Because acidic regions may coexist with hypoxic regions in solid tumors, we have studied the effect of acidic extracellular pH on the abilities of misonidazole, etanidazole, and cis-diamminedichloroplatinum(II) (CDDP) to radiosensitize hypoxic FSaIIC cells in vitro. For 1-h exposures to misonidazole prior to and during irradiation, the sensitizer enhancement ratios (SERs) were 2.10 ± 0.18 at 1 mM drug and 2.50 ± 0.16 at 5 mM drug at pH 7.40 but only 1.90 ± 0.14 and 2.30 ± 0.14, respectively, at pH 6.45. For entanidazole the SERs at pH 7.40 at 1 and 5 mM drug were 1.90 ± 0.13 and 2.40 ± 0.18, respectively, but only 1.25 ± 0.13 and 1.70 ± 0.17, respectively, at pH 6.45. The decrease in the SERs for both 2-nitroimidazole compounds was statistically significant (P < 0.01). When CDDP at concentrations of 1 and 5 μM was tested, SERs of 1.30 ± 0.15 and 1.60 ± 0.18, respectively, were observed at pH 7.40, and the increase was not significant at pH 6.45 (1.35 ± 0.15 and 1.80 ± 0.19, respectively). The cellular levels of misonidazole, etanidazole, and CDDP did not vary significantly at the environmental conditions tested. These results demonstrate that pH is a potentially important variable in the action of hypoxic cell radiosensitizing drugs and suggest that future evaluations of such agents should test the effects of pH.

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