Abstract G14

Foreign body carcinogenesis with silicone implants is associated with DNA strand breaks and p53 mutations
James, S.J., Pogribna, M., Pogribny, I., Miller, B.J., Division of Biochemical Toxicology, NCTR, Jefferson, AR 72079

Foreign body carcinogenesis is a classic model of multistage carcinogenesis in rats. Silicone elastomer and positive control cellulose acetate implants were placed subcutaneously in F344 rats and the acute inflammatory response and chronic fibrotic reaction were evaluated by in situ immuno- histochemistry. Unrepaired DNA strand breaks were found within spindle cells of the fibrotic capsule. After 10 months, hyperplastic inflammatory lesions, adjacent to the inner surface of the implant, stained positively for mutant p53 protein. After 12 months, fibrosarcoma in situ developed in 100% of rats implanted with either silicone or cellulose. These results suggest that tumor development is dependent on the foreign body reaction to the physical presence of the implant and independent of the chemical composition. A 40% incidence of p53 mutations (6/15 tumors) was found by PCR-SSCP analysis in tumor DNA. Direct sequencing revealed a hot spot mutation in codon 201 of exon 6 (GCT>CCC; ala>pro) in 50% of the tumors with p53 mutations. These results suggest for the first time that indirect genotoxic mechanisms resulting in p53 mutations are involved in implant-induced foreign body carcinogenesis.