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

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...

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Bibliographic Details
Published in:Biochemical pharmacology 1999-02, Vol.57 (3), p.309-312
Main Authors: Raghunand, Natarajan, Altbach, Maria I., van Sluis, Robert, Baggett, Brenda, Taylor, Charles W., Bhujwalla, Zaver M., Gillies, Robert J.
Format: Article
Language:English
Subjects:
3-aminopropylphosphonate
31P magnetic resonance spectroscopy
Animals
Antineoplastic agents
Biological and medical sciences
breast carcinoma
Cell Membrane - drug effects
Drug Resistance, Neoplasm
Female
General aspects
Humans
Hydrogen-Ion Concentration
Magnetic Resonance Spectroscopy - methods
Mammary Neoplasms, Experimental - drug therapy
MCF-7
Medical sciences
Mice
Mice, SCID
Neoplasm Transplantation
Pharmacology. Drug treatments
Phosphorus
Transplantation, Heterologous
tumor pH
xenograft
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Summary: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 (p K 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 p K 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.
ISSN:0006-2952
1873-2968
DOI:10.1016/S0006-2952(98)00306-2