Toward a Better Understanding of Methotrexate

Arthritis and Rheumatism

Volumn 50, Issue 5, 2004, Pages 1370-1382

  Kremer, Joel M ^a  

^a Center for Rheumatology LLP   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIRHEUMATIC AGENT; DIHYDROFOLATE REDUCTASE; DIHYDROFOLIC ACID; DISEASE MODIFYING ANTIRHEUMATIC DRUG; FOLIC ACID; METHOTREXATE; UNCLASSIFIED DRUG;

BONE MARROW SUPPRESSION; CELL MEMBRANE TRANSPORT; CELL METABOLISM; CYTOTOXICITY; DNA SYNTHESIS INHIBITION; DRUG ABSORPTION; DRUG DISTRIBUTION; DRUG EFFECT; DRUG EXCRETION; DRUG MECHANISM; DRUG METABOLISM; DRUG RESISTANCE; DRUG SAFETY; DRUG TRANSFORMATION; DRUG TRANSPORT; GASTROINTESTINAL TOXICITY; HUMAN; INTRACELLULAR TRANSPORT; LONG TERM CARE; MEDICAL DECISION MAKING; MUCOSA INFLAMMATION; PRIORITY JOURNAL; REVIEW; RHEUMATIC DISEASE; RHEUMATOID ARTHRITIS; URINARY EXCRETION;

ANTIRHEUMATIC AGENTS; HUMANS; METHOTREXATE; RHEUMATIC DISEASES;

EID: 2342499810     PISSN: 00043591     EISSN: None     Source Type: Journal    
DOI: 10.1002/art.20278     Document Type: Review

References (96)

1. Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff JA. Temporary remissions in acute leukemia in children produced by folic antagonist 4-amethopteroylglutamic acid (aminopterin). N Engl J Med 1948;238:787-93.
2. Tugwell P, Pincus T, Yocum D, Stein M, Gluck O, Kraag G, et al, The Methotrexate-Cyclosporine Combination Study Group. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med 1995;333:137-41.
3. O'Dell J, Haire CE, Erikson N, Drymalski W, Palmer W, Eckhoff PJ, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 1996;334:1287-91.
4. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmana mann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340:253-9.
5. Lipsky PE, van der Heijde DM, St. Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000;343:1594-602.
6. Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ, Furst DE, et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized comparison of efficacy, safety, and tolerability compared to methotrexate alone. Ann Intern Med 2002;37:726-33.
7. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48:35-45.
8. Kremer JM, Westhovens R, Leon M, Di Georgio E, Alten R, Steinfeld S, et al. Treatment of rheumatoid arthritis by prevention of T cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349:1907-15.
9. Chu E, Allegra C. Antifolates. In: Chabner BA, Longo DL, editors. Cancer chemotherapy and biotherapy. 2nd ed. Philadelphia: Lippincot-Raven; 1996. p. 109-47.
10. Matherly LH, Wong SC, Angeles SM, Taub JW, Smith GK. Distribution of the reduced folate carrier (RFC) versus the high affinity membrane folate binding protein (mFBP) in human tumors and tissues. Proc Am Assoc Cancer Res 1994;35:307-15.
11. Antony AC. The biological chemistry of folate receptors. Blood 1992;79:2807-20.
12. Wang J, Ginning W, Delley KM, Ratnam M. Evidence for segregation of heterologous GPI-anchored proteins into separate lipid rafts within the plasma membrane. J Membr Biol 2002;189:35-43.
13. Ross JF, Chaudhuri PK, Ratnam M. Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines: physiologic and clinical implications. Cancer 1994;73:2432-43.
14. Matherly LH, Goldman D. Membrane transport of folates. Vitam Horm 2003;66:403-56.
15. Nakashima-Matsushita N, Homma T, Yu S, Matsuda T, Sunahara N, Nakamura T, et al. Selective expression of folate receptor β and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis. Arthritis Rheum 1999;42:1609-16.
16. Turk MJ, Breur GJ, Widmer WR, Paulos CM, Xu LC, Grote LA, et al. Folate-targeted imaging of activated macrophages in rats with adjuvant-induced arthritis. Arthritis Rheum 2002;46:1947-55.
17. Kane MA, Portillo RM, Elwood PC, Antony AC, Kolhouse JF. The influence of extracellular folate concentration on methotrexate uptake by human KB cells: partial characterization of a membrane-associated methotrexate binding protein. J Biol Chem 1986;261:44-9.
18. Antony AC, Kane MA, Portillo RM, Elwood PC, Kolhouse JF. Studies of the role of a particulate folate-binding protein in the uptake of 5-methyltetrahydrofolate by cultured human KB cells. J Biol Chem 1985;260:14911-7.
19. Kamen BA, Capdevila A. Receptor-mediated folate accumulation regulated by the cellular folate content. Proc Natl Acad Sci U S A 1986;83:5983-7.
20. Weitman SD, Weinberg AG, Coney LR, Zurawski VR, Jennings DS, Kamen BA. Cellular localization of the folate receptor: potential role in drug toxicity and folate homeostasis Cancer Res 1992;52:6708-11.
21. Whetstine JR, Gifford AJ, Witt T, Liu XY, Flatley RM, Norris M, et al. Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers. Clin Cancer Res 2001;7:3416-22.
22. Rothem L, Aronheim A, Assaraf YG. Alterations in the expression of transcription factors and the reduced folate carrier as a novel mechanism of antifolate resistance in human leukemia cells. J Biol Chem 2002;278:8935-41.
23. Zager RF, Frisby SA, Oliverio VT. The effects of antibiotics and cancer chemotherapeutic agents on cellular transport and antitumor activity of methotrexate in L1210 murine leukemia. Cancer Res 1973;33:1670-6.
24. Chello PL, Sirotnak FM, Dorick DM. Alterations in the kinetics of methotrexate transport during growth of L1210 murine leukemia cells in culture. Mol Pharmacol 1980;18:274-80.
