THE BIOLOGICAL ACTIVITY OF FECAPENTAENE-12 IN HUMAN TISSUES AND CELLS

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Fecapentaene-12 (fec-12), a candidate carcinogen in the pathogenesis of colon cancer, is cytotoxic, mutagenic and induces DNA single strand breaks (SSB), sister chromatid exchanges (SEC) and unscheduled DNA synthesis (UDS) in normal human fibroblasts. DNA repair-deficient fibroblasts are more sensitive than normal fibroblasts to the cytotoxic and mutagenic effects, which are dose dependent. Accumulation of SSB as a result of inhibition of the polymerase component of the excision repair mechanism suggests that SSB may by mediated, in part, by DNA repair mechanisms. These results indicate that fec-12 is genotoxic, mutagenic and causes direct DNA damage in human cells. Further support for the hypothesis that fec-12 is an initiating agent in colon cancer comes from the finding that this compound induces transformation in murine Balb 3T3 cells. Plasmid assays investigating the mechanism of fec-12-DNA damage have shown evidence of interstrand DNA cross-links and direct SSB. Fec-12 induces plasmid mutations in excision repair- deficient (uvra-) E. coli. Restriction digest analysis and DNA sequencing of plasmids isolated from mutants indicated that approximately 10% had marked DNA rearrangements. Possible covalent binding of 3H fec-12 to calf thymus DNA is indicated by cesium chloride density gradient centrifugation. Separation of fec-12-DNA adducts by enzymic digestion of DNA and HPLC is currently in progress. Preliminary results with the 32P-postlabelling technique indicate that fec-12-DNA adducts may be present in DNA extracted from human fibroblasts exposed to 3H fec-12 in vitro.