A comparison of the cytological effects of three hypoxic cell radiosensitizers.
Misonidazole has entered Phase III clinical trials as a hypoxic cell radiosensitizer. Neurotoxocity is the major dose-limiting factor and has prompted the development of two further compounds with reduced lipophilicity and shorter half-life in vivo. Aside from the short-term problem of neurotoxocity, other potential long-term consequences should be considered. Such is the purpose of this investigation where the cytological effects of three radiosensitizers upon oxic and hypoxic Chinese hamster V-79 cells have been examined. Two newer compounds, desmethylmisonidazole and Stanford Research compound 2508, were compared with their clinically used predecessor, misonidazole. Under aerated conditions, cell killing was increased with SR-2508 in a concentration and time dependent manner, so as to exceed by more than three times the level produced by the other two drugs at 5 mM for 72 hours. Cell progression into mitosis was also markedly reduced by as much as 1/10,000 of control values. However, as the three compounds induced similar frequencies of sister chromatid exchange (SCE) and chromosome aberration, the enhanced cytotoxic effect of SR-2508 appears to be mediated via an interphase rather than a post-mitotic cell death. Cells were made hypoxic and treated with the three drugs for 4 hr, then mitoses sequentially collected for 16 hr. The three compounds produced similar levels of cell killing, slowing of cell cycle progression, SCE's and chromosome aberrations, with cycle-specific effect on S and G-1 phase cells for SCE induction. These results indicate that desmethylmisonidazole and misonidazole have similar cytotoxic and clastogenic properties under oxic and hypoxic conditions. SR-2508 is relatively more toxic to aerated cells and may deserve close clinical observation for toxicity to normal tissues; further, all three agents may enhance DNA damage and mutagenesis in tissues that are normally hypoxic.
D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D017341:Etanidazole; D008168:Lung; D008920:Misonidazole / Q000031:analogs & derivatives / Q000494:pharmacology; D009593:Nitroimidazoles / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012854:Sister Chromatid Exchange / Q000187:drug effects
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017341:Etanidazole; D008920:Misonidazole; D001973:Bromodeoxyuridine; C009997:desmethylmisonidazole