PharmGKB summary: Methotrexate pathway

Pharmacogenetics and Genomics

Volumn 21, Issue 10, 2011, Pages 679-686

  Mikkelsen, Torben S ^a,b   Thorn, Caroline F ^c   Yang, Jun J ^b   Ulrich, Cornelia M ^g   French, Deborah ^b   Zaza, Gianluigi ^b   Dunnenberger, Henry M ^b   Marsh, Sharon ^h   McLeod, Howard L ^e   Giacomini, Kathy ^d   Becker, Mara L ^f   Gaedigk, Roger ^f   Leeder, James Steven ^f   Kager, Leo ⁱ   Relling, Mary V ^b   Evans, William ^b   Klein, Teri E ^c   Altman, Russ B ^c  

^a AARHUS UNIVERSITY HOSPITAL   (Denmark)

^b ST JUDE CHILDREN S RESEARCH HOSPITAL   (United States)

^c STANFORD UNIVERSITY MEDICAL CENTER   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

^e University of North Carolina   (United States)

^f CHILDREN S MERCY HOSPITAL   (United States)

^g GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^h UNIVERSITY OF ALBERTA   (Canada)

ⁱ ST ANNA CHILDREN S HOSPITAL   (Austria)

Author keywords

5,10 methylenetetrahydrofolate reductase; methotrexate; pathway; pharmacogenomic; SLC19A1; thymidylate synthetase

Indexed keywords

ABC TRANSPORTER; METHOTREXATE;

ACUTE LYMPHOBLASTIC LEUKEMIA; ARTICLE; COLON CANCER; CROHN DISEASE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG METABOLISM; DRUG PROTEIN BINDING; GENE IDENTIFICATION; GENETIC LINKAGE; GENETIC VARIABILITY; HUMAN; NONHODGKIN LYMPHOMA; NUCLEOTIDE SEQUENCE; OSTEOSARCOMA; PHARMACOGENOMICS; PRIORITY JOURNAL; PSORIASIS; RHEUMATOID ARTHRITIS; SINGLE NUCLEOTIDE POLYMORPHISM;

EID: 80052780499     PISSN: 17446872     EISSN: 17446880     Source Type: Journal    
DOI: 10.1097/FPC.0b013e328343dd93     Document Type: Article

References (126)

