blood 
pressure and temperature normal; pulse rate and respiratory rate slightly 
elevated. 
Day 4: AM resting metabolic rate has decreased to normal level of 1.06. 
Neck tumor has decreased 64% in mass (volume) in three days; is soft and 
pliable, non-fixed. Patient feels fine. Blood pressure, pulse rate, 
temperature, and respiration rate are all normal. Patient continues on 
regular diet with high protein, calorically balanced to an effective 
metabolic rate of 1650 Kcal/d. LDH has risen to 261 U/L (from 184 U/L 
before protein restriction began), a 42% increase. 
Day 7: Resting metabolic rate has remained at approximately 
1.00.times.basal since Day 4. Body weight has remained constant; daily 
blood pressure, pulse rate, temperature and respiratory rate have been 
normal. Neck tumor has decreased 87% in mass since Day 1. Patient is in 
excellent condition. SGOT has decreased to 22 U/L (81% decline) and SGPT 
to 54 U/L (52% decline). 
EXAMPLE 15 
Types of Malignancies Demonstrating Clinical Oncolysis in Response to 
Therapy System of Present Invention 
______________________________________ 
Types of Malignancies Demonstrating 
Clinical Oncolysis in Response to 
Therapy System of Present Invention 
Patient Sex Age Malignant Neoplasm 
______________________________________ 
A F 52 Tongue 
B M 57 Throat 
C M 70 Stomach 
D F 47 Cecum 
E F 54 Colon 
F M 67 Rectum 
G F 45 Breast 
H F 57 Ovary 
I F 60 Uterus 
J M 65 Lung 
K M 65 Kidney 
L M 59 Prostate 
M M 49 Pancreas 
N M 49 Lymphoma 
O M 47 Melanoma 
P F 48 Skin: basal cell 
Q M 66 Leukemia 
R M 50 Bone: sarcoma 
______________________________________ 
The foregoing representative cases illustrate the 18 types of malignant 
neoplasms whose oncolytic responsiveness to administration of the present 
therapy system has been evaluated clinically. These 18 types embrace 
almost all malignant neoplasm forms of major clinical frequency. In every 
malignancy form evaluated to date, significant oncolysis has been 
observed, thus demonstrating the clinical validity of the underlying 
physiological rationale of the present invention, and verifying the 
results of the voluminous previous findings that malignantly transformed 
cells of essentially all forms of neoplasms do indeed possess a common 
metabolic aberrancy, vis. the inability to substantially metabolize 
glucose for energy purposes beyond the pyruvate stage of the 
Embden-Meyerhof Pathway under in vivo conditions. Of the 54 
advanced-malignancy patients evaluated to date with the present therapy 
system, the great majority have demonstrated significant oncolysis, while 
essentially all the rest have experienced at least an arrest of 
progression of their disease during the treatment period. 
While the invention has been described in connection with specific 
embodiments thereof, it will be understood that it is capable of further 
modification and that this application is intended to cover any 
variations, uses, or adaptations of the invention following, in general, 
the principles of the invention and including such departures from the 
present disclosure as come within the ordinary skill of the art to which 
the invention pertains, and as may be applied to the essential features 
hereinbefore set forth, within the spirit of the invention and the scope 
of the appended claims.