Molecular mechanisms of transformation of C3H/10T1/2 C1 8 mouse embryo cells and diploid human fibroblasts by carcinogenic metal compounds.
Carcinogenic arsenic, nickel, and chromium compounds induced morphological and neoplastic transformation but no mutation to ouabain resistance in 10T1/2 mouse embryo cells; lead chromate also did not induce mutation to ouabain or 6-thioguanine resistance in Chinese hamster ovary cells. The mechanism of metal-induced morphological transformation was likely not due to the specific base substitution mutations measured in ouabain resistance mutation assays, and for lead chromate, likely not due to this type of base substitution mutation or to frameshift mutations. Preliminary data indicate increases in steady-state levels of c-myc RNA in arsenic-, nickel-, and chromium-transformed cell lines. We also showed that carcinogenic nickel, chromium, and arsenic compounds and N-methyl-N-nitro-N-nitrosoguanidine (MNNG) induced stable anchorage independence (Al) in diploid human fibroblasts (DHF) but no focus formation or immortality. Nickel subsulfide and lead chromate induced Al but not mutation to 6-thioguanine resistance. The mechanism of induction of Al by metal salts in DHF was likely not by the type of base substitution or frameshift mutations measured in these assays. MNNG induced Al, mutation to 6-thioguanine resistance, and mutation to ouabain resistance, and might induce Al by base substitution or frameshift mutations. Dexamethasone, aspirin, and salicylic acid inhibited nickel subsulfide, MNNG, and 12-O-tetrade-canoylphorbol-13-acetate (TPA)-induced Al in DHF, suggesting that arachidonic acid metabolism and oxygen radical generation play a role in induction of Al. We propose that nickel compounds stimulate arachidonic acid metabolism, consequent oxygen radical generation, and oxygen radical attack upon DNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Microbiology, Kenneth Norris, Jr., Comprehensive Cancer Center, Los Angeles, California.
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Landolph
D000818:Animals; D002274:Carcinogens, Environmental / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D004171:Diploidy; D004622:Embryo, Mammalian / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D008670:Metals / Q000633:toxicity*; D051379:Mice; D008809:Mice, Inbred C3H
D002274:Carcinogens, Environmental; D008670:Metals