Newsgroup: it.salute
Titolo: Studi relativi al potere antiacido del bicarbonato di sodio nei tumori

Studi relativi al potere antiacido del bicarbonato di sodio nei tumori:
Anne McLean, "Malignant gliomas display altered pH regu1ation by� NHE1 
compared with non transformed astrocytes  (Am J Physiol Cell Physiol 278: 
C676-C688, 2000).
Marion Stubbs, "Causes and consequences of tumour acidity and implications 
for treatment", Molecular Medicine: Today, January 2000 (vol.6).
Robert J. Gillies, "Causes and consequences of hypoxia and acidity in 
turners - Novartis Foundat�on symposium", Molecular Medicine Vol.7 N� 2 
February 2001; "Causes and consequences of hypoxia and ac�dity in tumour 
microenvironments".
J.R. Griffiths, "Causes and consequences of hypoxia and ac�dity in tumour 
microenvironments", Glia 1994 Nov:12(3):196-210.
Tannock, I.F., "Acid pH in tumors and its potential for therapeutic 
exploitation", Cancer Res 1989 Aug 15;49(16):4373-84.
Raghunand, N., "Enhancement of chemotherapy by manipulation of tumour pH", 
Br J Cancer 1999 Jun;80(7):1005-11.
Davydova, I.G., "Dynamics of bioelectric activity of the brain and 
erythrocyte ultrastructure after intravenous infusion of sodium bicarbonate 
to oncologic patients." Biull Eksp Biol Med 1992 Apr;113(4):352-5.
Davydova, I.G., "Characteristics of the effects of artificial alkalosis on 
electrical activity of the brain and ultrastructure of blood cells in 
oncologic patients", Vestn Ross Akad Med Nauk 1995;(4):24-5.
Star, R.A., "Regulatory volume decrease in the presence of HCO3- by single 
osteosarcoma cells UMR-106-01", J Biol Chem 1992 Sep 5;267(25):17665-9.
LeBoeuf, R.A., "Intracellular acidification is associated with enhanced 
morphological transformation in Syrian hamster embryo cells", Cancer Res 
1992 Jan 1;52(1):144-8.
Raghunand, N., "Acute metabolic alkalosis enhances response of C3H mouse 
mammary tumors to the weak base mitoxantrone." Neoplasia. 2001 
May-Jun;3(3):227-35.
Raghunand, N., "pH and chemotherapy pH and chemotherapy" Novartis Found 
Symp. 200 1;240:199-21 l; discussion 265 -8.
Raghunand, N., "Enhancement of chemotherapy by manipulation of tumour pH." 
Br J Cancer. 1999 Jun;80(7):1005-1 I.
Raghunand, N., "Tumor acidity, ion trapping and chemotherapeutics. IL 
pll-dependent partition coefficients predict importance of ion trapping on 
pharmaeokinetics of weakly basic chemotherapeutie agents." B�ochem 
Pharmacol. 2003 Oct 1;66(7):1219-29."
Mahoney, B.P., "Tumor acidity, ion trapping and chemotherapeutics. I. Acid 
pl� affects the distribution of ehemotherapeutic agents in vitro." Biochem 
Phannacol. 2003 Oct 1;66(7):1207-18.
Schornack, P.A., "Contributions of cell metabolism and H+ diffusion to the 
acidic pH of tumors." Neoplasia. 2003 Mar-Apr;5(2):135-45.
Giffles, R.J., "MRI of the tumor microenvironment." J Magn Reson Imaging 
2002 Dec; 16(6):75 l.
Torigoe, T., "Vacuolar H(+)-ATPase: funetional mechanisms and potential as a 
target for cancer chemotherapy." Anticancer Drugs. 2002 Mar; 13 (3):23 7-43.
Griffiths, J.R., "Why are cancers acidic? A carrier-mediated diffusion model 
for H+ transport in the interstitial fluid." Novartis Found Symp. 200 
1;240:46-62; discussion 62-7, 152-3.
Webb, S.D., "Modelling tumour acidity and invasion." Novartis Found Symp. 
2001;240:169-8 l; discussion 181-5.
