Summary
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.
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16 November 2011
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References
Altan, N., Chen, Y., Schindler, M. & Simon, S. M. (1998). Defective acidification in human breast tumor cells and implications for chemotherapy. J Exp Med 187: 1583–1598.
Bearman, S. I., Overmoyer, B. A., Bolwell, B. J., Taylor, C. W., Shpall, E. J., Cagnoni, P. J., Mechling, B. E., Ronk, B., Baron, A. E., Purdy, M. H., Ross, M. & Jones, R. B. (1997). High-dose chemotherapy with autologous peripheral blood progenitor cell support for primary breast cancer in patients with 4–9 involved axillary lymph nodes. Bone Marrow Transplant 20: 931–937.
Cesano, A., Visonneau, S., Rovera, G. & Santoli (1997). Synergistic effects of adriamycin and TALL-104 cell therapy against a human gastric carcinoma in vivo. Anticancer Res 17: 1887–1892.
Corbett, T. H., Roberts, B. J., Trader, M. W., Laster, W. R. Jr, Griswold, D. P. J. & Schabel, F. M. Jr (1982). Response of transplantable tumors of mice to anthracenedione derivatives alone and in combination with clinically useful agents. Cancer Treat Rep 66: 1187–1200.
Durand, R. E. & LePard, N. E. (1997). Tumour blood flow influences combined radiation and doxorubicin treatments. Radiother Oncol 42: 171–179.
Gillies, R. J. & Deamer, D. W. (1978). Intracellular pH: methods and applications. Curr Top Bioenergetics 9: 63–87.
Gillies, R. J., Didier, N. & Denton, M. (1986). Determination of cell number in monolayer cultures. Analyt Biochem 159: 109–113.
Gillies, R. J., Liu, Z. & Bhujwalla, Z. (1994). 31P-MRS measurements of extracellular pH of tumors using 3-aminopropylphosphonate. Am J Physiol 195–203
Griffiths, J. R. (1991). Are cancer cells acidic?. Br J Cancer 64: 425–427.
Liu, C., Lambert, J. M., Teicher, B. A., Blattler, W. A. & O’Connor, R. (1996). Cure of multidrug-resistant human B-cell lymphoma xenografts by combinations of anti-B4-blocked ricin and chemotherapeutic drugs. Blood 87: 3892–3898.
Martinez-Zaguilan, R., Martinez, G. M., Lattanzio, F. & Gillies, R. J. (1991). Simultaneous measurement of intracellular pH and Ca2+ using the fluorescence of SNARF-1 and Fura-2. Am J Physiol 260: C297–C307.
McCoy, C. L., Parkins, C. S., Chaplin, D. J., Griffiths, J. R., Rodrigues, L. M. & Stubbs, M. (1995). The effect of blood flow modification on ontra- and extracellular pH measured by 31P magnetic resonance spectroscopy in murine tumours. Br J Cancer 72:
Negendank, W. (1992). Studies of human tumors by MRS: a review. NMR Biomed 5: 303–324.
Ordidge, R. J., Bowley, R. M. & McHale, G. (1988). A general approach to selection of multiple cubic volume elements using the ISIS technique. Magn Reson Med 8: 323–331.
Paine-Murrieta, G. D., Taylor, C. W., Curtis, R. A., Lopez, M. H. A., Dorr, R. T., Johnson, C. S., Funk, C. Y., Thompson, F. & Hersh, E. M. (1997). Human tumor models in the severe combined immune deficient (Scid) mouse. Cancer Chemother Pharmacol xx: 1–6.
Passfall, J., Pai, J., Spies, K. P., Haller, H. & Luft, F. C. (1997). Effect of water and bicarbonate loading in patients with chronic renal failure. Clin Nephrol 47: 92–98.
Polin, L., Valeriote, F., White, K., Panchapor, C., Pugh, S., Knight, J., LoRusso,, Hussain, M., Liversidge, E., Peltier, N., Golakoti, T., Patterson, G., Moore & Corbett, T. H. (1997). Treatment of human prostate tumors PC-3 and TSU-PR1 with standard and investigational agents in SCID mice. Invest New Drugs 15: 99–108.
Raghunand, N., Altbach, M. I., Van Sluis, R., Baggett, B., Taylor, C. W., Bhujwalla, Z. M. & Gillies, R. J. (1999a). Plasmalemmal pH-gradients in drug-sensitive and drug-resistant MCF-7 human breast carcinoma xenografts measured by 31P MR spectroscopy. Biopharm Pharmacol 57: 309–312.
Raghunand, N., Martinez-Zaguilan, R., Wright, S. H. & Gillies, R. J. (1999b). pH and drug resistance II: turnover of acidic vesicles and resistance to weakly basic chemotherapeutic drugs. Biochem Pharmacol 57: 1047–1058.
Roos, A. (1978). Weak acids, weak bases, and intracellular pH. Respir Physiol 33: 27–30.
Simon, S. M. & Schindler, M. (1994). Cell biological mechanisms of multidrug resistance in tumors. Proc Natl Acad Sci USA 91: 3497–3504.
Tannock, I. F. & Rotin, D. (1989). Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 49: 4373–4384.
Taylor, C. W., Dalton, W. S., Parrish, P. R., Gleason, M. C., Bellamy, W. T., Thompson, F. H., Roe, D. J. & Trent, J. M. (1991). Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line. Br J Cancer 63: 923–929.
Verbitsky, O., Mizrahi, J., Levin, M. & Isakov, E. (1997). Effect of ingested sodium bicarbonate on muscle force, fatigue, and recovery. J Appl Physiol 83: 333–337.
Warburg, O. (1956). On the origin of cancer cells. Science 123: 309–314.
Wike-Hooley, J. L., Haveman, J. & Reinhold, H. S. (1984). The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol 2: 343–366.
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Raghunand, N., He, X., Sluis, R. et al. Enhancement of chemotherapy by manipulation of tumour pH. Br J Cancer 80, 1005–1011 (1999). https://doi.org/10.1038/sj.bjc.6690455
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DOI: https://doi.org/10.1038/sj.bjc.6690455
Keywords
- doxorubicin
- acid-base balance
- chemotherapy
- MRS
- bicarbonate
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