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Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada L8N 3Z5 [R. S. G., R. G., B. E.]; Department of Pharmacology and Medicine, University of Florida, College of Medicine, Gainesville, Florida 32610 [R. B. L., W. E. R.]; and Departments of Medical Chemistry and Biomolecular Discovery, Smith, Kline and French Laboratories, Philadelphia, Pennsylvania 19101 [R. P. H., M. J. C., R. K. J.]
In Chinese hamster ovary cells, stable mutants that exhibit 250- to 350-fold resistance to camptothecin (CptR mutants) have been isolated from mutagen-treated cultures. The CptR mutants exhibited no cross-resistance towards drugs such as colchicine, vinblastine, taxol, or puromycin but showed slightly (2- to 3-fold) enhanced sensitivity towards various drugs that inhibit DNA topoisomerase II (namely teniposide, etoposide, doxorubicin, mitoxantrone, amsacrine, ellipticine), suggesting that the genetic lesion in these mutants was highly specific. In contrast to the wild-type cells, the CptR line was resistant to camptothecin-induced DNA strand breaks as measured by alkaline elution. Biochemical studies revealed that in CptR mutants the cellular activity as well as protein content of DNA topoisomerase I were reduced to about 40–50% of the level in wild-type cells. Normal levels of activity and content were observed for the related enzyme DNA topoisomerase II. Studies with DNA topoisomerase I purified from the wild-type and the mutant cells showed that the enzyme from the CptR cells was markedly resistant to camptothecin as assayed by the drug's effects either on relaxation of supercolled DNA or on stabilization of the covalent enzyme-DNA intermediate. The presence of a camptothecin-resistant form of DNA topoisomerase I in the mutant cells provides further evidence that this enzyme is the cellular target of camptothecin. Cell hybridization studies between the CptR and CptS cells showed that the hybrids formed between these two cell lines were sensitive to camptothecin. The recessive behavior of the CptR mutation provides a plausible explanation for the reduced topoisomerase I content (about one-half of wild-type cells) of the mutant cells and also for their enhanced sensitivity towards inhibitors of topoisomerase II.
1 To whom requests for reprints should be addressed. Work supported in part by a grant from the Medical Research Council of Canada and in part by Grant CA40884 from the National Cancer Institute.
Received 4/14/88. Revised 8/ 3/88. Accepted 8/ 9/88.
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