Reduction of tumour intracellular pH and enhancement of melphalan cytotoxicity by the ionophore Nigericin.
Nigericin is an ionophore which permits the influx of H+ ions into cells 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 31P magnetic resonance spectroscopy. Nigericin at 2.5 mg/kg i.p. reduced pHi by 0.2-0.3 pH unit in the KHT and RIF-I tumours but had no effect on pHi in the SCCVII/Ha tumour. In vitro studies have shown that reduced pH can increase the toxicity of melphalan. Therefore, the anti-tumour effect of combining nigericin with melphalan was also examined. Nigericin at 2.5 mg/kg i.p. given before various doses of melphalan resulted in substantial delay in growth of the RIF-I tumour over that induced by melphalan alone. This observation was confirmed by an in vivo/in vitro excision assay, where nigericin given before melphalan produced a 30-fold increase in cell killing. By contrast, no enhancement of melphalan-induced cell killing by nigericin was observed in the KHT and SCCVII/Ha tumours, using growth delay and in vivo/in vitro excision assays, respectively.
Wood
P J
PJ
MRC Radiobiology Unit, Didcot, Oxon, UK.
Sansom
J M
JM
Newell
K
K
Tannock
I F
IF
Stratford
I J
IJ
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006863:Hydrogen-Ion Concentration; D008297:Male; D008558:Melphalan / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009550:Nigericin / Q000494:pharmacology*
D008558:Melphalan; D009550:Nigericin