Effect of acidic pH on radiosensitization of FSaIIC cells in vitro by misonidazole, etanidazole, or cis-diamminedichloroplatinum (II).
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-diaminedichloroplatinum(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 etanidazole 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 less than 0.01). When CDDP at concentrations of 1 and 5 microM 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.
Herman
T S
TS
Dana-Farber Cancer Institute, Boston, Massachusetts.
Teicher
B A
BA
Pfeffer
M R
MR
Khandekar
V
V
Chapnick
R M
RM
Kalick
G S
GS
Rabow
A
A
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology*; D017341:Etanidazole; D005354:Fibrosarcoma / Q000473:pathology*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D051379:Mice; D008920:Misonidazole / Q000494:pharmacology*; D009593:Nitroimidazoles / Q000494:pharmacology*; D010100:Oxygen / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017341:Etanidazole; D008920:Misonidazole; D002945:Cisplatin; D010100:Oxygen