Abstract:
Hydrazine sulfate, alone or formulated with liquid or solid carriers, will prolong patient survival when administered to early-stage human cancer patients parenterally or orally.

Description:
This application is a continuation-in-part of pending Ser. No. 201,083, filed June 1, 1988, now abandoned, which is a continuation of Ser. No. 032,051, filed Mar. 27, 1987, now abandoned. 
     BACKGROUND OF THE INVENTION 
     Many different types of chemical compounds have been used in the past to retard or inhibit various tumors in man. More than thirty compounds are approved for use in cancer therapy in various countries, but the achievement of therapeutic benefit has reached a plateau, and the search for antitumor agents continues in various directions. 
     In 1967, Weitzel and co-workers reported in the Zeitschrift fuer Physiologische Chemie, 348, 433-442 that hydrazine acetate and sulfate inhibit in vivo the growth of ascites carcinoma and sarcoma 180 in the mouse and Walker carcinosarcoma in the rat. It is well known that the results from lower animals cannot be extrapolated in humans. Indeed, the experience at the U.S. National Institutes of Health has been that more than 200 new chemotypes having anticancer activity in animals have failed to show clinically useful anticancer activity in humans, as shown in the following table (Table I was compiled from various reports of the U.S. National Cancer Institute): 
     
                       TABLE I______________________________________New Chemotypes evaluated against cancer 1960-1985Succeeded    Failed______________________________________AdriamycinCisplatin    TripdiolideBleomycin    MaytansineMitomycin    SangivamycinVincristine  PentamethylmelamineCyclophosphamide*        TaxolEtopside**   Bactobolin        Alanosine        PALA        Acivicin        Methyl GAG        Menogarol        Triciribine        Disuccinimide        Flavoneacetic acid        Teroxirone        Acodazole        Benzisoquinolinedione        Didemnin B        Phyllanthoside        Ellipticine        Emetine        Indicine-N--oxide        Bouvardin        Thalicarpine        Tetrandrine        Acronycine        Tylocrebrine        Lapachol        Nitidine        Neocarzinostatin        Macromomycin        Largomycin        Streptimidone        Valinomycin        Piperazinedione        Fagaronine        Coralyne        Benzophenanthridine        Camptothecin        Acosamine        Acylagmatine        Allamandicin        Allamandin        Agolosamine        Anguidine        Angustmycin        Ansamycin        Aureolic acid        Baccharin        Bakkenolide        Baumycin        Bisnorditerpene        Bouvardin        Bredenine        Bruceolide        Bryogenin        Bufadienolide        Cardenolides        Catharanthus        Cephalotaxine        Chapparinone        Coformycin        Colcemid        Colchicine        Colubrinol        Coralyne        Cucurbitacin        Daphnetoxin        Datiscacin        Cecoyinine        Angustmycin        Scirpenol        Isobruceine        Nitidine        Duborimycin        Elemanolide        Elephantopin        Ellipticine        Elephantopin        Enteromycin        Eremantholides        Eriofertopin        Eudesmanolides        Eupacunin        Euparotin        Fabacein        Fagaronine        Fusarenon        Germacranolide        Glaucarubinone        Guaianolide        Helenolin        Homoerythrina        Hycanthone        Picrasin        Iridoid lactone        Isobruceine        Isocucurbitacin        Isoplumericin        Iatrophone        Lapachol        leurosidine        Leurosine        Liatrin        Masine        Maysenine        Maytanbutacine        Maytanbutine        Maytanprine        Maytanvaline        Miracil D        Mitrymicin        Mycophenolic acid        Neosolaneol        Nitidine        Nivalenol        Normaysine        Oxazinomycin        Peltatin        Penstemide        Phleomycin        Picrasane        Picropodophyllin        Piptocarphins        Plumericin        Porfiromycin        Pseudoguaianolides        Puromycin        Pyrazomycin        Quadrone        Quassimarin        Roridin        Samaderine        Sangivamycin        Eudesmanolide        Showdomysin        Sikkimototoxin        Simalikalactone        Simaroubolide        Stachybotrytoxin        Steganacin        Streptonigrin        Taxodione        Tenulin        Tetrandrine        Thalicarpine        Trichodermin        Undulatone        Vernolepin        Verrucarin        Vincadioline        Vindoline        Withaferin        Withanolide        Phosphonoacetic acid        Pentostatin        Deazaguanine        Tiazofurin        Ocodazole        Bisbenzimidazole        ICRF        JB-11        Dihydrotriazine benzene sulfonyl fluorid        Glyoxylic acid sulfonylhydrazone        N--Methylformamide        Caracemide        Isopropylpyrrolizine deriv.        Phyllanthoside        Aphidicolin        Largomycin______________________________________ *Analog of nitrogen mustard **Analog of podophyllotoxin 
    
