ROLE OF MUTAGENESIS IN CARCINOGENESIS

大多数化学致癌物会引起DNA损伤，并在特定情况下具有诱变性

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.