Methotrexate, a folic acid antagonist, is used extensively notonly for the treatment of cancer but also for the treatmentof rheumatoid arthritis, psoriasis, and autoimmune disease andfor the prevention of graft-versus-host disease after transplantation.The drug is also used as an abortifacient.1,2 Other folate antagonistsare used to treat bacterial infections (trimethoprim), malaria(pyrimethamine), and Pneumocystis carinii infection (trimetrexatewith leucovorin).3,4 As with other drugs used to treat infectiousdiseases or cancers, the development of resistance limits theeffectiveness of these folate antagonists. An understandingof the mechanisms of resistance to this class of drugs is importantfor . . . [Full Text of this Article]
Mechanisms of Action
Mechanisms of Resistance to Methotrexate
Acquired Resistance to Methotrexate
Intrinsic Resistance to Methotrexate
Tumor-Suppressor Genes and Methotrexate Resistance
Strategies to Overcome or Exploit Methotrexate Resistance
Conclusions
Source Information
From the Departments of Pediatrics (R.G., T.T.) and Molecular Pharmacology and Therapeutics (E.G., M.W., D.B., J.R.B.), Memorial Sloan-Kettering Cancer Center, New York.
Address reprint requests to Dr. Bertino at the Department of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.
References
This article has been cited by other articles:
Moorman, A. V.
(2008). One man's dose, another man's poison. Blood
111: 3303-3304
[Full Text]
Dulucq, S., St-Onge, G., Gagne, V., Ansari, M., Sinnett, D., Labuda, D., Moghrabi, A., Krajinovic, M.
(2008). DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL. Blood
111: 3692-3700
[Abstract][Full Text]
Mishra, P. J., Humeniuk, R., Mishra, P. J., Longo-Sorbello, G. S. A., Banerjee, D., Bertino, J. R.
(2007). A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc. Natl. Acad. Sci. USA
104: 13513-13518
[Abstract][Full Text]
Matheson, E. C., Hogarth, L. A., Case, M. C., Irving, J. A.E., Hall, A. G.
(2007). DHFR and MSH3 co-amplification in childhood acute lymphoblastic leukaemia, in vitro and in vivo. Carcinogenesis
28: 1341-1346
[Abstract][Full Text]
Ge, Y., Haska, C. L., LaFiura, K., Devidas, M., Linda, S. B., Liu, M., Thomas, R., Taub, J. W., Matherly, L. H.
(2007). Prognostic Role of the Reduced Folate Carrier, the Major Membrane Transporter for Methotrexate, in Childhood Acute Lymphoblastic Leukemia: A Report from the Children's Oncology Group. Clin. Cancer Res.
13: 451-457
[Abstract][Full Text]
Liu, M., Ge, Y., Payton, S. G., Aboukameel, A., Buck, S., Flatley, R. M., Haska, C., Mohammad, R., Taub, J. W., Matherly, L. H.
(2006). Transcriptional Regulation of the Human Reduced Folate Carrier in Childhood Acute Lymphoblastic Leukemia Cells. Clin. Cancer Res.
12: 608-616
[Abstract][Full Text]
van Trommel, N. E., Massuger, L. F., Schijf, C. P., ten Kate-Booij, M. J., Sweep, F. C., Thomas, C. M.
(2006). Early Identification of Resistance to First-Line Single-Agent Methotrexate in Patients With Persistent Trophoblastic Disease. JCO
24: 52-58
[Abstract][Full Text]
Cole, P. D., Drachtman, R. A., Smith, A. K., Cate, S., Larson, R. A., Hawkins, D. S., Holcenberg, J., Kelly, K., Kamen, B. A.
(2005). Phase II Trial of Oral Aminopterin for Adults and Children with Refractory Acute Leukemia. Clin. Cancer Res.
11: 8089-8096
[Abstract][Full Text]
Rothem, L., Berman, B., Stark, M., Jansen, G., Assaraf, Y. G.
(2005). The Reduced Folate Carrier Gene Is a Novel Selectable Marker for Recombinant Protein Overexpression. Mol. Pharmacol.
68: 616-624
[Abstract][Full Text]
Spees, W. M., Gade, T. P.F., Yang, G., Tong, W. P., Bornmann, W. G., Gorlick, R., Koutcher, J. A.
