title: Human glucocorticoid receptor gene deletion following exposure to cancer chemotherapeutic drugs and chemical mutagens.
abstract: The sensitivity of the human glucocorticoid receptor (hGR) gene to mutagenesis by the cancer chemotherapeutic drugs adriamycin, bleomycin, and chlorambucil was evaluated using glucocorticoid-sensitive (dexs) subclones of the human leukemic cell line CEM-C7. Treatment of cells with either bleomycin or chlorambucil increased the frequency of glucocorticoid-resistant (dexr) clones 3.3- and 10-fold, respectively. Measurement of steroid-binding activity in intact dexr cells demonstrated that the predominant phenotype of drug-induced dexr clones was receptorless (r-). dexs CEM cells express only one functional hGR allele and, in addition, are heterozygous for a BclI restriction fragment length polymorphism in the hGR gene (L. A. Palmer and J. M. Harmon, Cancer Res., 51:5224-5231, 1991). To determine the basis of the r- phenotype, BclI digests of genomic DNA isolated from r+ and r- cell lines were examined for the presence of the polymorphic 2.4- and 4.4-kilobase digestion products. A deletion of all or part of the hGR gene was demonstrated by the absence of the 4.4-kilobase fragment in one of two bleomycin-induced dexr clones, as well as the ICR191-induced dexr cell line ICR27TK.3. Cytogenetic analysis of ICR27TK.3 showed that the distal portion of the long arm of one chromosome 5 had been replaced with a portion of chromosome 15. Thus, in at least two dexr cell lines, deletions and/or chromosome breaks in the hGR locus appear to account for the r- phenotype.
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799.
authors.forename: L A
authors.initials: LA
authors.lastname: Palmer
authors.forename: B
authors.initials: B
authors.lastname: Hukku
authors.forename: J M
authors.initials: JM
authors.lastname: Harmon
mesh_terms: D000483:Alleles; D001761:Bleomycin / Q000494:pharmacology*; D002478:Cells, Cultured; D002699:Chlorambucil / Q000494:pharmacology*; D002895:Chromosomes, Human, Pair 5; D003907:Dexamethasone / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D017353:Gene Deletion; D006801:Humans; D007621:Karyotyping; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis*; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D001761:Bleomycin; D002699:Chlorambucil; D003907:Dexamethasone; D004317:Doxorubicin