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Double Knockout of the MRP Gene Leads to Increased Drug Sensitivity in Vitro¹

Department of Pharmacology and Developmental Therapeutics Program [A. L. G. R., A. C. S.] and Howard Hughes Medical Institute, Section of Immunobiology [R. A. F.] and Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520

Overexpression of the multidrug resistance-associated protein (MRP) gene has been implicated in the resistance of tumor cell lines to a wide array of chemotherapeutic agents, but its normal physiological function(s) remains unknown. We have compared the sensitivity to chemotherapeutic drugs and toxins of wild-type W9.5 embryonic stem cells (ES) and of single and double MRP gene knockout cells derived therefrom. MRP expression was totally abrogated in the double knockout cell line and partially abrogated in the single knockout cell line. Reverse transcription-PCR analyses demonstrated that the MDR1, MDR2, and MDR3 genes were not expressed in either wild-type or MRP knock-out cells. The cytotoxic activities of etoposide, teniposide, vincristine, doxorubicin, daunorubicin, and sodium arsenite were significantly greater in double knockout cells than in parental wild-type ES cells; single knockout ES cells displayed an intermediate level of sensitivity. In contrast, no difference in sensitivity to colchicine and 1-ß-D-arabinofuranosylcytosine existed between the cell lines. Etoposide accumulation in double knockout ES cells was 2-fold higher than in wild-type ES cells. These findings indicate that baseline MRP expression has the capacity to exert a protective role against the toxicity of multiple chemotherapeutic agents and natural toxins.

¹ This research was supported in part by USPHS Grant CA-66739 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Pharmacology, Yale University School of Medicine, Sterling Hall of Medicine, 333 Cedar Street, New Haven, CT 06520-8066. Phone: (203) 785-4533.

Received 8/23/96. Accepted 10/15/96.

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