Measurements of DNA damage in Chinese hamster cells treated with equitoxic and equimutagenic doses of nitrosoureas.
The DNA of V-79 Chinese hamster cells was examined by alkaline elution following treatment of cultures with eight different nitrosoureas. Drug incubations were performed under consistent biological conditions of equal toxicity and equal mutation induction at the hypoxanthineguanine phosphoribosyltransferase locus. The goals of this study were to determine whether DNA damage could be detected in cells treated with biologically relevant doses of nitrosoureas and to determine whether the type and number of observed DNA lesions could be correlated with the cytotoxic and mutagenic effects of the drugs. All of the compounds tested produced, to some degree, lesions that were observed as DNA strand breaks upon exposure of the DNA to alkali. The levels of DNA strand breaks and/or alkali-labile lesions were comparable for all of the drugs at the equimutagenic doses. DNA cross-linking was observed at both the equitoxic and the equimutagenic concentrations of the haloethylnitrosoureas, but cross-linking was not observed with methylnitrosourea or streptozotocin. Methylnitrosourea and streptozotocin required approximately 40 times the drug concentration to produce toxicity equal to the haloethylnitrosoureas. These data suggest that the ability to cross-link DNA confers increased cytotoxicity to the haloethylnitrosoureas.
D002330:Carmustine / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003485:Cyanates / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005018:Ethyl Chloride / Q000031:analogs & derivatives / Q000627:therapeutic use; D008130:Lomustine / Q000494:pharmacology; D008770:Methylnitrosourea / Q000494:pharmacology; D009154:Mutation / Q000187:drug effects; D009607:Nitrosourea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D013311:Streptozocin / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
D003485:Cyanates; D009607:Nitrosourea Compounds; D005018:Ethyl Chloride; D013311:Streptozocin; D008770:Methylnitrosourea; D008130:Lomustine; D004247:DNA; D002330:Carmustine