1. Dervieux T, Wessels JA, Van der ST, Penrod N, Moore JH, Guchelaar HJ, et al. Gene-gene interactions in folate and adenosine biosynthesis pathways affect methotrexate efficacy and tolerability in rheumatoid arthritis. Pharmacogenet Genomics 2009; 19:935-944.
2. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360:2730-2741.
3. Widemann BC, Balis FM, Kempf-Bielack B, Bielack S, Pratt CB, Ferrari S, et al. High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma. Cancer 2004; 100:2222-2232. (Pubitemid 38580344)
4. Trevino LR, Shimasaki N, Yang W, Panetta JC, Cheng C, Pei D, et al. Germ line genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol 2009; 27:5972-5978.
5. Buitenkamp TD, Mathot RAA, de Haas V, Pieters R, Zwaan CM. Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia. Haematologica 2010; 95:1106-1113.
6. Tetef ML, Margolin KA, Doroshow JH, Akman S, Leong LA, Morgan RJ Jr, et al. Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis. Cancer Chemother Pharmacol 2000; 46:19-26. (Pubitemid 30432170)
7. Costea I, Moghrabi A, Laverdiere C, Graziani A, Krajinovic M. Folate cycle gene variants and chemotherapy toxicity in pediatric patients with acute lymphoblastic leukemia. Haematologica 2006; 91:1113-1116. (Pubitemid 44204780)
8. Robien K, Bigler J, Yasui Y, Potter JD, Martin P, Storb R, et al. Methylenetetrahydrofolate reductase and thymidylate synthase genotypes and risk of acute graft-versus-host disease following hematopoietic cell transplantation for chronic myelogenous leukemia. Biol Blood Marrow Transplant 2006; 12:973-980.
9. Chiusolo P, Reddiconto G, Casorelli I, Laurenti L, Sora F, Mele L, et al. Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate. Ann Oncol 2002; 13:1915-1918. (Pubitemid 36040780)
10. Gemmati D, Ongaro A, Tognazzo S, Catozzi L, Federici F, Mauro E, et al. Methylenetetrahydrofolate reductase C677T and A1298C gene variants in adult non-Hodgkin's lymphoma patients: association with toxicity and survival. Haematologica 2007; 92:478-485. (Pubitemid 350144293)
11. 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; 98:231-234.
12. Ranganathan P, Culverhouse R, Marsh S, Mody A, Scott-Horton TJ, Brasington R, et al. Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J Rheumatol 2008; 35:572-579. (Pubitemid 351500051)
13. Chandran V, Siannis F, Rahman P, Pellett FJ, Farewell VT, Gladman DD. Folate pathway enzyme gene polymorphisms and the efficacy and toxicity of methotrexate in psoriatic arthritis. J Rheumatol 2010; 37:1508-1512.
14. Chiusolo P, Reddiconto G, Farina G, Mannocci A, Fiorini A, Palladino M, et al. MTHFR polymorphisms' influence on outcome and toxicity in acute lymphoblastic leukemia patients. Leuk Res 2007; 31:1669-1674. (Pubitemid 350051399)
15. Robien K, Schubert MM, Chay T, Bigler J, Storb R, Yasui Y, et al. Methylenetetrahydrofolate reductase and thymidylate synthase genotypes modify oral mucositis severity following hematopoietic stem cell transplantation. Bone Marrow Transplant 2006; 37:799-800.
16. Robien K, Schubert MM, Bruemmer B, Lloid ME, Potter JD, Ulrich CM. Predictors of oral mucositis in patients receiving hematopoietic cell transplants for chronic myelogenous leukemia. J Clin Oncol 2004; 22:1268-1275. (Pubitemid 41079841)
17. 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; 44:2525-2530. (Pubitemid 33049330)
18. Xiao H, Xu J, Zhou X, Stankovich J, Pan F, Zhang Z, et al. Associations between the genetic polymorphisms of MTHFR and outcomes of methotrexate treatment in rheumatoid arthritis. Clin Exp Rheumatol 2010; 28:728-733.
19. Tukova J, Chladek J, Hroch M, Nemcova D, Hoza J, Dolezalova P. 677TT genotype is associated with elevated risk of methotrexate (MTX) toxicity in juvenile idiopathic arthritis: treatment outcome, erythrocyte concentrations of MTX and folates, and MTHFR polymorphisms. J Rheumatol 2010; 37:2180-2186.
20. Shimasaki N, Mori T, Torii C, Sato R, Shimada H, Tanigawara Y, et al. Influence of MTHFR and RFC1 polymorphisms on toxicities during maintenance chemotherapy for childhood acute lymphoblastic leukemia or lymphoma. J Pediatr Hematol Oncol 2008; 30:347-352. (Pubitemid 351643456)
21. Krajinovic M, Lemieux-Blanchard E, Chiasson S, Primeau M, Costea I, Moghrabi A. Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J 2004; 4:66-72. (Pubitemid 38256607)
22. Aplenc R, Thompson J, Han P, La M, Zhao H, Lange B, et al. Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia. Cancer Res 2005; 65:2482-2487. (Pubitemid 40490161)
23. Nuckel H, Frey UH, Durig J, Duhrsen U, Siffert W. Methylenetetrahydrofolate reductase (MTHFR) gene 677C> T and 1298A >C polymorphisms are associated with differential apoptosis of leukemic B cells in vitro and disease progression in chronic lymphocytic leukemia. Leukemia 2004; 18:1816-1823. (Pubitemid 39530011)
24. Kishi S, Griener J, Cheng C, Das S, Cook EH, Pei D, et al. Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. J Clin Oncol 2003; 21:3084-3091. (Pubitemid 46606289)
25. Hughes LB, Beasley TM, Patel H, Tiwari HK, Morgan SL, Baggott JE, et al. Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis 2006; 65:1213-1218. (Pubitemid 44277399)
26. Warren RB, Smith RL, Campalani E, Eyre S, Smith CH, Barker JN, et al. Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms. Br J Dermatol 2009; 160:438-441.
27. Mena JP, Salazar-Paramo M, Gonzalez-Lopez L, Gamez-Nava JI, Sandoval-Ramirez L, Sanchez JD, et al. Polymorphisms C677T and A1298C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate: implication with elevation of transaminases. Pharmacogenomics J 2010. [Epub ahead of print]
28. Huang L, Tissing WJ, de Jonge R, Van Zelst BD, Pieters R. Polymorphisms in folate-related genes: association with side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia. Leukemia 2008; 22:1798-1800.
29. Rocha JC, Cheng C, Liu W, Kishi S, Das S, Cook EH, et al. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood 2005; 105:4752-4758. (Pubitemid 40807300)
30. Shimasaki N, Mori T, Samejima H, Sato R, Shimada H, Yahagi N, et al. Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma. J Pediatr Hematol Oncol 2006; 28:64-68.
31. Seidemann K, Book M, Zimmermann M, Meyer U,Welte K, Stanulla M, et al. MTHFR 677 (C-> T) polymorphism is not relevant for prognosis or therapy-associated toxicity in pediatric NHL: results from 484 patients of multicenter trial NHL-BFM 95. Ann Hematol 2006; 85:291-300. (Pubitemid 43732651)
32. Hayashi H, Fujimaki C, Daimon T, Tsuboi S, Matsuyama T, Itoh K. Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis. J Clin Pharm Ther 2009; 34:355-361.
33. Jazbec J, Kitanovski L, Aplenc R, Debeljak M, Dolzan V. No evidence of association of methylenetetrahydrofolate reductase polymorphism with occurrence of second neoplasms after treatment of childhood leukemia. Leuk Lymphoma 2005; 46:893-897. (Pubitemid 40959678)
34. Pakakasama S, Kanchanakamhaeng K, Kajanachumpol S, Udomsubpayakul U, Sirachainan N, Thithapandha A, et al. Genetic polymorphisms of folate metabolic enzymes and toxicities of high-dose methotrexate in children with acute lymphoblastic leukemia. Ann Hematol 2007; 86:609-611. (Pubitemid 47018479)
35. Wessels JAM, de Vries-Bouwstra JK, Heijmans BT, Slagboom PE, Goekoop-Ruiterman YPM, Allaart CF, et al. Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with singlenucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum 2006; 54:1087-1095. (Pubitemid 43672921)
36. Robien K, Ulrich CM, Bigler J, Yasui Y, Gooley T, Bruemmer B, et al. Methylenetetrahydrofolate reductase genotype affects risk of relapse after hematopoietic cell transplantation for chronic myelogenous leukemia. Clin Cancer Res 2004; 10:7592-7598. (Pubitemid 39557521)
37. Laverdiere C, Chiasson S, Costea I, Moghrabi A, Krajinovic M. Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood 2002; 100:3832-3834. (Pubitemid 35303961)
