Cytotoxic potential of monoalkylation products between mitomycins and DNA: studies of decarbamoyl mitomycin C in wild-type and repair-deficient cell lines.
Hypoxic regions in solid neoplasms have been associated with tumor recurrence and resistance to several cancer treatment modalities including radiation therapy. Various strategies have been designed to target these resistant cells, including the use of the bioreductive alkylating agent mitomycin C (MC), which exerts preferential cytotoxicity under hypoxic conditions in most cell lines. Analyses of the mechanism of action of MC indicate that this drug can form cross-links with DNA; it is currently thought that this bisadduct is the critical lesion responsible for inhibiting DNA synthesis. Computer-generated models suggest that the MC adduct fits snugly into the minor groove of B-DNA without imposing major distortion on the structure of the DNA molecule. To gain additional insight into the role of cross-linkage in the cytotoxicity of MC, we studied the analogue, decarbomoyl mitomycin C (DMC). The structure of DMC is identical to that of MC with the exception of the substitution of the carbamoyl group at the C-10 position by a nonalkylating hydroxyl group (-OH); this alteration would be expected to prevent DMC from forming bisadducts with DNA. In chemical systems, DMC produces only DNA monoadducts. If indeed it is the MC-DNA cross-links which are responsible for cell kill, one would predict DMC to be less cytotoxic than MC. However, tissue culture studies using DMC revealed that DMC is at least as toxic as MC to EMT6 mouse mammary tumor cells and to wild-type AA8 Chinese hamster ovary (CHO) cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)
Rockwell
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Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520-8040, USA.
Kim
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D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D016466:CHO Cells; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects*; D006224:Cricetinae; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair; D016685:Mitomycin / Q000378:metabolism / Q000494:pharmacology*; D008937:Mitomycins; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D008937:Mitomycins; C067795:10-decarbamoylmitomycin C; D016685:Mitomycin