Plasmalemmal pH-gradients in drug-sensitive and drug-resistant MCF-7 human breast carcinoma xenografts measured by 31P magnetic resonance spectroscopy

Natarajan Raghunand, Maria I. Altbach, Robert Van Sluis, Brenda Baggett, Charles W. Taylor, Zaver M. Bhujwalla, Robert J. Gillies

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

31P Magnetic resonance spectroscopy (MRS) was employed to investigate tumor pH in xenografts of drug-sensitive and drug-resistant MCF-7 human breast carcinoma cells. Measured extracellular pH values were found to be lower than the intracellular pH in all three tumor types investigated. The magnitude of this acid-outside plasmalemmal pH gradient increased with increasing tumor size in tumors of two drug-resistant variants of MCF-7 cells, but not in tumors of the parent (drug-sensitive) cells. The partitioning of weak-base or weak-acid drug molecules across the plasma membrane of a tumor cell is dependent upon the acid-dissociation constant (pK(a)) of the drug as well as the plasmalemmal pH gradient. A large acid-outside pH gradient, such as those seen in MCF-7 xenografts, can exert a protective effect on the cell from weak-base drugs such as anthracyclines and Vinca alkaloids, which have pK(a) values of 7.5 to 9.5. The possibility of enhancing the therapeutic efficacy of weak-base drugs by dietary or metabolic manipulation of the extracellular pH, in order to reduce or reverse the plasmalemmal pH gradient, deserves investigation. Copyright (C) 1999 Elsevier Science Inc.

Original languageEnglish (US)
Pages (from-to)309-312
Number of pages4
JournalBiochemical Pharmacology
Volume57
Issue number3
DOIs
StatePublished - Feb 1 1999

Keywords

  • 3-Aminopropylphosphonate
  • Breast carcinoma
  • MCF-7
  • P magnetic resonance spectroscopy
  • Tumor pH
  • Xenograft

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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