| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
-Glutamyl Hydrolase Activity1
Wadsworth Center for Laboratories and Research, New York State Dept. of Health, Albany, New York 12201-0509 [M. S. R., Y. W., J. G.], and Department of Biochemistry, University of South Alabama, Mobile, Alabama 36688 [M. G. N.]
A subline of H35 hepatoma cells has been developed which exhibits 80-fold resistance to 5,10-dideazatetrahydrofolate, an antifolate which inhibits glycinamideribonucleotide transformylase. The cells are cross-resistant to methotrexate, an inhibitor of dihydrofolate reductase and 10-propargyl-5,8-dideazafolate and its 2-desamino-2-methyl derivative, both inhibitors of thymidylate synthase. The resistant cells are characterized by an impaired activity of the reduced folate transport system which affects cellular import of methotrexate, 5,10-dideazatetrahydrofolate, and 2-desamino-2-methyl-10-propargyl-5,8-dideazafolate but not 10-propargyl-5,8-dideazafolate. In addition, the resistant cells exhibit a severalfold increased activity of 
-glutamyl hydrolase, the enzyme which cleaves the intracellular polyglutamate derivatives of the antifolates. Evidence for the involvement of -glutamyl hydrolase in resistance is derived from the observation that polyglutamate derivatives of 10-propargyl-5,8-dideazafolate in resistant cells are maintained at one-third the amount of that in parental cells in the presence of the same extracellular concentration. This is the first observation that an increase in -glutamyl hydrolase contributes to acquired resistance to antifolates.
1 Supported by NIH Grants CA25933 (J. G.) and CA32687 (M. G. N.).
2 To whom requests for reprints should be addressed, at the Wadsworth Center, New York State Department of Health, Empire State Plaza, P. O. Box 509, Albany, NY 12201-0509.
Received 3/11/93. Accepted 4/ 6/93.
This article has been cited by other articles:
|
|
 |
|
  A. Llombart-Cussac, M. Martin, N. Harbeck, R. M. Anghel, A. E. Eniu, M. W. Verrill, P. Neven, J. De Greve, A. S. Melemed, R. Clark, et al. A Randomized, Double-Blind, Phase II Study of Two Doses of Pemetrexed as First-Line Chemotherapy for Advanced Breast Cancer Clin. Cancer Res., June 15, 2007; 13(12): 3652 - 3659. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Chattopadhyay, R. G. Moran, and I. D. Goldman Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications Mol. Cancer Ther., February 1, 2007; 6(2): 404 - 417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Fotoohi, G. Jansen, Y. G. Assaraf, L. Rothem, M. Stark, I. Kathmann, J. Gregorczyk, G. J. Peters, and F. Albertioni Disparate mechanisms of antifolate resistance provoked by methotrexate and its metabolite 7-hydroxymethotrexate in leukemia cells: implications for efficacy of methotrexate therapy Blood, December 15, 2004; 104(13): 4194 - 4201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Odin, Y. Wettergren, S. Nilsson, R. Willen, G. Carlsson, C. P. Spears, L. Larsson, and B. Gustavsson Altered Gene Expression of Folate Enzymes in Adjacent Mucosa Is Associated with Outcome of Colorectal Cancer Patients Clin. Cancer Res., December 1, 2003; 9(16): 6012 - 6019. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Volk and E. Schneider Wild-Type Breast Cancer Resistance Protein (BCRP/ABCG2) is a Methotrexate Polyglutamate Transporter Cancer Res., September 1, 2003; 63(17): 5538 - 5543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Sawyer, M. J. Ratain, D. Bertucci, R. P. Smith, R. L. Schilsky, N. J. Vogelzang, K. Shulman, E. C. Douglass, and G. F. Fleming Phase I Study of an Oral Formulation of ZD9331 Administered Daily for 28 Days J. Clin. Oncol., May 1, 2003; 21(9): 1859 - 1865. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Volk, K. M. Farley, Y. Wu, F. Li, R. W. Robey, and E. Schneider Overexpression of Wild-Type Breast Cancer Resistance Protein Mediates Methotrexate Resistance Cancer Res., September 1, 2002; 62(17): 5035 - 5040. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Li, T. J. Ryan, K. J. Chave, and P. Van Roey Three-dimensional Structure of Human gamma -Glutamyl Hydrolase. A CLASS I GLUTAMINE AMIDOTRANSFERASE ADAPTED FOR A COMPLEX SUBSTRATE J. Biol. Chem., June 28, 2002; 277(27): 24522 - 24529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Worm, A. F. Kirkin, K. N. Dzhandzhugazyan, and P. Guldberg Methylation-dependent Silencing of the Reduced Folate Carrier Gene in Inherently Methotrexate-resistant Human Breast Cancer Cells J. Biol. Chem., October 19, 2001; 276(43): 39990 - 40000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zeng, Z.-S. Chen, M. G. Belinsky, P. A. Rea, and G. D. Kruh Transport of Methotrexate (MTX) and Folates by Multidrug Resistance Protein (MRP) 3 and MRP1: Effect of Polyglutamylation on MTX Transport Cancer Res., October 1, 2001; 61(19): 7225 - 7232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. D. Cole, B. A. Kamen, R. Gorlick, D. Banerjee, A. K. Smith, E. Magill, and J. R. Bertino Effects of Overexpression of {{gamma}}-Glutamyl Hydrolase on Methotrexate Metabolism and Resistance Cancer Res., June 1, 2001; 61(11): 4599 - 4604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Leclerc and J. C. Barredo Folylpoly-{{gamma}}-glutamate Synthetase Gene mRNA Splice Variants and Protein Expression in Primary Human Leukemia Cells, Cell Lines, and Normal Human Tissues Clin. Cancer Res., April 1, 2001; 7(4): 942 - 951. [Abstract] [Full Text]
|
|
|
|
|
|
E. L. Volk, K. Rohde, M. Rhee, J. J. McGuire, L. A. Doyle, D. D. Ross, and E. Schneider Methotrexate Cross-Resistance in a Mitoxantrone-selected Multidrug-resistant MCF7 Breast Cancer Cell Line Is Attributable to Enhanced Energy-dependent Drug Efflux Cancer Res., July 1, 2000; 60(13): 3514 - 3521. [Abstract] [Full Text]
|
|
|
|
|
|
S. J. Welsh, J. Titley, L. Brunton, M. Valenti, P. Monaghan, A. L. Jackman, and G. W. Aherne Comparison of Thymidylate Synthase (TS) Protein Up-Regulation after Exposure to TS Inhibitors in Normal and Tumor Cell Lines and Tissues Clin. Cancer Res., June 1, 2000; 6(6): 2538 - 2546. [Abstract] [Full Text]
|
|
|
|
|
|
M. J. Barnes, E. J. Estlin, G. A. Taylor, G. W. Aherne, A. Hardcastle, J. J. McGuire, J. A. Calvete, J. Lunec, A. D. J. Pearson, and D. R. Newell Impact of Polyglutamation on Sensitivity to Raltitrexed and Methotrexate in Relation to Drug-induced Inhibition of de Novo Thymidylate and Purine Biosynthesis in CCRF-CEM Cell Lines Clin. Cancer Res., September 1, 1999; 5(9): 2548 - 2558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Sirotnak Enhancing Cytotoxic Sensitivity of Tumor Cells to Antifolates: Another Opportunity for Gene Therapy? J Natl Cancer Inst, July 21, 1999; 91(14): 1178 - 1179. [Full Text] [PDF]
|
|
|
|
|
|
M. G. Rots, R. Pieters, G. J. Peters, P. Noordhuis, C. H. van Zantwijk, G. J.L. Kaspers, K. Hahlen, U. Creutzig, A. J.P. Veerman, and G. Jansen Role of Folylpolyglutamate Synthetase and Folylpolyglutamate Hydrolase in Methotrexate Accumulation and Polyglutamylation in Childhood Leukemia Blood, March 1, 1999; 93(5): 1677 - 1683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Tse and R. G. Moran Cellular Folates Prevent Polyglutamation of 5,10-Dideazatetrahydrofolate. A NOVEL MECHANISM OF RESISTANCE TO FOLATE ANTIMETABOLITES J. Biol. Chem., October 2, 1998; 273(40): 25944 - 25952. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Rhee, B. Lindau-Shepard, K. J. Chave, J. Galivan, and T. J. Ryan Characterization of Human Cellular gamma -Glutamyl Hydrolase Mol. Pharmacol., June 1, 1998; 53(6): 1040 - 1046. [Abstract] [Full Text]
|
|
|
|
|
|
M. C. Waltham, W.-W. Li, H. Gritsman, W. P. Tong, and J. R. Bertino gamma -Glutamyl Hydrolase from Human Sarcoma HT-1080 Cells: Characterization and Inhibition by Glutamine Antagonists Mol. Pharmacol., May 1, 1997; 51(5): 825 - 832. [Abstract] [Full Text]
|
|
|
|
|
|
K. Roy, M. G. Egan, S. Sirlin, and F. M. Sirotnak Posttranscriptionally Mediated Decreases in Folylpolyglutamate Synthetase Gene Expression in Some Folate Analogue-resistant Variants of the L1210 Cell. EVIDENCE FOR AN ALTERED COGNATE mRNA IN THE VARIANTS AFFECTING THE RATE OF DE NOVO SYNTHESIS OF THE ENZYME J. Biol. Chem., March 14, 1997; 272(11): 6903 - 6908. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Gorlick, E. Goker, T. Trippett, M. Waltham, D. Banerjee, and J. R. Bertino Intrinsic and Acquired Resistance to Methotrexate in Acute Leukemia N. Engl. J. Med., October 3, 1996; 335(14): 1041 - 1048. [Full Text] [PDF]
|
|
|
|
 |
|
 J.R. Bertino, E. Goker, R. Gorlick, W.W. Li, and D. Banerjee Resistance Mechanisms to Methotrexate in Tumors Oncologist, August 1, 1996; 1(4): 223 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Yao, Z. Nimec, T. J. Ryan, and J. Galivan Identification, Cloning, and Sequencing of a cDNA Coding for Rat [IMAGE]-Glutamyl Hydrolase J. Biol. Chem., April 12, 1996; 271(15): 8525 - 8528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Takimoto New Antifolates: Pharmacology and Clinical Applications Oncologist, February 1, 1996; 1(1): 68 - 81. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Bertino, E Goker, R Gorlick, W. Li, and D Banerjee Resistance mechanisms to methotrexate in tumors Stem Cells, January 1, 1996; 14(1): 5 - 9. [Abstract]
|
|
|
|
|
|
K. Roy, K. Mitsugi, S. Sirlin, B. Shane, and F. M. Sirotnak Different Antifolate-resistant L1210 Cell Variants with either Increased or Decreased Folylpolyglutamate Synthetase Gene Expression at the Level of mRNA Transcription J. Biol. Chem., November 10, 1995; 270(45): 26918 - 26922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Egan, S. Sirlin, B. G. Rumberger, T. A. Garrow, B. Shane, and F. M. Sirotnak Rapid Decline in Folylpolyglutamate Synthetase Activity and Gene Expression during Maturation of HL-60 Cells J. Biol. Chem., March 10, 1995; 270(10): 5462 - 5468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zhao, S. Titus, F. Gao, R. G. Moran, and I. D. Goldman Molecular Analysis of Murine Leukemia Cell Lines Resistant to 5,10-Dideazatetrahydrofolate Identifies Several Amino Acids Critical to the Function of Folylpolyglutamate Synthetase J. Biol. Chem., August 18, 2000; 275(34): 26599 - 26606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Chave, I. E. Auger, J. Galivan, and T. J. Ryan Molecular Modeling and Site-directed Mutagenesis Define the Catalytic Motif in Human gamma -Glutamyl Hydrolase J. Biol. Chem., December 15, 2000; 275(51): 40365 - 40370. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
