Enhancement of chemotherapy by manipulation of tumour pH

N. Raghunand, X. He, R. Van Sluis, B. Mahoney, B. Baggett, C. W. Taylor, G. Paine-Murrieta, D. Roe, Z. M. Bhujwalla, R. J. Gillies

Research output: Contribution to journalArticle

219 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1005-1011
Number of pages7
JournalBritish journal of cancer
Volume80
Issue number7
DOIs
StatePublished - May 29 1999

Keywords

  • Acid-base balance
  • Bicarbonate
  • Chemotherapy
  • Doxorubicin
  • MRS

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Raghunand, N., He, X., Van Sluis, R., Mahoney, B., Baggett, B., Taylor, C. W., Paine-Murrieta, G., Roe, D., Bhujwalla, Z. M., & Gillies, R. J. (1999). Enhancement of chemotherapy by manipulation of tumour pH. British journal of cancer, 80(7), 1005-1011. https://doi.org/10.1038/sj.bjc.6690455