Gillies, R.J., "The tumour microenvironment: causes and consequences of 
hypoxia and acidity. Introduction." Novartis Found Symp. 200 1;240:1-6.
Gillies, R.J., "Causes and consequences of hypoxia and acidity in tumors" 
Novartis Foundation symposium. Trends Mol Med. 2001 Feb;7(2):47-9.
Griffiths, JR. "Causes and consequences of hypoxia and acidity in tumour 
microenvironments. Bioessays. 2001 Mar;23(3):295-6.
Gillies, R.J., "Causes and effects of heterogeneous perfusion in tumors." 
Neoplasia. 1999 Aug; 1 (3):197-207.
Stubbs, M., "Causes and consequences of tumour acidity and implications for 
treatment." Mol Med Today. 2000 Jan;6(1):15-9
Stubbs, M., "Causes and consequences of acidic ph in tumors: a magnetic 
resonance study." Adv. Enzyme Regul. 1999;39;13-30.
Webb, S.D., "Mathematical modelling of tumour acidity: regulation of 
intracellular pH." J Theor Biol. 1999 Jan 21; 196(2);237-50.
Yamagata, M., "The contribution of lactic acid to acidification of tumours: 
studies of variant cells lacking lactate dehydrogenase." Br J Cancer. 1998 
Jun;77(11):1726~3 I.
Martin, G.R., "Non invasive measurement of interstitial pH profiles in 
normal and neoplastie tissue using fluorescence ratio imaging microscopy." 
Cancer Res. 1994 Nov 1;54(21):5670-4.
Boyer, M.J., "Regulation of intracellular pH in subpopulations of cefis 
derived from spheroids and solid tumours." Br J Cancer. 1993 
Nov;68(5):890-7.
Newell, K., "Studies with gIyeolysis-dericient celIs suggest that production 
of lactic acid is not the only cause of tumor acidity."
 Enhancement of chemotherapy by manipulation of tumour pH.
 Raghunand N, He X, van Sluis R, Mahoney B, Baggett B, Taylor CW, 
Paine-Murrieta G, Roe D, Bhujwalla ZM, Gillies RJ. - Arizona Cancer Center, 
Tucson 85724-5024, USA.
 The extracellular (interstitial) pH (pHe) of solid tumours is significantly 
more acidic compared to normal tissues. In-vitro, low pH reduces the uptake 
of weakly basic chemotherapeutic drugs and, hence, reduces their 
cytotoxicity. This phenomenon has been postulated to contribute to a 
'physiological' resistance to weakly basic drugs in vivo. Doxorubicin is a 
weak base chemotherapeutic agent that is commonly used in combination 
chemotherapy to clinically treat breast cancers. This report demonstrates 
that MCF-7 human breast cancer cells in vitro are more susceptible to 
doxorubicin toxicity at pH 7.4, compared to pH 6.8. Furthermore 31P-magnetic 
resonance spectroscopy (MRS) has shown that the pHe of MCF-7 human breast 
cancer xenografts can be effectively and significantly raised with sodium 
bicarbonate in drinking water. The bicarbonate-induced extracellular 
alkalinization leads to significant improvements in the therapeutic 
effectiveness of doxorubicin against MCF-7 xenografts in vivo. Although 
physiological resistance to weakly basic chemotherapeutics is 
well-documented in vitro and in theory, these data represent the first in 
vivo demonstration of this important phenomenon.
 Fluorescence ratio imaging of interstitial pH in solid tumours: effect of 
glucose on spatial and temporal gradients.
 Dellian M, Helmlinger G, Yuan F, Jain RK. - Edwin L Steele Laboratory, 
Department of Radiation Oncology, Massachusetts General Hospital, Harvard 
Medical School, Boston 02114, USA.