     In addition, hundreds of analogs of the new and old chemotypes have failed to show anticancer activity in man, in spite of good antitumor activity in animals. In contrast to the above, only about five new chemotype anticancer drugs have reached the market in the last 25 years. Hence, early reports that hydrazine sulfate had antitumor activity in animals did not serve to predict that it might have anticancer activity in humans. 
     Because of this poor predictability of animal models, the National Cancer Institute of the U.S. National Institutes of Health has now abandoned the mouse model after 25 years of unproductive trial and is instituting a new in vitro program for discovering new antitumor drugs (E. Eckholm, New York Times, Dec. 23, 1986, p. C1). 
     A total inventory of cancer drugs approved for sale in the United States is set forth in Table II, and it will be seen that most of these are analogs of other drugs. Table III shows that, with one exception, all of the recent New Drug Applications filed for anticancer drugs led to unapprovable ratings by the U.S. Food and Drug Administration. Table IV shows that the last new chemotype which succeeded in the clinic was discovered more than 20 years ago. 
     
                       TABLE II______________________________________Anticancer Drugs Approved in U.S. in Order of Approval by______________________________________FDAleuprolide - Lupron              Takeda-Abbott                          4/9/85(gonadotropin releasing hormone)etoposide - Vepesid              BMY         11/10/83streptozotocin - Zanosar              Upjohn      7/7/82estramustine - Emcyt              Roche       12/24/81daunorubicin - Cerubidine              Ives        12/19/79cisplatin - Platinol              BMY         12/19/78tamoxifen - Nolvadex              ICI         12/30/77(antiestrogen)carmustine         BiCNU       3/7/77lomustine - CEENU  BMY         8/4/76dacarbazine - DTIC-Dome              Miles       5/27/75doxorubicin - Adriamycin              Farmitalia  8/7/74mitomycin C - Mutamycin              BMY         5/28/74bleomycin - Blenoxane              BMY         7/31/73megestrol acetate - Megace              BMY         8/18/71floxuridine - FUDR Roche       12/18/70mitotane - Lysodren              BMY         7/8/70plicamycin - Mithracin              Pfizer      5/5/70procarbazine - Matulane              Roche       7/22/69cytarabine - Cytosar U              Upjohn      6/17/69testolactone - Teslac              Squibb      6/3/69hydroxyurea - Hydrea              Squibb      12/7/67pipobroman - Vercyte              Abbott      7/1/66melphalan - Alkeran              BW          1/17/64vincristine - Oncovin              Lilly       7/10/63uracil mustard - Uracil Mustard              Upjohn      9/13/625-fluorouracil - Fluorouracil              Roche       4/25/62dromostanolone - Drolban              Lilly       10/26/61vinblastine - Velban              Lilly       3/6/61cyclophosphamide - Cytoxan              BMY         11/16/59thiotepa - Thio-Tepa              Lederle     3/9/59chlorambucil - Leukeran              BW          3/18/57busulfan - Myleran BW          6/26/54methotrexate - Methotrexate              Lederle     12/7/53______________________________________ 
    
     A review of the FDA&#39;s New Drug Evaluation - Statistical Report (March 1986) shows that no novel anticancer drug is pending approval at the FDA. 
     
