Carcinogen specificity in the activation of transforming genes by direct-acting alkylating agents

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Abstract
DNAs from rat nasal and mouse skin carcinomas and fibrosarcomas induced by the alkylating agents methylmethane sulfonate (MMS), β-propiolactone (BPL), and dimethyl-carbamyl chloride (DMCC) were tested for their ability to transform NIH3T3 cells by DNA transfection. Each of eight MMS-induced rat nasal carcinomas and two of five BPL-induced mouse skin tumors were positive in the transfection assay while all of four fibrosarcomas and six carcinomas induced by DMCC were negative. Anchorage independent growth, tumorigenicity in nude mice, and secondary transfection confirmed the transformed phenotype of the positive transfectants. The transfectants from MMS-induced tumor DNAs did not contain restriction fragments homologous to rat H-, K- or N-ras oncogenes although exogenous (rat) tumor-derived DNA sequences were detected in transfectant genomes by Southern analysis. In contrast a BPL-induced mouse skin tumor showed evidence of containing activated H-ras. These results suggest specificity among causal carcinogens for activation of transforming genes in experimental tumors.