(2005). An 19F Magnetic Resonance-Based In Vivo Assay of Solid Tumor Methotrexate Resistance: Proof of Principle. Clin. Cancer Res.
11: 1454-1461
[Abstract][Full Text]
Winick, N. J., Carroll, W. L., Hunger, S. P.
(2004). Childhood Leukemia -- New Advances and Challenges. NEJM
351: 601-603
[Full Text]
Flatley, R. M., Payton, S. G., Taub, J. W., Matherly, L. H.
(2004). Primary Acute Lymphoblastic Leukemia Cells Use a Novel Promoter and 5'Noncoding Exon for the Human Reduced Folate Carrier That Encodes a Modified Carrier Translated from an Upstream Translational Start. Clin. Cancer Res.
10: 5111-5122
[Abstract][Full Text]
Spees, W. M., Yang, G., Veach, D., Rubio, M. B., Koutcher, J. A., Bornmann, W.
(2003). A fluorine-labeled methotrexate as a probe for monitoring tumor antifolate pharmacokinetics: Synthesis, in vitro cytotoxicity, and pilot in vivo 19F magnetic resonance spectra. Molecular Cancer Therapeutics
2: 933-939
[Abstract][Full Text]
Sowers, R., Toguchida, J., Qin, J., Meyers, P. A., Healey, J. H., Huvos, A., Banerjee, D., Bertino, J. R., Gorlick, R.
(2003). mRNA Expression Levels of E2F Transcription Factors Correlate with Dihydrofolate Reductase, Reduced Folate Carrier, and Thymidylate Synthase mRNA Expression in Osteosarcoma. Molecular Cancer Therapeutics
2: 535-541
[Abstract][Full Text]
Yang, R., Sowers, R., Mazza, B., Healey, J. H., Huvos, A., Grier, H., Bernstein, M., Beardsley, G. P., Krailo, M. D., Devidas, M., Bertino, J. R., Meyers, P. A., Gorlick, R.
(2003). Sequence Alterations in the Reduced Folate Carrier Are Observed in Osteosarcoma Tumor Samples. Clin. Cancer Res.
9: 837-844
[Abstract][Full Text]
Laverdiere, C., Chiasson, S., Costea, I., Moghrabi, A., Krajinovic, M.
(2002). Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood
100: 3832-3834
[Abstract][Full Text]
Panetta, J. C., Wall, A., Pui, C.-H., Relling, M. V., Evans, W. E.
(2002). Methotrexate Intracellular Disposition in Acute Lymphoblastic Leukemia: A Mathematical Model of {gamma}-Glutamyl Hydrolase Activity. Clin. Cancer Res.
8: 2423-2429
[Abstract][Full Text]
Worm, J., Kirkin, A. F., Dzhandzhugazyan, K. N., Guldberg, P.
(2001). Methylation-dependent Silencing of the Reduced Folate Carrier Gene in Inherently Methotrexate-resistant Human Breast Cancer Cells. J. Biol. Chem.
276: 39990-40000
[Abstract][Full Text]
Trippett, T. M., Garcia, S., Manova, K., Mody, R., Cohen-Gould, L., Flintoff, W., Bertino, J. R.
(2001). Localization of a Human Reduced Folate Carrier Protein in the Mitochondrial as Well as the Cell Membrane of Leukemia Cells. Cancer Res.
61: 1941-1947
[Abstract][Full Text]
Belur, L. R., Boelk-Galvan, D., Diers, M. D., McIvor, R. S., Zimmerman, C. L.
(2001). Methotrexate Accumulates to Similar Levels in Animals Transplanted with Normal versus Drug-resistant Transgenic Marrow. Cancer Res.
61: 1522-1526
[Abstract][Full Text]
Mahoney, D. H. Jr, Shuster, J. J., Nitschke, R., Lauer, S., Steuber, C. P., Camitta, B.
(2000). Intensification With Intermediate-Dose Intravenous Methotrexate Is Effective Therapy for Children With Lower-Risk B-Precursor Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study. JCO
18: 1285-1294
[Abstract][Full Text]
Jarvinen, T. A. H., Tanner, M., Rantanen, V., Barlund, M., Borg, A., Grenman, S., Isola, J.