 Tumour pH plays a significant role in cancer treatment. However, because of 
the limitations of the current measurement techniques, spatially and 
temporally resolved pH data, obtained non-invasively in solid tumours, are 
not available. Fluorescence ratio imaging microscopy (FRIM) has been used 
previously for noninvasive, dynamic evaluation of pH in neoplastic tissue in 
vivo (Martin GR, Jain RK 1994, Cancer Res., 54, 5670-5674). However, owing 
to problems associated with quantitative fluorescence in thick biological 
tissues, these studies were limited to thin (50 microns) tumours. We, 
therefore, adapted the FRIM technique for pH determination in thick 
(approximately 2 mm) solid tumours in vivo using a pinhole 
illumination-optical sectioning (PIOS) method. Results show that (1) steep 
interstitial pH gradients (5 microns resolution), with different spatial 
patterns, exist between tumour blood vessels; (2) pH decreased by an average 
of 0.10 pH units over a distance of 40 microns away from the blood vessel 
wall, and by 0.33 pH units over a 70 microns distance; (3) the maximum pH 
drop, defined as the pH difference between the intervessel midpoint and the 
vessel wall, was positively correlated with the intervessel distance; (4) 45 
min following a systemic glucose injection (6 g kg-1 i.v), interstitial pH 
gradients were shifted to lower pH values by an average of 0.15 pH units, 
while the spatial gradient (slope) was maintained, when compared with 
preglucose values. This pH decrease was not accompanied by significant 
changes in local blood flow. pH gradients returned to near-baseline values 
90 min after glucose injection; (5) interstitial tumour pH before 
hyperglycaemia and the glucose-induced pH drop strongly depended on the 
local vessel density; and (6) sodium bicarbonate treatment, either acute (1 
M, 0.119 ml h-1 for 3 h i.v.) or chronic (1% in drinking water for 8 days), 
did not significantly change interstitial tumour pH. Modified FRIM may be 
combined with other optical methods (e.g. phosphorescence quenching) to 
evaluate non-invasively the spatial and temporal characteristics of 
extracellular pH, intracellular pH and pO2 in solid tumours. This will offer 
unique information about tumour metabolism and its modification by treatment 
modalities used in different cancer therapies.
 J Pain Symptom Manage 1996 Jul;12(1):11-7 Related Articles, Books, LinkOut
 Comment in:  J Pain Symptom Manage. 1997 Jun;13(6):316-8
 Effects of induced metabolic alkalosis on perception of dyspnea during 
flow-resistive loading.
 Taguchi N, Ishikawa T, Sato J, Nishino T. - Department of Anesthesiology, 
School of Medicine, Chiba University, Japan.
 Treatment of dyspnea in patients with advanced cancer is an important 
issue. The purpose of the present study was to assess the effect of 
induced-metabolic alkalosis produced by administration of sodium bicarbonate 
on dyspneic sensation. In seven healthy subjects, dyspnea was induced by 
having them breathe with a flow-resistive load (24 cm H2O/L/sec) for 6 min 
before and after administration of sodium bicarbonate (0.5 mmol/kg, per os+2 
mmol/kg, IV). The intensity of dyspnea was rated using a visual analogue 
scale (VAS). The VAS scores and minute ventilation during loaded breathing 
after administration of sodium bicarbonate were significantly lower than 
those before administration of sodium bicarbonate. These results indicate 
that induced metabolic alkalosis may alleviate the intensity of dyspneic 
sensation by a reduction in ventilatory drive.
 Diminuzione del volume in presenza di -HCO3 in cellule di osteosarcoma
 Si registra simultaneamente la variazione di voume e di Ph intracellulare, 
per studiare il ruolo di HCO3- nella diminuzione del volume cellulare.
L'aumento di Ph intracellulare - risulta - coincide con una diminuzione del 
volume cellulare.
Appare evidente, in questo modo, il coinvolgimento del Na+ (HCO3-) nella 
regolazione del volume cellulare.
 J Biol Chem 1992 Sep 5;267(25):17665-9 Related Articles, Books, LinkOut
 Regulatory volume decrease in the presence of HCO3- by single osteosarcoma 
cells UMR-106-01.
 Star RA, Zhang BX, Loessberg PA, Muallem S. - Department of Medicine, 
University of Texas Southwestern Medical Center, Dallas 75235-9040.
