title: Differential protective effects of varying degrees of hypoxia on the cytotoxicities of etoposide and bleomycin.
abstract: Oxygen is thought to be involved both directly and indirectly in the mechanisms of action of several anti-cancer agents. We studied the effects of various oxygen concentrations on the cytotoxicities of the following drugs: bleomycin (BLM), etoposide (VP-16), doxorubicin (DOX), and mitomycin C (MMC). Human sarcoma cells, MESSA, were exposed to drug for 1 h at one of several oxygen concentrations: less than 1%, 2.5%, 5%, 21%, and 95%. Cytotoxicity was assessed by cellular incorporation of 3H-thymidine into DNA 5 days after drug exposure. Control experiments varying oxygen concentration without drugs demonstrated toxicity only at the highest concentration (95%). Three different responses of drug sensitivity to varying oxygen tensions were observed. BLM, which has been shown to utilize oxygen as a substrate in generating free radicals and producing DNA scission, demonstrated a progressive increase in cytotoxicity over the entire range of increasing oxygen concentrations. This is consistent with the model of a BLM-cation-oxygen complex and catalytic reduction of oxygen. VP-16, which also produces DNA strand breakage but by interaction with topoisomerase II, exhibited a threshold response. VP-16 toxicity was ameliorated by anoxic conditions (less than 1% O2), but not by oxygen concentrations of 2.5%-95%. The reason for this protective effect of anoxia with VP-16 is not clear. In contrast, acute anoxia had no effect on the cytotoxicities of DOX and MMC. We conclude that acute hypoxia protects cells from both BLM and VP-16 but that the nature of that protection is different. VP-16 toxicity is blunted only by severe anoxia, whereas BLM exhibits a dose response effect over the entire range of oxygen concentrations.
mesh_terms: D001761:Bleomycin / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D016685:Mitomycin; D008937:Mitomycins / Q000494:pharmacology; D008940:Mitotic Index; D010100:Oxygen / Q000494:pharmacology*; D012509:Sarcoma / Q000473:pathology
chemical_list: D008937:Mitomycins; D001761:Bleomycin; D016685:Mitomycin; D005047:Etoposide; D004317:Doxorubicin; D010100:Oxygen