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Genetics of Multidrug Resistance: Relationship of a Cloned Gene to the Complete Multidrug Resistant Phenotype¹

Department of Pediatric Hematology and Oncology, The Children's Hospital, and Dana-Farber Cancer Institute, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 [J. M. C.]; Department of Biology, Massachusetts Institute of Technology [J. M. C., B. C. G., D. E. H.] and Whitehead Institute for Biomedical Research, [B. C. G.]; Cambridge, Massachusetts 02139; and Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6 [P. G.]

Resistance to multiple chemotherapeutic agents remains the major cause of failure in cancer chemotherapy. Multidrug resistant cell lines developed in vitro have provided a useful model for analyzing this phenomenon. We describe a complementary DNA, DR11, which is present in normal cells and overexpressed in multidrug resistant cell lines. We have placed this complementary DNA in an expression vector which uses the ß-actin promoter to drive transcription and introduced this vector via transfection into drug sensitive cells. Cells expressing increased levels of DR11 are resistant to the same broad spectrum of chemotherapeutic agents which characterize the multidrug resistant phenotype. The expression of this complementary DNA in transfected clones is dependent upon the number of copies of DR11 integrated in the genome as well as the amount of selective pressure placed on the clone during selection of the clone. Furthermore, the number of copies of DR11 in the genome and the expression of DR11 can be modulated by releasing an individual clone from selective pressure or by increasing the selective pressure on the clone. The endogenous sequences encoding the multidrug resistance gene are not amplified in transfected drug resistant clones. Finally, the drug resistant phenotype is reversed in the transfected clones by verapamil just as drug resistance is reversed in multidrug resistant cell lines.

¹ This work was supported by USPHS Science Grant CA17575 from the NIH and a grant from the Ajinomoto Corporation to D. E. H.

² Supported by NIH Training Grant 5T 32HL07574. To whom requests for reprints should be addressed, at E17-540A, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.

³ Supported by a National Research Service Award from the National Cancer Institute (5F 32CA07864-02).

Received 5/ 8/87. Revised 8/12/87. Accepted 8/19/87.

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