 The technique for the simultaneous recording of cell volume changes and pHi 
in single cells was used to study the role of HCO3- in regulatory volume 
decrease (RVD) by the osteosarcoma cells UMR-106-01. In the presence of 
HCO3-, steady state pHi is regulated by Na+/H+ exchange, Na+ (HCO3-)3 
cotransport and Na(+)-independent Cl-/HCO3- exchange. Following swelling in 
hypotonic medium, pHi was reduced from 7.16 +/- 0.02 to 6.48 +/- 0.02 within 
3.4 +/- 0.28 min. During this period of time, the cells performed RVD until 
cell volume was decreased by 31 +/- 5% beyond that of control cells (RVD 
overshoot). Subsequently, while the cells were still in hypotonic medium, 
pHi slowly increased from 6.48 +/- 0.02 to 6.75 +/- 0.02. This increase in 
pHi coincided with an increase in cell volume back to normal (recovery from 
RVD overshoot or hypotonic regulatory volume increase (RVI)). The same 
profound changes in cell volume and pHi after cell swelling were observed in 
the complete absence of Cl- or Na+, providing HCO3- was present. On the 
other hand, depolarizing the cells by increasing external K+ or by 
inhibition of K+ channels with quinidine, Ba2+ or tetraethylammonium 
prevented the changes in pHi and RVD. These findings suggest that in the 
presence of HCO3-, RVD in UMR-106-01 cells is largely mediated by the 
conductive efflux of K+ and HCO3-. Removal of external Na+ but not Cl- 
prevented the hypotonic RVI that occurred after the overshoot in RVD. 
Amiloride had no effect, whereas pretreatment with 
4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) strongly inhibited 
hypotonic RVI. Thus, hypotonic RVI is mediated by a Na+(out)-dependent, 
Cl(-)-independent and DIDS-inhibitable mechanism, which is indicative of a 
Na+(HCO3-)3 cotransporter. This is the first evidence for the involvement of 
this transporter in cell volume regulation. The present results also stress 
the power of the new technique used in delineating complicated cell volume 
regulatory mechanisms in attached single cells.
 Effetto dell'alcalosi artificiale nell'attivit� del cervello e nelle 
cellule del sangue in pazienti oncologici: Vengono studiati 40 pazienti 
oncologici, di differenti istotipi, sedi e dimensioni.
Il lavoro evidenzia che i pazienti hanno un'acidosi intracellulare 
generalizzata, che pu� essere diminuita con l'alcalinizzazione del plasma.
 Vestn Ross Akad Med Nauk 1995;(4):24-5 Related Articles, Books, LinkOut
 [Characteristics of the effects of artificial alkalosis on electrical 
activity of the brain and ultrastructure of blood cells in oncologic 
patients]. [Article in Russian]
 Davydova IG, Kassil' VL, Filippova NA, Barinov MV.
 The authors examined 40 patients with malignant tumors of various 
histogenesis, sites and extent, as well as 5 patients with benign tumors and 
other non-tumorous diseases. They also studied their electroencephalography 
and peripheral blood lymphocytic and erythrocytic ultrastructure in 
metabolic alkalosis temporarily induced by intravenous sodium hydrogen 
carbonate. In cancer patients without late metastases, alkalosis caused a 
transient normalization of previously altered electroencephalography, 
erythrocyte disaggregation and substantially reduced the count of killer 
cells in small and middle lymphocytes. These findings suggest that patients 
with malignant neoplasms have a generalized intracellular acidosis which can 
be temporarily abolished by plasma alkalinization.
 Cancer Res 1989 Jan 1;49(1):205-11 Related Articles, Books, LinkOut
 Requirement of the Na+/H+ exchanger for tumor growth.
 Rotin D, Steele-Norwood D, Grinstein S, Tannock I. - Department of Medicine 
and Medical Biophysics, Ontario Cancer Institute, Toronto, Canada.
