Human glucocorticoid receptor gene deletion following exposure to cancer chemotherapeutic drugs and chemical mutagens

• Published in: Cancer research (Chicago, Ill.) Vol. 52; no. 23; pp. 6612 - 6618
• Main Authors: PALMER, L. A, HUKU, B, MARMON, J. M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.12.1992
• Subjects: Alleles; Biological and medical sciences; Bleomycin - pharmacology; Cells, Cultured; Chlorambucil - pharmacology; Chromosomes, Human, Pair 5; Dexamethasone - metabolism; Doxorubicin - pharmacology; Drug toxicity and drugs side effects treatment; Gene Deletion; Humans; Karyotyping; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Pharmacology. Drug treatments; Phenotype; Receptors, Glucocorticoid - drug effects; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; RNA, Messenger - analysis; Antineoplastic agent; Human; Dexamethasone; Steroid hormone; Toxicity; Mutagen; Glucocorticoid; In vitro; Resistance; Cell line; Gene; Deletion; Tumor cell; Hormonal receptor
• ISSN: 0008-5472; 1538-7445

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.