Role of Mutagenesis in Carcinogenesis

Barrett, J

Abstract

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 in that it disrupts microtubule organization. DES also can be metabolically activated to mutagenic intermediates which is another mechanism for DES carcinogenicity. Currently, DES- induced DNA adducts are being examined in the treated cells. 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 in vivo for mesothelioma induction. We have proposed that asbestos induces cell transformation due to its ability to induce chromosomal changes in the treated cells. Arsenicals were effective inducers of cell transformation. Sodium arsenite and sodium arsenate were inactive as gene mutagens but were potent inducers of chromosome aberrations and also gene amplification. Benzene induced cell transformation and was a weak gene mutagen. This chemical was a very effective inducer of aneuploidy in this system. These results further support our hypothesis that cell transformation involves a chromosomal mutation. Thus, our results suggest an important role for carcinogen-induced aneuploidy in carcinogenesis.