Mechanism of oncogenicity for bioreductive drugs.
The oncogenic transforming potential of a series of bifunctional bioreductive drugs were examined under either aerated or hypoxic conditions to assess the contribution of side chains or nitroreduced products toward their carcinogenic mechanisms. Both the cytotoxicity and transforming effects of these drugs increased as a function of dose under hypoxia. In air and at doses that resulted in comparable cell killing, RSU-1069 and RB-88716 were substantially more oncogenic than RSU-1164 or SR-4233. In nitrogen, the oncogenicity of SR-4233 as a function of survival increased, whereas the transforming effect for the aziridine-containing drugs, RSU-1969 and RB-88716, decreased. These data suggest that, among the drugs examined, the transforming moiety in air is largely a function of the alkylating aziridine group. In hypoxia, the reduction of the nitro-moiety to the corresponding active metabolites may be responsible for much of the transformation observed.
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Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
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Hall
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D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001388:Aziridines / Q000633:toxicity; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives / Q000633:toxicity; D016609:Neoplasms, Second Primary; D009581:Nitrofurans / Q000633:toxicity; D011355:Prodrugs / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000633:toxicity*; D012306:Risk; D000077704:Tirapazamine; D014227:Triazines / Q000633:toxicity
C049944:1-(2-nitro-1-imidazoly)-3-(2,3-dimethylaziridino)-2-propanol; D000970:Antineoplastic Agents; D001388:Aziridines; D009581:Nitrofurans; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; D014227:Triazines; C066399:RB 88716; D000077704:Tirapazamine; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole