JPET Assistant Professor of Medicine (Clinician-Educator)

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by O'Brien, M. L.
Right arrow Articles by Tew, K. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by O'Brien, M. L.
Right arrow Articles by Tew, K. D.

Vol. 291, Issue 3, 1348-1355, December 1999

Glutathione Peptidomimetic Drug Modulator of Multidrug Resistance-Associated Protein1

Miechelle L. O'Brien, Bojana Vulevic, Seema Freer, Jonathan Boyd, Hongxie Shen and Kenneth D. Tew

Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

The peptidomimetic drug gamma -glutamyl-S-(benzyl)cysteinyl-R-(-)-phenyl glycine diethyl ester (TER199) is an analog of glutathione designed to be an isozyme-specific inhibitor of GSTP1-1 protein1-1. This compound (and the de-esterified moiety) is shown to be an effective inhibitor of multidrug resistance-associated protein1 (MRP1)-mediated drug resistance. Kinetic analyses revealed that gamma -glutamyl-S-(benzyl)cysteinyl-R-(-)-phenyl glycine reversibly inhibits the transport of 2,4-dinitrophenyl-S-glutathione with a Ki of 752 µM. TER199 reversed the accumulation deficit of daunorubicin in MRP1-transfected NIH3T3 fibroblasts and maintained intracellular levels for >2 h after daunorubicin removal. Cytotoxicity assays revealed that TER199 significantly reversed the resistance of MRP1-transfected NIH3T3 cells for vincristine, doxorubicin, etoposide, and mitoxantrone. HL-60 cells made resistant to TER199 by chronic, long-term selection had increased mRNA and protein levels of multidrug resistance-associated protein, MRP1, and gamma -glutamyl cysteine synthetase heavy and light subunits (the rate-limiting enzyme in GSH synthesis). In spite of increased gamma -glutamyl cysteine synthetase, their glutathione content was reduced ~35% from that of parental HL-60 cells. These cells also exhibited a drug resistance profile commensurate with the previously described MRP1 overexpressing phenotype, with resistance to Vinca alkaloids, epipodophyllotoxins, and anthracyclines; additional cross-resistance to paclitaxel (Taxol), mitoxantrone, and 5-fluorouracil was observed.

0022-3565/99/2913-1348$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Physiol. Rev.Home page
R. G. Deeley, C. Westlake, and S. P. C. Cole
Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins.
Physiol Rev, July 1, 2006; 86(3): 849 - 899.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S. Hohaus, A. Di Ruscio, A. Di Febo, G. Massini, F. D'Alo', F. Guidi, G. Mansueto, M. T. Voso, and G. Leone
Glutathione S-transferase P1 Genotype and Prognosis in Hodgkin's Lymphoma
Clin. Cancer Res., March 15, 2005; 11(6): 2175 - 2179.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. M. Leslie, A. Haimeur, and M. P. Waalkes
Arsenic Transport by the Human Multidrug Resistance Protein 1 (MRP1/ABCC1): EVIDENCE THAT A TRI-GLUTATHIONE CONJUGATE IS REQUIRED
J. Biol. Chem., July 30, 2004; 279(31): 32700 - 32708.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
R. K. Dasgupta, P. J. Adamson, F. E. Davies, S. Rollinson, P. L. Roddam, A. J. Ashcroft, A. M. Dring, J. A. L. Fenton, J. A. Child, J. M. Allan, et al.
Polymorphic variation in GSTP1 modulates outcome following therapy for multiple myeloma
Blood, October 1, 2003; 102(7): 2345 - 2350.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J. E. Ruscoe, L. A. Rosario, T. Wang, L. Gate, P. Arifoglu, C. R. Wolf, C. J. Henderson, Z.'e. Ronai, and K. D. Tew
Pharmacologic or Genetic Manipulation of Glutathione S-Transferase P1-1 (GSTpi ) Influences Cell Proliferation Pathways
J. Pharmacol. Exp. Ther., July 1, 2001; 298(1): 339 - 345.
[Abstract] [Full Text]

Home page
 Mol. Pharmacol.Home page
L. A. Rosario, M. L. O'Brien, C. J. Henderson, C. R. Wolf, and K. D. Tew
Cellular Response to a Glutathione S-Transferase P1-1 Activated Prodrug
Mol. Pharmacol., July 1, 2000; 58(1): 167 - 174.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics.