ROLE OF MUTAGENESIS IN CARCINOGENESIS

大多数化学致癌物会引起DNA损伤并具有诱变性

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 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. DES has colcemid-like activity and disrupts microtubule organization. Currently, DES-induced aneuploidy is being examined in the newborn mouse genital tract to test whether these changes occur in vivo in the target tissue. The mechanism of another important human carcinogen, asbestos, was also examined. The ability of asbestos and other mineral fibers to induce cell transformation depends on fiber dimension similar to the results in vivo for mesothelioma induction. We have proposed that asbestos induces cell transformation due to its ability to induce chromosomal changes. We have examined the role of proto-oncogene activation in human mesotheliomas, which are associated with asbestos exposure. DNAs from several mesotheliomas were positive for transforming activity in the NIH/3T3 nude mouse tumorigenicity assay. The transforming genes do not appear to be members of the ras gene family and we are currently cloning these genes. Arsenicals are effective inducers of cell transformation. Sodium arsenite and sodium arsenate are inactive as gene mutagens but are potent inducers of chromosome aberrations and also gene amplification. Benzene induces cell transformation but is a weak gene mutagen. This chemical is a very effective inducer of aneuploidy in this system. These results further support our hypothesis that cell transformation involves a chromosomal mutation and suggest an important role for carcinogen-induced aneuploidy in carcinogenesis.