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Human Glucocorticoid Receptor Gene Deletion following Exposure to Cancer Chemotherapeutic Drugs and Chemical Mutagens¹

Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799 [L. A. P., J. M. H.] and Cell Culture Laboratory, Children's Hospital of Michigan, and Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan 48201-9985 [B. H.]

³ To whom requests for reprints should be addressed, at Department of Pharmacology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814-4799.

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 (dex^s) subclones of the human leukemic cell line CEM-C7. Treatment of cells with either bleomycin or chlorambucil increased the frequency of glucocorticoid-resistant (dex^r) clones 3.3- and 10-fold, respectively. Measurement of steroid-binding activity in intact dex^r cells demonstrated that the predominant phenotype of drug-induced dex^r clones was receptorless (r^–). dex^s 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 dex^r clones, as well as the ICR191-induced dex^r 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 dex^r cell lines, deletions and/or chromosome breaks in the hGR locus appear to account for the r^- phenotype.

¹ This investigation was supported by USPHS Grant CA32226 awarded by the National Cancer Institute. Cytogenetic analysis was carried out under National Cancer Institute contract N01-CP-85645 to Children's Hospital of Michigan, Detroit, MI 48201. The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences.

² Present address: Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5/12/92. Accepted 9/23/92.

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