 The Na+/H+ exchanger is involved in a variety of cellular processes, 
including regulation of intracellular pH and possibly the control of cell 
growth and proliferation. To study the role of the Na+/H+ exchanger in tumor 
growth, human sodium proton exchanger-deficient (HSPD) mutants were derived 
from the human bladder carcinoma cell line MGH-U1 (EJ) by the proton suicide 
selection technique (J. Pouyssegur et al., Proc. Natl. Acad. Sci. USA, 81: 
4833-4837, 1984). The HSPD cells were approximately 40% larger and contained 
approximately 70% more DNA than the parental cells. They were unable to grow 
in vitro in the absence of bicarbonate at pH less than 7.0, whereas the 
parental cells grew well at pH greater than or equal to 6.6. This difference 
in acid sensitivity was abolished in the presence of bicarbonate. In 
contrast to the parental MGH-U1 cells, the Na+/H+-deficient HSPD cells 
either failed to grow tumors, or showed severely retarded tumor growth when 
implanted into immune-deprived mice. This difference in tumor growth was not 
attributed to differences in cell size and DNA content, because Na+/H+ 
exchange-competent large cells (HLC), derived during the same proton suicide 
selection process as the HSPD cells, grew tumors at a rate close to that of 
the parental cells. Cells derived from the few tumors which grew after 
implantation of HSPD mutant cells were revertants which had regained Na+/H+ 
activity. HSPD cells also failed to form spheroids in culture, and the only 
spheroid formed consisted of revertant cells which had regained both Na+/H+ 
exchange activity and tumorigenic capacity. These results suggest that the 
Na+/H+ exchanger is important for tumor growth.
 Eur J Biochem 1987 Dec 30;170(1-2):43-9 Related Articles, Books
 Properties of the Na+-dependent Cl-/HCO3- exchange system in U937 human 
leukemic cells.
 Ladoux A, Krawice I, Cragoe EJ Jr, Abita JP, Frelin C. - Institut National 
de la Sante et de la Recherche Medicale Unite 204, Hopital Saint-Louis, 
Paris, France.
 U937 cell possess two mechanisms that allow them to recover from an 
intracellular acidification. The first mechanism is the amiloride-sensitive 
Na+/H+ exchange system. The second system involves bicarbonate ions. Its 
properties have been defined from intracellular pH (pHi) recovery 
experiments, 22Na+ uptake experiments, 36Cl- influx and efflux experiments. 
Bicarbonate induced pHi recovery of the cells after a cellular acidification 
to pHi = 6.3 provided that Na+ ions were present in the assay medium. Li+ or 
K+ could not substitute for Na+. The system seemed to be electroneutral. 
22Na+ uptake experiments showed the presence of a bicarbonate-stimulated 
uptake pathway for Na+ which was inhibited by 
4,4'-diisothiocyanostilbene-2,2'-disulfonate. The bicarbonate-dependent 
22Na+ uptake component was reduced by depleting cells of their internal Cl- 
and increased by removal of external Cl-. 36Cl- efflux experiments showed 
that the presence of both external Na+ and bicarbonate stimulated the efflux 
of 36Cl- at a cell pHi of 6.3. Finally a 36Cl- uptake pathway was 
documented. It was inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonate 
(K0.5 = 10 microM) and bicarbonate (K0.5 = 2 mM). These results are 
consistent with the presence in U937 cells of a coupled exchange of Na+ and 
bicarbonate against chloride. It operates to raise the intracellular pH. Its 
pHi and external Na+ dependences were defined. No evidence for a 
Na+-independent Cl-/HCO3- exchange system could be found. The Na+-dependent 
Cl-/HCO3- exchange system was relatively insensitive to (aryloxy)alkanoic 
acids which are potent inhibitors of bicarbonate-induced swelling of 
astroglia and of the Li(Na)CO3-/Cl- exchange system of human erythrocytes. 
It is concluded that different anionic exchangers exist in different cell 
types that can be distinguished both by their biochemical properties and by 
their pharmacological properties.
 L'acidificazione intracellulare � associata ad un aumento di trasformazioni 
morfologiche nelle cellule embrionali di criceto siriano
 Lo studio indica che le cellule di criceto possiedono attivit� regolatorie 
intracellulari, e che l'acidificazione cellulare gioca un ruolo nell'aumento 
di frequenza delle trasformazioni osservate nelle cellule coltivate in 
condizioni di acidit�.
 Cancer Res 1992 Jan 1;52(1):144-8 Related Articles, Books
 Intracellular acidification is associated with enhanced morphological 
transformation in Syrian hamster embryo cells.
 LeBoeuf RA, Lin PY, Kerckaert G, Gruenstein E. - Procter and Gamble Co., 
Miami Valley Laboratories, Cincinnati, Ohio 45239-8707.
