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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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

Miechelle O'Brien, Gary D. Kruh and Kenneth D. Tew
Journal of Pharmacology and Experimental Therapeutics August 2000, 294 (2) 480-487;
Miechelle O'Brien
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Gary D. Kruh
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Kenneth D. Tew
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Abstract

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 GSTπ, γ-glutamylcysteine synthetase (γ-GCS) (regulatory plus catalytic subunits), or MRP1 enhanced resistance to a number of anticancer drugs. Cotransfection of GSTπ 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 GSTπ 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.

Footnotes

  • Send reprint requests to: Dr. Kenneth D. Tew, Department of Pharmacology, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111. E-mail: kd_tew{at}fccc.edu

  • ↵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

  • Abbreviations:
    GST
    glutathioneS-transferase
    GS-conjugate
    glutathione conjugate
    GSH
    glutathione
    MRP1
    multidrug resistance-associated protein 1
    γ-GCS
    γ-glutamylcysteine sythetase
    CDNB
    1-chloro-2,4-dinitrobenzene
    PCR
    polymerase chain reaction
    ROS
    reactive oxygen species
    • Received January 21, 2000.
    • Accepted April 17, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 2
1 Aug 2000
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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

Miechelle O'Brien, Gary D. Kruh and Kenneth D. Tew
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 480-487;

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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

Miechelle O'Brien, Gary D. Kruh and Kenneth D. Tew
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 480-487;
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