ROLE OF MUTAGENESIS IN CARCINOGENESIS

大多数化学致癌物诱导DNA损伤，并在特定条件下具有诱变性。 遗传位点;然而，某些致癌物（包括人类致癌物） 己烯雌酚、石棉、砷剂和苯）通常不会诱发 基因突变 我们已经研究了这些化学物质的活性， 致癌但不致突变，以诱导形态转化， 叙利亚仓鼠胚胎细胞中的基因突变和染色体突变， 文化 我们以前曾报道，己烯雌酚（DES）诱导 在特定遗传基因座不存在突变的情况下进行转化。 此外，我们提出DES的作用机制是 与其诱导染色体数目变化的能力有关，即， 非整倍性。 我们现在已经证明DES具有秋水仙胺样活性， 它会破坏微管组织。 聚合抑制 因此，纺锤体微管是DES诱导的细胞凋亡的可能机制。 非整倍体和可能的细胞转化根据我们的假设。 这一假设进一步得到了我们观察到的秋水仙胺和 硫酸长春新碱是两种众所周知的非整倍体诱导剂， 形态转化的诱导剂。 另一种机制 还对重要的人类致癌物石棉进行了检查。 的能力 石棉和其他矿物纤维诱导细胞转化， 观察到依赖于纤维尺寸，类似于体内发现的结果 在间皮瘤诱导的研究中。 我们建议石棉 由于其诱导染色体的能力， 被处理细胞的变化。 我们最近发现石棉纤维 诱导分裂后期异常，表明直接的物理相互作用 在有丝分裂过程中，纤维与染色体的结合发生。 在 石棉诱导的细胞系染色体非随机变化， 这些结果进一步支持了我们的假设 石棉引起的转化机制是由于 染色体突变 因此，我们的研究结果表明， 致癌物诱发的非整倍体。

Most chemical carcinogens induce DNA damage and are mutagenic at specific genetic loci; however, certain carcinogens (including the human carcinogens diethylstilbestrol, asbestos, arsenicals and benzene) usually do not induce gene mutations. We have examined the activity of these chemicals, proposed as carcinogenic but not mutagenic, to induce morphological transformation, gene mutations and chromosome mutations in Syrian hamster embryo cells in culture. We have reported previously that diethylstilbestrol (DES) induces transformation in the absence of mutations at specific genetic loci. Furthermore, we have proposed that the mechanism of action of DES is related to its ability to induce numerical chromosome changes, i.e., aneuploidy. We have now shown that DES has colcemid-like activity in that it disrupts microtubule organization. Inhibition of polymerization of spindle microtubules is therefore a possible mechanism for DES-induced aneuploidy and possibly cell transformation according to our hypothesis. This hypothesis is further supported by our observations that colcemid and vincristine sulfate, two well-known inducers of aneuploidy, are also inducers of morphological transformation. The mechanism of another important human carcinogen, asbestos, was also examined. The ability of asbestos and other mineral fibers to induce cell transformation was observed to depend on fiber dimension similar to the results found in vivo in studies on mesothelioma induction. We have proposed that asbestos induces cell transformation due to its ability to induce chromosomal changes in the treated cells. We recently found that asbestos fibers induce anaphase abnormalities indicating that a direct physical interaction of the fibers with chromosomes occurs during mitosis. In the asbestos-induced cell lines a nonrandom chromosome change, trisomy of chromosome 11, was found. These results further support our hypothesis that the mechanism of asbestos-induced transformation is due to a chromosomal mutation. Thus, our results suggest an important role for carcinogen-induced aneuploidy in carcinogenesis.