 A series of studies has indicated that the frequency of morphological 
transformation induced by chemical carcinogens in early passage Syrian 
hamster embryo (SHE) cells is significantly higher when these cells are 
cultured in medium of reduced bicarbonate concentration and pH (6.70) 
compared with cells cultured in medium of higher pH. It has also been shown 
that intercellular gap junctional communication is decreased in these cells 
when they are cultured at pH 6.70 compared with medium of higher pH. The 
purpose of the studies reported here was to characterize the effect of 
changing extracellular pH on intracellular pH in SHE cells. The frequency of 
morphological transformation induced by benzo(a)pyrene was established at 
various extracellular pHs and compared with intracellular pH values. Cells 
cultured in medium of pH ranging from 6.70 to 7.35 were loaded with the 
pH-sensitive fluorescent dye 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein, 
and either the steady-state intracellular pH values or the kinetics of 
change in intracellular pH following refeeding of the cultures with medium 
of pH ranging from pH 6.70 to pH 7.35 was monitored via image analysis 
techniques. Results from these studies indicate that, at culture medium pH 
above 6.95, SHE cells were relatively insensitive to changes in 
extracellular pH, maintaining an intracellular pH of 7.30 to 7.35 in medium 
containing 0% serum or pH 7.05 to 7.10 in medium containing 20% fetal bovine 
serum. At extracellular pHs below 6.95, intracellular pH decreased and, in 
the presence of serum, equilibrated with extracellular pH. The decrease in 
intracellular pH was closely associated with an increase in 
benzo(a)pyrene-induced morphological transformation frequency observed in 
parallel studies. These results indicate that SHE cells have active 
intracellular pH regulatory activities and suggest that intracellular 
acidification plays a role in the increased frequency of transformation 
observed in SHE cells cultured under acidic conditions.
Dinamiche dell'attivit� bioelettrica del cervello e dell'ultrastruttura 
eritrocitaria, dopo infusione di bicarbonato di sodio in pazienti oncologici
Partendo dall'ipotesi di un'acidosi intracellulare generalizzata, 23 
paziente affetti da neoplasia in diverse sedi anatomiche e di differenti 
tipi istologici, sono stati trattati con NaHCO3.
L'alcalosi metabolica ha indotto miglioramento nellEEG e nelle alterazioni 
di aggregazione eritrocitaria.
Il risultato conferma l'ipotesi di partenza.
Biull Eksp Biol Med 1992 Apr;113(4):352-5
[Dynamics of bioelectric activity of the brain and erythrocyte 
ultrastructure after intravenous infusion of sodium bicarbonate to oncologic 
patients]. - [Article in Russian]
Davydova IG, Kassil' VL, Raikhlin NT, Filippova NA.
23 patients with malignant tumors of different location and histogenesis 
were investigated. There were no metastases in 9 cases. 10 patients had 
metastases in regional areas and 4--distant. The results were compared with 
those obtained in 4 patients with nonmalignant diseases. EEG, blood gases, 
plasma acid--base balance and ultrastructure of erythrocytes were explored 
before and after intravenous infusion of 4.2% sodium bicarbonate solution. 
The metabolic alkalosis induced amelioration of EEG, which was changed 
basically, the condense of pre-membrane layer disappeared or decreased in 
erythrocytes, and disaggregation of erythrocytes took place in cancer 
patients vs those with nonmalignant tumors. The results confirm the 
suggestion of generalized intracellular acidosis in malignant tumor 
patients. This acidosis can be temporarily avoided or diminished 
artificially by blood alkalosis.
Liver Transpl Surg 1999 Mar;5(2):151-2 Related Articles, Books
Prolonged lactic acidosis after extended hepatectomy under in situ 
hypothermic perfusion.
Davidson BR, Rai R. - Department of Surgery, The Royal Free Hospital, 
London, England.
 46-year-old woman underwent right extended hepatectomy under total vascular 
occlusion with in situ hypothermic perfusion for colorectal metastasis. 
