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

点击翻译按钮获取中文摘要

Fecapentaene-12 (fec-12), a possible initiating agent in colon cancer, is cytotoxic and mutagenic in human fibroblasts. DNA repair-deficient fibroblasts are more sensitive than normal fibroblasts to both these effects, which are dose dependent. Further studies with human fibroblasts have shown that fec-12 is a potent inducer of DNA single strand breaks (SSB) and sister chromatid exchanges (SCE). Accumulation of SSB as a result of inhibition of the polymerase component of the excision repair mechanism suggests that SSB may be mediated in part by DNA repair mechanisms. Autoradiographic techniques have shown that fec-12 is capable of inducing unscheduled DNA synthesis (UDS) in normal human fibroblasts. 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. This is of interest because it is known that DNA cross-linking agents are potent inducers of SCE. Fec-12 induces plasmid mutations in excision repair-deficient AB 1886 (uvra-) but not AB 2463 (recA-) or wild type strains of E. coli. These results suggests that direct DNA damage and DNA excision repair mechanisms are involved in fec-12-induced mutations. The restriction enzyme digest profile in 10% of plasmids isolated from fec-12-induced mutants showed marked differences from control plasmids, indicating that fec-12 can induce DNA rearrangements.