25. Kremer JM, Lee JK. The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis Rheum 1986;29:822-31.
26. Chen ZS, Lee K, Walther S, Raftogianis RB, Kuwano M, Zeng H, et al. Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABC4): MRP4 is a component of the methotrexate efflux system. Cancer Res 2002;62:3144-50.
27. Ranganathan P, Eisen S, Yokoyama WM, McLeod HL. Will pharmacogenetics allow better prediction of methotrexate toxicity and efficacy in patients with rheumatoid arthritis? Ann Rheum Dis 2003;62:4-9.
28. Volk S, Farley KM, Wu Y, Li F, Robey RW, Schneider E. Expression of wild-type breast cancer resistance protein mediates methotrexate resistance. Cancer Res 2002;62:5035-40.
29. Sirotnak FM, Moccio DM, Hancock CH, Young CW. Improved methotrexate therapy of murine tumors obtained by probenecid-mediated pharmacocological modulation at the level of membrane transport. Cancer Res 1981;41:3944-9.
30. Trippett T, Schlemmer S, Elisseyeff Y, Goker E, Wachter M, Steinherz P, et al. Defective transport as a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia. Blood 1992;80:1158-62.
31. Rodenhuis S, Kremer JM, Bertino JR. Increase of dihydrofolate reductase in peripheral blood lymphocytes of rheumatoid arthritis patients treated with low-dose oral methotrexate. Arthritis Rheum 1987;30:369-74.
32. Dervieux T, Orentas Lein D, Park G, Barham R, Smith K, Walsh M, et al. Single nucleotide polymorphisms in the folate/purine synthesis pathway predict methotrexate's effects in rheumatoid arthritis [abstract]. Arthritis Rheum 2003;48 Suppl 9:S438.
33. McGuire JJ, Coward JK Pteroylpolyglutamates: biosynthesis, degradation, and function. In: Blakley RL, Benkovic SJ, editors. Folates and pterins. Vol. 1. Chemistry and biochemistry of folates. New York: John Wiley; 1984. p. 135-90.
34. Kumar P, Kisliuk RL, Gaumont Y, Freisheim JH, Nair MG. Inhibition of human dihydrofolate reductase by antifolyl polyglutamates. Biochem Pharmacol 1989;38:541-3.
35. Morrison PF, Allegra CJ. Folate cycle kinetics in human breast cancer cells. J Biol Chem 1989;264:10552-66.
36. Kremer JM, Galivan J, Streckfuss A, Kamen B. Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients: association with hepatic folate deficiency and formation of polyglutamates. Arthritis Rheum 1986;29:832-5.
37. Koizumi S, Curt GA, Fine RL, Griffin JD, Chabner BA. Formation of methotrexate polyglutamates in purified myeloid precursor cells from normal human bone marrow. J Clin Invest 1985;75:1008-14.
38. Rosenblatt DS, Whitehead VM, Dupont MM, Vuchich MJ, Vera N. Synthesis of methotrexate polyglutamates in cultured human cells. Mol Pharmacol 1978;14:210-4.
39. Morgan SL, Baggott JE, Refsum H, Ueland PM. Homocysteine levels in patients with rheumatoid arthritis treated with low-dose methotrexate. Clin Pharmacol Ther 1991;50:547-56.
40. Morgan SL, Baggott JE, Lee JY, Alarcon GS. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during long-term, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol 1998;25:441-6.
41. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111-3.
42. Van Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA, et al. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum 2001;44:2525-30.
43. Ulrich CM, Yasui Y, Storb R, Schubert MM, Wagner JL, Bigler J, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001;98:231-4.
44. Nesher G, Moore TL. The in vitro effects of methotrexate on peripheral blood mononuclear cells: modulation by methyl donors and spermidine. Arthritis Rheum 1990;33:954-9.
45. Abraham AK, Pihl A. Role of polyamines in macromolecular synthesis. Trends Biochem Sci 1981;6:106-7.
46. Galivan J, Johnson T, Rhee M, McGuire JJ, Priest D, Kesevan V. The role of folylpolyglutamate synthase and γ-glutamyl hydrolase in altering cellular folyl- and antifolylpolyglutamates. Adv Enzyme Regul 1987;26:147-55.
47. Angelis-Stoforidis P, Vajda FJ, Christophidis N. Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis. Clin Exp Rheumatol 1999;17:313-20.
48. Dervieux T, Orentas Lein D, Park G, Marcelletti J, Meyer G, Smith K, et al. Methotrexate polyglutamate concentrations in red blood cells correlate with disease activity and clinical response to methotrexate in rheumatoid arthritis [abstract]. Arthritis Rheum 2003;48 Suppl 9:S135.
