THERMOSENSITIZATION BY LOWERING INTRACELLULAR PH WITH 5-(N-ETHYL-N-ISOPROPYL) AMILORIDE

It has previously been reported that amiloride, a diuretic drug, sensi tizes cells to hyperthermia by inhibiting the Na+/H+ exchange through the plasma membrane and thus decreasing the intracellular pH (pHi), pa rticularly in a low extracellular pH (pHe) environment. In the present study, the efficacy of 5-(N-ethyl-N-isopropyl) amiloride (EIPA), an a nalog of amiloride, to lower the pHi and sensitize tumor cells to hype rthermia was investigated. It was observed that 10 muM EIPA was as eff ective as 500 muM amiloride to lower the pHi and to increase the therm al sensitivity of SCK tumor cells in vitro. The fact that lowering the pHi and increasing thermal sensitivity of tumor cells by EIPA are mor e pronounced in acidic medium suggests that the acidic intratumor envi ronment may be exploited to selectively increase the thermal damage in tumors relative to normal tissues by EIPA or its analogs.