Immediately after surgery, she developed severe lactic acidosis, which 
required correction with sodium bicarbonate solution and ventilatory support 
for 36 hours. After 2 days, her lactate normalized, and the acidosis was 
corrected. She made an uneventful recovery. Persistent lactic acidosis after 
major hepatic resection under in situ hypothermic perfusion is a rare but 
reversible problem.
Cancer Res 1998 May 1;58(9):1901-8 Related Articles, Books, LinkOut
Heterogeneity of intracellular pH and of mechanisms that regulate 
intracellular pH in populations of cultured cells.
Lee AH, Tannock IF. - Department of Medical Biophysics, Ontario Cancer 
Institute, Toronto, Canada.
Cells within solid tumors are known to exist in a microenvironment that may 
be acidic and depend on membrane-based mechanisms (Na+/H+ antiport and 
Na+-dependent Cl-/HCO3- exchanger) that regulate intracellular pH (pHi). We 
have used the fluorescent pH indicator 2',7'-bis-(2-carboxyethyl) 5 (and 
6)-carboxyfluorescein and flow cytometry to study the distribution of pHi 
and the activity of these pHi-regulating mechanisms among populations of 
murine mammary sarcoma (EMT6), human breast cancer (MCF-7), and Chinese 
hamster ovary cells exposed to different levels of extracellular pH (pHe). 
Cells were exposed to Na+ buffer in the presence or absence of HCO3- and of 
5-(N-ethyl-N-isopropyl)-amiloride (a potent inhibitor of the Na+/H+ 
antiport) to determine the relative importance of each exchanger in the 
regulation of pHi. Our results indicate that: (a) the distribution of pHi at 
any value of pHe is broader than can be accounted for by machine noise; (b) 
cells maintain levels of pHi that are higher than pHe under acidic 
conditions; (c) the distribution of pHi is narrower when the Na+-dependent 
Cl-/HCO3- exchanger is active; and (d) populations that are derived from 
selected cells with values of pHi at lower and higher ends of the pHi 
distribution generate pHi distributions that are similar to those of 
controls, suggesting a stochastic variation in the activity of 
membrane-based mechanisms that regulate pHi.
Our data suggest that the Na+-dependent Cl-/HCO3- exchanger is the dominant 
mechanism for regulation of pHi under moderately acidic conditions such as 
may occur in the microenvironment of solid tumors
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http://www.healthsalon.org:80/373/cancer-is-a-fungus-alternative-cancer-treatments/
Science Daily
October 8, 2007
How A Benign Fungus Can Become Life-Threatening
Researchers at the Agency for Science, Technology and Research's Institute
of Molecular and Cell Biology have discovered new molecular mechanisms that
provide a more detailed understanding of how the normally benign Dr.
Jekyll-like fungus known as Candida albicans transforms into a serious and
often life-threatening Mr. Hyde-like form.
C. albicans can cause serious and potentially life-threatening infections in
the mouth, blood and other tissues of people who are undergoing cancer
chemotherapy or radiation treatments, or who have developed AIDS or other
diseases that damage the immunity of the individual.
In two separate papers recently published in Developmental Cell and the EMBO
journal, the team of scientists led by Wang Yue, principal investigator at
IMCB, have managed to reveal previously unknown mechanisms which are
responsible for causing the infectious phase of C. albicans.
The fungus starts its 'attack' on a patient by changing its oval shape into
a filamentous form, which has thin, threadlike appendages emerging from the
cell body. Wang's team, who has been studying C. albicans for more than
seven years, was responsible for identifying the master "controller" protein
called Hgc1 in 2004.
This "controller" functions like a regulator and tells the fungus when to
start the transformation from the harmless oval shape to the infectious
filamentous form.
"One question remained, however - how does it activate the cellular
machineries that determine the fungal cell shape?" said Wang.
Wang's team found the answer to this question in two proteins called Rga2
and Cdc11. They discovered that they each function like a switch on two
different cellular machineries that normally determines cell shape. "The
master regulator Hgc1 acts like the 'finger' that flips the switches to
start the infection process," said Wang.
"Our findings have uncovered detailed molecular mechanisms which define how
these two proteins interact with the master 'controller' to cause
infections. This has opened new opportunities for us to investigate further
into a new range of therapeutic targets for fungal infections," explained
Wang.
