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. 1999 Jun;80(7):1005–1011. doi: 10.1038/sj.bjc.6690455

Enhancement of chemotherapy by manipulation of tumour pH

N Raghunand 1,#, X He 1,#, R van Sluis 1, B Mahoney 1, B Baggett 1, C W Taylor 1, G Paine-Murrieta 1, D Roe 1, Z M Bhujwalla 2, R J Gillies 1
PMCID: PMC2363059  PMID: 10362108

Abstract

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. © 1999 Cancer Research Campaign

Keywords: doxorubicin, acid-base balance, chemotherapy, MRS, bicarbonate

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Selected References

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