Cellular oncogenes have been identified in numerous transformed cells and tumors, and may be activated by environmental carcinogens. This proposal seeks to use a well defined chemical carcinogenesis model - induction of rat nasal carcinomas by inhalation of direct-acting carcinogens - to address the issue of oncogene activation and carcinogenic etiology. Four direct-acting alkylating agents, methylmethane sulfonate (MMS), beta-propiolactone (BPL), dimethylcarbamyl chloride (DMCC) and formaldehyde (HCHO), which have been shown to produce pathologically identical nasal carcinomas by inhalation, and to produce distinct, non-overlapping adducts with DNA, will be used. Transforming genes from tumors induced by these agents will be identified following transformation of NIH 3T3 cells by DNA mediated gene transfer using tumor DNA. Southern blot hybridization of DNA from transformed NIH 3T3 foci with specific oncogene probes will be used to specifically identify the transforming genes in each tumor. Transforming genes from different tumors will also be compared by restriction endonuclease mapping. Preliminary data has indicated that 5 out of 5 rat nasal tumors induced by inhalation of MMS were positive in the NIH 3T3 transfection focus assay. The question of oncogenes activation as a function of tumor progression will be examined in nasal epithelial cell lines established from nasal tissue cultured at various times after in vivo carcinogen exposure. The DNA from established monoclonal populations of preneoplastic cells will be used in transfection to determine the point during the year long latent period at which active oncocones may be identified.
Showing the most recent 10 out of 14 publications