                       TABLE III______________________________________The following are the dispositions of antineoplasticsfiled in 1980 to 1984:______________________________________Filed in 1980    Not approvable                NDA No. 18-348                             Antineoplastic    Not approvable                NDA No. 18-529                             Antineoplastic    Not approvable                NDA No. 18-554                             AntineoplasticFiled in 1981    Not approvable                NDA No. 18-641                             Antineoplastic    Not approvable                NDA No. 18-653                             AntineoplasticFiled in 1982    Not approvable                NDA No. 50-569                             AntineoplasticFiled in 1984    Not approvable                NDA No. 50-595                             Antineoplastic______________________________________ 
    
     Table IV lists the anticancer drugs approved in the United States. The last non-hormonal anticancer agent to be approved in the U.S. was etoposide in 1983. 
     The following are the years of discovery of the major anticancer drugs on the U.S. market (arbitrarily assumed to be one year before the first publication): 
     
                       TABLE IV______________________________________Etoposide               1966Adriamycin              1966Bleomycin               1966Cisplatin               1965Mitomycin C             1965Vincristine             19615-Fluorouracil          1957Cyclophosphamide        1957Methotrexate            1949______________________________________ 
    
     Thus, there have been no new chemotype cytotoxic anticancer drugs discovered in the past twenty years. Consequently, there remains an unfulfilled need for additional cancer drugs for clinical use against tumors in humans. 
     Up the present time, it has been generally unrecognized that a specific anticachexia agent (by virtue of its ability to interrupt those specific thermodynamic metabolic processes leading to cancer cachexia) possesses antitumor potential, by virtue of a systematic thermodynamic interrelationship between tumor progression (tumor energy gain) and cancer cachexia (host energy loss); this has been taught in the scientific literature since 1974 (J. Gold, Cancer Cachexia and Gluconeogenesis, Ann. N.Y. Acad. Sci., 230, 103-110 (1974)). Thus, while it is true that any antitumor agent may have anticachexia potential, if curative, it is also true that a specific anticachexia agent may have potential for increased patient survival. However, it is not obvious, nor predictable, from the prior art that hydrazine sulfate would possess this potential. 
     In 1978, the present inventor was issued U.S. Pat. No. 4,110,437 for the treatment of cancer cachexia with hydrazine sulfate. Investigations were also undertaken to ascertain whether hydrazine sulfate could retard tumor growth in humans. However, these early studies were inadequate and failed to statistically demonstrate antitumor activity. 
     A group at Sloan-Kettering concluded after a trial that: &#34;The clinical observations recorded in this report fail to support a role for hydrazine sulfate as an anticancer agent. We conclude that its clinical utilization is not warranted at present and do not plan further trials.&#34;(Ochoa et al., Cancer Chemotherapy Reports, Part 1, Vo. 59, No. 6, Nov./Dec. 1975; pp. 1151-1154). 
     In addition, a group at the University of Virginia repoted that: &#34;Hydrazine sulfate as administered in this series failed to demonstrate any objective or subjective antitumor activity and no further trials are currently planned.&#34;(Lerner and Regelson, Cancer Treatment Reports, Vol. 60, No. 7, July 1976, pp. 959-966). Another later publication by Regelson et al. stated: &#34;In conclusion, we feel that hydrazine sulfate as given in this study is an inactive compound.&#34;(Cancer Chemother. Pharmacol., 3, 121-124, 1979). 
     Thus, the prior art taught that hydrazine sulfate appeared to be inactive against primary tumor growth in man. 
     SUMMARY OF THE INVENTION 
     This invention is based on the discovery that hydrazine sulfate, when administered parenterally or orally in effective, non-toxic amounts to humans with tumors of the lung, prostate, breast, ovaries, thyroid, pancreas, lymph, cervix, gastrointestinal tract and other sites will significantly prolong survival of early-stage human cancer patients, while improving the patient&#39;s quality of life. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The dosages of hydrazine sulfate employed in the present invention can varyfrom 1 to 5 mg/kg daily, which is well below the LD50 and has been found tobe well tolerated in the majority of early-stage patients so treated for periods of up to four years. 
     Preferably, the regimen followed is one 60 mg capsule of hydrazine sulfate daily for the first three days, then two such capsules daily for the next three days, and then three 60 mg capsules each day thereafter. In actual practice, patients weighing over 130 pounds do well on three or four 60 mgcapsules daily. For patients weighing less than 100 pounds, the regimen followed is preferably one 30 mg capsule of hydrazine sulfate daily for the first three days, then two such capsules daily for the next three days, and then two or three 30 mg capsules each day thereafter. For best results blood levels of hydrazine sulfate should be determined on these patients in order to establish a most effective non-toxic dose. 
     Hydrazine sulfate therapy can advantageously be combined with other modalities for cancer treatment like chemotherapy, immunotherapy, radiation and surgery. 
     Hydrazine sulfate is most effective when administered usually by itself oneor two hours before meals in the form of a gelatin capsule. If desired, thesulfate can be dissolved or suspended in sterile, aqueous, isotonic saline solution and given orally and parenterally. Likewise, hydrazine sulfate can be formulated with solid carriers such as talc, corn starch or stearicacid and compressed into tablets for oral administration. Such tablets can be enteric coated with shellac or cellulose acetate phthalate in a manner well known to those skilled in the pharmaceutical art. 
     The efficacy of hydrazine sulfate in prelonging survival in early-stage human cancer patients has now been demonstrated for the first time in a placebo-controlled, double-blind experiment with a statistically significant number of subjects. 
     Early-stage human cancer patients are distinguished from late-stage human cancer patients on the basis of the nature of their symptoms. These symptoms have been quantitatively correlated by two recognized methods of categorization: the Eastern Cooperative Oncology Group (ECOG) Performance Status Score (also known as Zubrod&#39;s ) and the Karnofsky Rating Scale. Therelationship between these two methods and the resulting division of human cancer patients into early-stage and late-stage, as recognized by ECOG andKarnofsky rating criteria, is set forth as follows: 
     
         ______________________________________Stage of   ECOG Performance                  Karnofsky Nature ofCancer  Status Score   Rating    Symptoms______________________________________Early   0              100       Asymptomatic                            without                            physical                            limitationEarly   1              80-90     Symptomatic,                            but fully                            ambulatoryLate    2              60-70     Symptomatic,                            but in bed                            less than                            50% of dayLate    3              40-50     Symptomatic,                            in bed more                            than 50% of                            day, but not                            bedriddenLate    4              20-30     Bedridden______________________________________ 
    
     In the placebo-controlled, double-blind experiemnt referred to above, to determine whether hydrazine sulfate treatment is associated with a survival benefit (R.T. Chlebowski et al., &#34;Influence of Hydrazine Sulfate on Survival in Non-Small Cell Lung Cancer: A Randomized Placebo-ControlledTrial&#34;, presented at the Annual Meeting of the American Society for Clinical Oncology, May 17-19, 1987, Atlanta, Georgia), sixty-five patientswith unresectable, non-small cell lung cancer and no prior chemotherapy were randomized to receive combination chemotherapy with either hydrazine sulfate or placebo addition for a period of up to four years. All receivedPlatinol/Velban/Blenoxane (PVB) chemotherapy every 28 days, consisting of Platinol 100 mg/m 2  ; Velban 4 mg/m 2 , days 1 and 2; and Blenoxane10 units every 8 hours for three doses. After the initial three cycles, theBlenoxane was discontinued and the Platinol dose was reduced to 50 mg/m 2 . 
     Pre-chemotherapy factors including age, sex, performance status (PS), priorweight loss and disease extent were comparable in the two groups, with pre-chemotherapy performance status (0-vs. 2) and prior weight loss (&gt;10%)subsequently influencing overall survival (p&lt;0.05). Toxicity was that expected from PVB with three patients not continuing hydrazine sulfate because of additional nausea. Survival by hydrazine sulfate or placebo were: 
     
         ______________________________________Median Survival bv Patient GroupTreatment Group          All Patients                    PS 0-1 Patients______________________________________Hydrazine Sulfate          292 days  328 days*Placebo        173 days  209 days______________________________________Statistical analysis of the data was by the generalized Wilcoxon (Breslau) method. Comparison of the hydrazine sulfate and placebo groups showed statistical significance at the *P&lt;0.01 level. All of the survival benefitof hydrazine sulfate was in the performance status 0-1 group. For the performance status (PS) 2 patients, whose condition was poor, survivals were short (median 132 days) and closely comparable whether on placebo or hydrazine sulfate. Thus, hydrazine sulfate addition, as an anti-cachexia agent directed primarily at correcting abnormal host mechanism, significantly increased patient survival in early-stage patients with non-small cell lung cancer. 
    
     Specifically, this increased survival time occurred in early-stage human cancer patients with Performance Status 0 or 1 (PS 0-1), whereas late-stage patients (PS 2) did not exhibit prolonged survival. 
     Several patients with tumors of the prostate, lung, breast, ovary, lymph, cervix, thyroid, pancreas and other tumor sites were treated with hydrazine sulfate according to the preferred regimen previously set forth.