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

P-31 Magnetic resonance spectroscopy (MRS) was employed to investigate tumo r pH in xenografts of drug-sensitive and drug-resistant MCF-7 human breast carcinoma cells. Measured extracellular pH values were found to be lower th an the intracellular pH in all three tumor types investigated. The magnitud e of this acid-outside plasmalemmal pH gradient increased with increasing t umor 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-ba se or weak-acid drug molecules across the plasma membrane of a tumor cell i s 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 hav e 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 ext racellular pH, in order to reduce or reverse the plasmalemmal pH gradient, deserves investigation. (C) 1998 Elsevier Science Inc.