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

Fecapentaene-12(FEC-12)是一种可能的结肠癌启动剂， 对人成纤维细胞的细胞毒性和致突变性。DNA修复缺陷 成纤维细胞比正常成纤维细胞对这两种物质都更敏感。 效应，这是剂量依赖的。人成纤维细胞的进一步研究 已经证明FEC-12是DNA单链断裂的有效诱导剂 (SSB)和姐妹染色单体交换(SCE)。SSB的积累作为一种 切除修复的聚合酶成分被抑制的结果 机制提示SSB可能部分由DNA修复所介导 机械装置。放射自显影技术已经表明FEC-12能够 在正常人成纤维细胞中诱导程序外DNA合成(UDS)。 这些结果表明FEC-12具有遗传毒性、致突变性和致病作用。 直接对人类细胞造成DNA损伤。进一步支持这一假设 FEC-12是结肠癌的启动剂来自于一项发现 该化合物可诱导小鼠Balb 3T3细胞转化。 研究FEC-12-DNA损伤机制的质粒分析表明 链间DNA交联和直接SSB的证据。这是 感兴趣是因为我们知道DNA交联剂是有效的 姐妹染色单体互换的诱导物。FEC-12在切除过程中诱导质粒突变 修复缺陷的AB 1886(uvra-)，但不是AB 2463(recA-)或野生型 大肠埃希菌菌株。这些结果表明，DNA直接损伤和DNA 切除修复机制参与了FEC-12诱导的突变。这个 猪瘟病毒分离的10%质粒的限制性内切酶酶切图谱 FEC-12诱导的突变体与对照质粒有显著差异， 提示FEC-12可诱导DNA重排。

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.