In the same issue of Developmental Cell, the team's work was given an expert
mention by a leading C. albicans researcher, Dr. Peter Sudbery, stating its
importance in bringing awareness of the cellular processes that is necessary
for C. albicans to transform to its infectious state.
In addition, the new knowledge of the detailed interaction of these proteins
with other cellular machineries has also revealed critical information on
how cells in general determine their shape, a fundamental question in
biology as Rga2 and Cdc11 are also found in nearly all eukaryotic organisms.
Largely due to the AIDS pandemic in the last 25 years, the once nearly
harmless and commensal fungus Candida albicans has become one of the most
prevalent microbial pathogens in AIDS patients, causing life-threatening
infections with high death rate, especially in infected children.
References: XD Zheng, RTH Lee, YM Wang, QS Lin, and Y Wang. Phosphorylation
of Rga2, a Cdc42 GAP, by CDK/Hgc1 is crucial for Candida albicans hyphal
growth. The EMBO Journal 26, 3760-3769 (2007).
I Sinha, YM Wang, R Philp, CR Li, WH Yap, and Y Wang Cyclin-Dependent
Kinases Control Septin Phosphorylation in Candida albicans Hyphal
Development. Developmental Cell 13: 421-432 (2007).
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1: Cancer Res. 2009 Mar 15;69(6):2260-8. Epub 2009 Mar 10. Links
Bicarbonate increases tumor pH and inhibits spontaneous metastases.
Robey IF, Baggett BK, Kirkpatrick ND, Roe DJ, Dosescu J, Sloane BF, Hashim 
AI, Morse DL, Raghunand N, Gatenby RA, Gillies RJ.
Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA.
The external pH of solid tumors is acidic as a consequence of increased 
metabolism of glucose and poor perfusion. Acid pH has been shown to 
stimulate tumor cell invasion and metastasis in vitro and in cells before 
tail vein injection in vivo. The present study investigates whether 
inhibition of this tumor acidity will reduce the incidence of in vivo 
metastases. Here, we show that oral NaHCO(3) selectively increased the pH of 
tumors and reduced the formation of spontaneous metastases in mouse models 
of metastatic breast cancer. This treatment regimen was shown to 
significantly increase the extracellular pH, but not the intracellular pH, 
of tumors by (31)P magnetic resonance spectroscopy and the export of acid 
from growing tumors by fluorescence microscopy of tumors grown in window 
chambers. NaHCO(3) therapy also reduced the rate of lymph node involvement, 
yet did not affect the levels of circulating tumor cells, suggesting that 
reduced organ metastases were not due to increased intravasation. In 
contrast, NaHCO(3) therapy significantly reduced the formation of hepatic 
metastases following intrasplenic injection, suggesting that it did inhibit 
extravasation and colonization. In tail vein injections of alternative 
cancer models, bicarbonate had mixed results, inhibiting the formation of 
metastases from PC3M prostate cancer cells, but not those of B16 melanoma. 
Although the mechanism of this therapy is not known with certainty, low pH 
was shown to increase the release of active cathepsin B, an important matrix 
remodeling protease.
PMID: 19276390 [PubMed - in process]
gg 

 Biochem Pharmacol. 2003 Oct 1;66(7):1219-29
 riporto qui quello che avevo gia' evidenziato 
 a suo tempo (Date: Mon, 1 Sep 2008) (*)
   Uno studio sperimentale condotto su 4 gruppi di topi affetti da
tumore condotto con lo scopo di valutare il possibile incremento di
efficacia   terapeutica di 3 agenti chemioterapici per alcalinizzazione
con   bicarbonato di sodio mostra,  che il bicarbonato *da solo* non
ha nessun effetto nel contrastare la crescita tumorale.
 
    A pag. 1222 e 1228 dell'articolo di cui sopra tra i risultati
    e nella  discussione si legge:
 
   "Neither acute nor cronic NaHCO3 alone altered tumor growth rates".
 
 [*] scorrere in fondo:
 
http://tinyurl.com/kvcft7
 C U Soon ;-)
 

 
Devi tradurlo, gg ignora anche l'inglese!