Induction of glucocorticoid-resistant variants in a murine thymoma line by antitumor drugs.
Several antitumor drugs are shown to be mutagenic in murine thymoma lines: mitomycin C, bleomycin, streptonigrin, Colcemid, and BD40, an analog of ellipticine. Using conditions yielding 3 to 40% cell survival, all five drugs tested increase the frequency of glucocorticoid-resistant variants. Mitomycin C is as efficient as the classical alkylating agents N-methyl-N'-nitro-N-nitrosoguanidine and ethyl methanesulfonate. The other drugs, previously untested for mutagenic activity on mammalian cells, are weak mutagens yielding variants at frequencies 1 to 2 orders of magnitude lower than the alkylating agents. All 152 variants obtained result from defects in the glucocorticoid receptor. Variants induced by mitomycin C, streptonigrin, Colcemid, and BD40 have very reduced receptor activity, as measured by dexamethasone binding. In contrast, bleomycin or the combination of mitomycin C and dexamethasone induce a majority of variants having dexamethasone-binding activity comparable to the parental line. However, assays of nuclear transfer capacity and genetic complementation show that these receptors are nonfunctional and may result from point mutations in the gene encoding the glucocorticoid receptor. This study suggests that, in combination therapies, antitumor drugs might induce glucocorticoid-resistant lymphoid cell variants that could be selected by the hormone.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D010641:Phenotype; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013945:Thymoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid