31P MRS Measurements of Tumor pH in Mice Subjected to Acute Metabaolic Alkalosis

Introduction Drug-sensitive and drug-resistant MCF7 tumor xenografts in SCID mice have a lower extracellular pH (pHe) than intracellular pH (pHi) (1). Such an acid-outside pH gradient acts to exclude weak-base species such as the commonly used drugs mitoxantrone and doxorubicin (2). We have recently shown that the extracellular milieu of MCF7 tumor xenografts in SCID mice can be alkalinized by chronic supplementation of the ad lib. water provided to the host animal with 200 mM NaHCO, (3). We have further demonstrated that this alkalinization reverses the direction of the plasmalemmal pH gradient and enhances the effectiveness of doxorubicin against MCF7 xenografis (3). Chronic treatment of mice with NaHCO, can have adverse effects, including hypernatremia, on the host animal. Pharmacokinetic studies of common weak-base chemotherapeutic agents like mitoxantrone show that the lifetime of free drug in the mouse is on the order of several hours (4). Acute alkalinization of tumor-bearing mice with NaHCO, concomitant with drug treatment may therefore be sufficient for enhancing drug effectiveness. We have investigated the intraperitoneal (i.p.) delivery of NaHCO, to transiently alter the (pHe pHi) gradient in tumors.