The effects of amiloride (an inhibitor of Na+/ H+ antiport), DIDS (an inhibitor of Na+-coupled and Na+-independent <tex-math>${\rm HCO}_{3}^{-}/{\rm Cl}-$</tex-math> exchange) and nigericin (<tex-math>${\rm K}^{+}/{\rm H}^{+}$</tex-math> ionophore) alone and in various combinations on the intracellular pH ( pH i) and thermosensitivity of SCK tumor cells were studied. Hyperthermia alone at 43°C for 2 h decreased pH i of SCK cells by 0.15-0.20 pH units, as measured fluorometrically using the pH-sensitive dye BCECF. When the cells were treated with 0.5 mM amiloride at 37°C, the pH i declined by 0.10-0.15 pH units at an extracellular pH ( pH e) of both 7.2 and 6.6. Amiloride at 0.5 mM enhanced the thermal damage to SCK cells at pH e 6.6 but not at pH e 7.2. DIDS alone at 0.1 mM exerted no effect on pH i or cellular thermosensitivity. DIDS, however, enhanced the effects of amiloride in decreasing pH i and in increasing the thermoresponse of SCK cells, particularly at pH e 6.6. Treatment of the cells with nigericin at 0.1-1.0 μg/ml lowered the pH i and enhanced the thermosensitivity of the cells in a dose-dependent manner. Reductions in pH i and increases in thermosensitivity by nigericin at the lower concentration at pH e 6.6 were far greater than at pH e 7.2. When a mixture of 1.0 μg/ml nigericin, 0.5 mM amiloride, and 0.1 mM DIDS was present in the medium, the pH i rapidly decreased by about 0.3 and 0.4 pH units at pH e 7.2 and 6.6, respectively. This drug combination was also extremely effective in sensitizing SCK cells to heat, particularly at pH e 6.6. The fact that the thermosensitization by these drugs at pH e 6.6 is more pronounced than at pH e 7.2 and that intratumor environments are known to be acidic strongly suggested that it may then be possible to enhance the thermal damage with such drugs preferentially in tumors relative to normal tissues.

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