REDUCTION OF TUMOR INTRACELLULAR PH AND ENHANCEMENT OF MELPHALAN CYTOTOXICITY BY THE IONOPHORE NIGERICIN

Nigericin is an ionophore which permits the influx of H+ ions into cel ls down a concentration gradient, thus reducing intracellular pH (pHi) when extracellular pH is low. The effects of nigericin on the pHi of solid murine tumours in vivo were examined using P-31 magnetic resonan ce spectroscopy. Nigericin at 2.5 mg/kg i.p. reduced pHi by 0.2-0.3 pH unit in the KHT and RIF-1 tumours but had no effect on pHi in the SCC VlI/Ha tumour. In vitro studies have shown that reduced pH can increas e the toxicity of melphalan. Therefore, the anti-tumour effect of comb ining nigericin with melphalan was also examined. Nigericin at 2.5 mg/ kg i.p. given before various doses of melphalan resulted in substantia l delay in growth of the RIF-1 tumour over that induced by melphalan a tone. This observation was confirmed by an in vivo/in vitro excision a ssay, where nigericin given before melphalan produced a 30-fold increa se in cell killing. By contrast, no enhancement of melphalan-induced c ell killing by nigericin was observed in the KHT and SCCVII/Ha tumours , using growth delay and in vivo/in vitro excision assays, respectivel y. (C) 1995 Wiley-Liss, Inc.