(2000). Amplification and Deletion of Topoisomerase II{alpha} Associate with ErbB-2 Amplification and Affect Sensitivity to Topoisomerase II Inhibitor Doxorubicin in Breast Cancer. Am. J. Pathol.
156: 839-847
[Abstract][Full Text]
Felix, C. A., Lange, B. J., Chessells, J. M.
(2000). Pediatric Acute Lymphoblastic Leukemia: Challenges and Controversies in 2000. ASH Education Book
2000: 285-302
[Abstract][Full Text]
Rots, M. G., Pieters, R., Peters, G. J., van Zantwijk, C. H., Mauritz, R., Noordhuis, P., Willey, J. C., Hahlen, K., Creutzig, U., Janka-Schaub, G., Kaspers, G. J.L., Veerman, A. J.P., Jansen, G.
(1999). Circumvention of Methotrexate Resistance in Childhood Leukemia Subtypes by Rationally Designed Antifolates. Blood
94: 3121-3128
[Abstract][Full Text]
Hooijberg, J. H., Broxterman, H. J., Kool, M., Assaraf, Y. G., Peters, G. J., Noordhuis, P., Scheper, R. J., Borst, P., Pinedo, H. M., Jansen, G.
(1999). Antifolate Resistance Mediated by the Multidrug Resistance Proteins MRP1 and MRP2. Cancer Res.
59: 2532-2535
[Abstract][Full Text]
Guo, W., Healey, J. H., Meyers, P. A., Ladanyi, M., Huvos, A. G., Bertino, J. R., Gorlick, R.
(1999). Mechanisms of Methotrexate Resistance in Osteosarcoma. Clin. Cancer Res.
5: 621-627
[Abstract][Full Text]
Belkov, V. M., Krynetski, E. Y., Schuetz, J. D., Yanishevski, Y., Masson, E., Mathew, S., Raimondi, S., Pui, C.-H., Relling, M. V., Evans, W. E.
(1999). Reduced Folate Carrier Expression in Acute Lymphoblastic Leukemia: A Mechanism for Ploidy but not Lineage Differences in Methotrexate Accumulation. Blood
93: 1643-1650
[Abstract][Full Text]
Rots, M. G., Pieters, R., Peters, G. J., Noordhuis, P., van Zantwijk, C. H., Kaspers, G. J.L., Hahlen, K., Creutzig, U., Veerman, A. J.P., Jansen, G.
(1999). Role of Folylpolyglutamate Synthetase and Folylpolyglutamate Hydrolase in Methotrexate Accumulation and Polyglutamylation in Childhood Leukemia. Blood
93: 1677-1683
[Abstract][Full Text]
Jansen, G., Mauritz, R., Drori, S., Sprecher, H., Kathmann, I., Bunni, M., Priest, D. G., Noordhuis, P., Schornagel, J. H., Pinedo, H. M., Peters, G. J., Assaraf, Y. G.
(1998). A Structurally Altered Human Reduced Folate Carrier with Increased Folic Acid Transport Mediates a Novel Mechanism of Antifolate Resistance. J. Biol. Chem.
273: 30189-30198
[Abstract][Full Text]
Marra, G., Iaccarino, I., Lettieri, T., Roscilli, G., Delmastro, P., Jiricny, J.
(1998). Mismatch repair deficiency associated with overexpression of the MSH3 gene. Proc. Natl. Acad. Sci. USA
95: 8568-8573
[Abstract][Full Text]
Zhao, R., Assaraf, Y. G., Goldman, I. D.
(1998). A Reduced Folate Carrier Mutation Produces Substrate-dependent Alterations in Carrier Mobility in Murine Leukemia Cells and Methotrexate Resistance with Conservation of Growth in 5-Formyltetrahydrofolate. J. Biol. Chem.
273: 7873-7879
[Abstract][Full Text]
Longo, G. S.A., Gorlick, R., Tong, W. P., Ercikan, E., Bertino, J. R.
(1997). Disparate Affinities of Antifolates for Folylpolyglutamate Synthetase From Human Leukemia Cells. Blood
90: 1241-1245
[Abstract][Full Text]