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Vol. 294, Issue 2, 480-487, August 2000

The Influence of Coordinate Overexpression of Glutathione Phase II Detoxification Gene Products on Drug Resistance1

Miechelle O'Brien2 , Gary D. Kruh and Kenneth D. Tew

Department of Pharmacology (M.O., K.D.T) and Division of Medical Sciences (G.D.K.), Fox Chase Cancer Center, Philadelphia, Pennsylvania

Glutathione (GSH), glutathione S-transferases (GSTs), and the multidrug resistance-associated protein 1 (MRP1) have been independently studied for their contributions to drug resistance. Single cDNA transfection experiments have provided inconsistent and disparate conclusions with respect to the importance of GSH and GST in conferring a resistant phenotype. Because these three proteins can act as a concerted coordinated pathway, we reasoned that equivalent increases may be required for enhanced resistance to be expressed. We have assembled these proteins together, or in various combinations, to determine whether they show cooperativity in determining drug response. Increased expression through single cDNA transfection of GSTpi , gamma -glutamylcysteine synthetase (gamma -GCS) (regulatory plus catalytic subunits), or MRP1 enhanced resistance to a number of anticancer drugs. Cotransfection of GSTpi and GCS, gave higher resistance to doxorubicin, etoposide, and vincristine than with either alone. Resistance toward chlorambucil and ethacrynic acid was similar in cells overexpressing either component or overexpressing GST alone. Coexpression of GSTpi with MRP1 conferred significant resistance above that seen for MRP1 alone to chlorambucil, etoposide, ethacrynic acid, and vincristine. The combination of GCS and MRP1 did not afford additional resistance above MRP1 alone. When all three were transfected, significantly higher levels of resistance were found for doxorubicin and etoposide. These results support the concept that coordinate enhancement of focal thiol elements of detoxification pathways provides a more efficient protective phenotype than do single components alone.

1 This work was supported in part by National Institutes of Health Grants CA06927 and RR05539, by National Institutes of Health Grant CA53893 to K.D.T., and by an appropriation from the Commonwealth of Pennsylvania.

2 Present address: New York Medical College, Valhalla, NY 10595

0022-3565/00/2942-0480$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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