Branimir I. Sikic, M. D.

Publication Details

  • DIFFERENTIAL PROTECTIVE EFFECTS OF VARYING DEGREES OF HYPOXIA ON THE CYTOTOXICITIES OF ETOPOSIDE AND BLEOMYCIN CANCER CHEMOTHERAPY AND PHARMACOLOGY Yamauchi, T., Raffin, T. A., Yang, P., Sikic, B. I. 1987; 19 (4): 282-286

    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.

    View details for Web of Science ID A1987J198800003

    View details for PubMedID 2439223

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