49. Schlemmer SR, Sirotnak FM. Retentiveness of methotrexate polyglutamates in cultured L1210 cells: evidence against a role for mediated plasma membrane transport outward. Biochem Pharmacol 1993;45:1261-6.
50. Galivan J, Rhee MS. Insulin-dependent suppression in glutamyl hydrolase activity and elevated cellular methotrexate polyglutamates. Biochem Pharmacol 1995;50:1959-63.
51. Jolivet J, Cole DE, Holcenberg JS, Poplack DG. Prevention of methotrexate cytotoxicity by asparaginase inhibition of methotrexate polyglutamate formation. Cancer Res 1985;45:217-20.
52. Kremer JM, Alarcon GS, Lightfoot RW Jr, Willkens RF, Furst DE, Williams HJ, et al. Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity. Arthritis Rheum 1994;37:316-28.
53. Alarcon GS, Kremer JM, Macaluso M, Weinblatt ME, Cannon GW, Palmer WR, et al, Methotrexate-Lung Study Group. Risk factors associated with lung injury in methotrexate-treated rheumatoid arthritis patients: a multicenter, case-control study. Ann Intern Med 1997;127:356-64.
54. Fabre I, Fabre G, Goldman ID. Polyglutamylation, an important element in methotrexate cytotoxicity and selectivity in tumor versus murine granulocytic progenitor cells in vitro. Cancer Res 1984;44:3190-5.
55. Bertino JR. Ode to methotrexate: Karnofsky memorial lecture. J Clin Oncol 1993;11:5-14.
56. Rots MG, Pieters R, Kaspers GJ, Veerman AJ, Peters GJ, Jansen G. Classification of ex vivo methotrexate resistance in acute lymphoblastic and myeloid leukaemia. Br J Haematol 2000;110:791-800.
57. Zhao R, Goldman ID. Resistance to antifolates. Oncogene 2003;22:7431-57.
58. Friedkin M, Crawford E, Humphreys SR, Goldin A. The association of increased dihydrofolate reductase with amethopterin resistance in mouse leukemia. Cancer Res 1962;22:600-6.
59. Milbrandt JD, Heintz NH, White WC, Rothman SM, Hamlin JL. Methotrexate-resistant Chinese hamster ovary cells have amplified a 135-kilobase-pair region that includes the dihydrofolate reductase gene. Proc Natl Acad Sci U S A 1981;78:6043-7.
60. Domin BA, Grill SP, Cheng Y. Establishment of dihydrofolate reductase from a methotrexate-resistant human cell line and relationship between dihydrofolate reductase levels and gene copy. Cancer Res 1983;43:2155-8.
61. Hall MJ, Lawrence DA, Lansiedel JC, Walsh AC, Comstock LL, Kremer JM. Long-term exposure to methotrexate induces immunophenotypic changes, decreased methotrexate uptake and increased dihydrofolate gene copy number in Jurkat T cells. Int J Immunopharmacol 1997;19:709-20.
62. Bertino JR, Donohue DR, Gabrio BW, Silber R, Alenty A, Meyer M, et al. Increased level of dihydrofolate reductase in leukocytes of patients treated with amethopterin. Nauchni Tr Vissh Med Inst Sofiia 1962;193:140-2.
63. Haber DA, Schimke RT. Unstable amplification of an altered dihydrofolate reductase gene associated with double-minute chromosomes. Cell 1981;26:355-62.
64. Brown PC, Beverley SM, Schimke RT. Relationship of amplified dihydrofolate reductase genes to double minute chromosomes in unstably resistant mouse fibroblast cell lines. Mol Cell Biol 1981;1:1077-83.
65. Meltzer PS, Cheng YC, Trent JM. Analysis of dihydrofolate reductase gene amplification in a methotrexate-resistant human tumor cell line. Cancer Genet Cytogenet 1985;17:289-300.
66. Domin BA, Grill SP, Bastow KF, Cheng YC. Effect of methotrexate on dihydrofolate reductase activity in methotrexate-resistant human KB cells. Mol Pharmacol 1982;21:478-82.
67. Bastow KF, Prabhu R, Cheng YC. The intracellular content of dihydrofolate reductase: possibilities for control and implications for chemotherapy. Adv Enzyme Regul 1984;22:15-26.
68. Chu E, Takimoto CH, Voeller D, Grem JL, Allegra CJ. Specific binding of human dihydrofolate reductase protein to dihydrofolate reductase messenger RNA in vitro. Biochemistry 1993;32:4756-60.
69. Kleinberger T, Etkin S, Lave S. Carcinogen-mediated methotrexate resistance and dihydrofolate reductase amplification in Chinese hamster cells. Mol Cell Biol 1986;6:1958-64.
70. Sharma RC, Schimke RT. Enhancement of the frequency of methotrexate resistance by γ-radiation in Chinese hamster ovary and mouse 3T6 cells. Cancer Res 1989;49:3861-6.
71. Rice GC, Ling V, Schimke RT. Frequencies of independent and simultaneous selection of Chinese hamster cells for methotrexate and doxorubicin (Adriamycin) resistance. Proc Natl Acad Sci U S A 1987;84:9261-4.
72. Pinedo HM, Zaharko DS, Bull J, Chabner BA. The relative contribution of drug concentration and duration of exposure to mouse bone marrow toxicity during continuous methotrexate infusion. Cancer Res 1977;37:445-50.
73. Urano W, Taniguchi A, Yamanaka H, Tanaka E, Nakajima H, Matsuda Y, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenetics 2002;12:183-90.
74. Chungi VS, Bourne DW, Dittert LW. Drug absorption. VIII. Kinetics of GI absorption of methotrexate J Pharm Sci 1978;67:560-1.
75. Hamilton RA, Kremer JM. Why intramuscular methotrexate works better than oral drug in patients with rheumatoid arthritis. Br J Rheumatol 1997;36:86-90.
76. Hamilton RA, Kremer JM. The effect of food on methotrexate absorption. J Rheumatol 1995;22:2072-7.
77. Wegrzyn J, Adeleine P, Miossec P. Better efficacy of methotrexate administered by intramuscular injections versus oral route in patients with rheumatoid arthritis. Ann Rheum Dis. In press.
78. Chabner BA, Stoller RG, Hande K, Jacobs S, Young RC. Methotrexate disposition in humans: case studies in ovarian cancer and following high-dose infusion. Drug Metab Rev 1978;8:107-17.
79. Kremer JM, Alarcon GS, Weinblatt ME, Kaymakcian MV, Macaluso M, Cannon GW, et al. Clinical, laboratory, radiographic and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review. Arthritis Rheum 1997;40:1829-37.
80. Fossa SD, Heilo A, Bormer O. Unexpectedly high serum methotrexate levels in cystectomized bladder cancer patients with an ileal conduit treated with intermediate doses of the drug. J Urol 1990;143:498-501.
81. Calvert AH, Bondy PK, Harrap KR. Some observations on the human pharmacology of methotrexate. Cancer Treat Rep 1977; 61:1647-56.
82. Hande KR, Balow JE, Drake JC, Rosenberg SA, Chabner BA. Methotrexate and hemodialysis. Ann Intern Med 1977;87:495-6.
83. Monjanel S, Rigault JP, Cano JP, Carcassonne Y, Favre R. High-dose methotrexate: preliminary evaluation of a pharmacokinetic approach. Cancer Chemother Pharmacol 1979;3:189-96.
84. Huang KC, Wenczak BA, Liu YK. Renal tubular transport of methotrexate in the rhesus monkey and dog. Cancer Res 1979;39:4843-8.
85. Kremer JM, Petrillo GF, Hamilton RA. Pharmacokinetics and renal function in patients with rheumatoid arthritis receiving a standard dose of oral weekly methotrexate over a period of 24 months: association with significant decreases in creatinine clearance and renal clearance of the drug. J Rheumatol 1995;22:38-40.
86. Iven H, Brasch H. The effects of antibiotics and uricosuric drugs on the renal elimination of methotrexate in rabbits. Cancer Chemother Pharmacol 1990;26:139-43.
87. Carmichael SJ, Beal J, Day RO, Tett SE. Combination therapy with methotrexate and hydroxychloroquine for rheumatoid arthritis increases exposure to methotrexate. J Rheumatol 2002;29:2077-83.
88. Kremer JM, Hamilton RA. The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg. J Rheumatol 1995;22:2072-7.
89. Baggott JE, Morgan SL, Ha T, Vaughn WH, Hine RJ. Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs. Biochem J 1992;282:197-202.
90. Godfrey C, Sweeney K, Miller K, Hamilton R, Kremer J. The population pharmacokinetics of long-term methotrexate in rheumatoid arthritis. Br J Clin Pharmacol 1998;46:369-76.
91. Chabner BA, Young RC. Threshold methotrexate concentration for in vivo inhibition of DNA synthesis in normal and tumorous target tissues. J Clin Invest 1973;52:1804-11.
92. Sirotnak F, Moccio DM. Pharmacokinetic basis for differences in methotrexate sensitivity of normal proliferative tissues in the mouse. Cancer Res 1980;40:1230-4.
93. Morgan SL, Baggott JE, Vaughn WH, Young PK, Austin JV, Krumdieck CL, et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1990;33:9-18.
94. Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, et al. Supplementation with folinic acid during methotrexate therapy for rheumatoid arthritis: a double-blind, placebo-controlled trial. Ann Intern Med 1994;121:833-41.
95. Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH. Antiinflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 2001;60:729-35.
96. Cronstein BN. Molecular therapeutics: methotrexate and its mechanism of action. Arthritis Rheum 1996;39:1951-60.