Cytotoxicity of mitomycin C on clonogenic human carcinoma cells is not enhanced by hypoxia.
The bioreductive alkylating agent mitomycin C (mitomycin) has been shown to have greater activity under hypoxic than oxic conditions on murine cell lines such as the EMT-6 fibrosarcoma cell line. Solid tumors are known to contain hypoxic cells and are relatively resistant to ionizing radiation and some chemotherapeutic agents. We tested the cytotoxicity of mitomycin against fresh biopsies of human carcinomas under both hypoxic and oxic conditions in the human tumor clonogenic assay (HTCA). Additionally, we examined the metabolism of mitomycin by sonicates of the murine EMT-6 cells and the human WiDR colon carcinoma cells. We confirmed that under our clonogenic assay conditions the EMT-6 cell line was more sensitive to mitomycin under hypoxic than oxic conditions. Additionally, we established that EMT-6 cells also metabolize mitomycin at a more rapid rate under hypoxic than oxic conditions. However, these effects of hypoxia on mitomycin activity were not demonstrable for the human WiDR colon cancer cell line. In addition to these findings, the cytotoxicity of mitomycin was either unchanged or reduced under hypoxic conditions for ten fresh human tumors tested for mitomycin sensitivity in HTCA. Based on these observations, we conclude that the potentiating effect of hypoxia on mitomycin metabolism and biological activity may be peculiar to the murine EMT-6 and S-180 cell lines and that mitomycin C is not likely to have differential efficacy against hypoxic human carcinoma cells.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use*; D002460:Cell Line; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D051379:Mice; D016685:Mitomycin; D008937:Mitomycins / Q000378:metabolism / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010100:Oxygen; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000378:metabolism; D014410:Tumor Stem Cell Assay
D000903:Antibiotics, Antineoplastic; D008937:Mitomycins; D016685:Mitomycin; D010100:Oxygen