38. Kishi S, Cheng C, French D, Pei D, Das S, Cook EH, et al. Ancestry and pharmacogenetics of antileukemic drug toxicity. Blood 2007; 109:4151-4157. (Pubitemid 46743376)
39. Imanishi H, Okamura N, Yagi M, Noro Y, Moriya Y, Nakamura T, et al. Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood acute lymphoblastic leukemia and malignant lymphoma. J Hum Genet 2007; 52:166-171. (Pubitemid 46188292)
40. Gregers J, Christensen IJ, Dalhoff K, Lausen B, Schroeder H, Rosthoej S, et al. The association of reduced folate carrier 80G> A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number. Blood 2010; 115:4671-4677.
41. Drozdzik M, Rudas T, Pawlik A, Gornik W, Kurzawski M, Herczynska M. Reduced folate carrier-1 80G> A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics J 2007; 7:404-407. (Pubitemid 350192886)
42. James HM, Gillis D, Hissaria P, Lester S, Somogyi AA, Cleland LG, et al. Common polymorphisms in the folate pathway predict efficacy of combination regimens containing methotrexate and sulfasalazine in early rheumatoid arthritis. J Rheumatol 2008; 35:562-571. (Pubitemid 351500050)
43. Krajinovic M, Costea I, Chiasson S. Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukaemia. Lancet 2002; 359:1033-1034. (Pubitemid 34286543)
44. Costea I, Moghrabi A, Krajinovic M. The influence of cyclin D1 (CCND1) 870A >G polymorphism and CCND1-thymidylate synthase (TS) gene-gene interaction on the outcome of childhood acute lymphoblastic leukaemia. Pharmacogenetics 2003; 13:577-580. (Pubitemid 37159635)
45. Dulucq S, St-Onge G, Gagne V, Ansari M, Sinnett D, Labuda D, et al. DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL. Blood 2008; 111:3692-3700.
46. Stamp LK, Chapman PT, O'Donnell JL, Zhang M, James J, Frampton C, et al. Polymorphisms within the folate pathway predict folate concentrations but are not associated with disease activity in rheumatoid arthritis patients on methotrexate. Pharmacogenet Genomics 2010; 20:367-376.
47. Lauten M, Asgedom G, Welte K, Schrappe M, Stanulla M. Thymidylate synthase gene polymorphism and its association with relapse in childhood B-cell precursor acute lymphoblastic leukemia. Haematologica 2003; 88:353-354. (Pubitemid 36358728)
48. Sharma S, Das M, Kumar A, Marwaha V, Shankar S, Aneja R, et al. Interaction of genes from influx-metabolism-efflux pathway and their influence on methotrexate efficacy in rheumatoid arthritis patients among Indians. Pharmacogenet Genomics 2008; 18:1041-1049.
49. Kooloos WM, Wessels JA, Van der Straaten T, Allaart CF, Huizinga TW, Guchelaar HJ. Functional polymorphisms and methotrexate treatment outcome in recent-onset rheumatoid arthritis. Pharmacogenomics 2010; 11:163-175.
50. Letourneau IJ, Deeley RG, Cole SP. Functional characterization of nonsynonymous single nucleotide polymorphisms in the gene encoding human multidrug resistance protein 1 (MRP1/ABCC1). Pharmacogenet Genomics 2005; 15:647-657. (Pubitemid 41113337)
51. Warren RB, Smith RL, Campalani E, Eyre S, Smith CH, Barker JN, et al. Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis. J Invest Dermatol 2008; 128:1925-1929. (Pubitemid 352001201)
52. Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD. Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res 2001; 61:7225-7232. (Pubitemid 32946519)
53. Vlaming ML, Van Esch A, Pala Z, Wagenaar E, Van de Wetering K, Van Tellingen O, et al. Abcc2 (Mrp2), Abcc3 (Mrp3), and Abcg2 (Bcrp1) are the main determinants for rapid elimination of methotrexate and its toxic metabolite 7-hydroxymethotrexate in vivo. Mol Cancer Ther 2009; 8:3350-3359.
54. Ansari M, Sauty G, Labuda M, Gagne V, Laverdiere C, Moghrabi A, et al. Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia. Blood 2009; 114:1383-1386.
55. Volk EL, Farley KM,Wu Y, Li F, Robey RW, Schneider E. Overexpression of wild-type breast cancer resistance protein mediates methotrexate resistance. Cancer Res 2002; 62:5035-5040. (Pubitemid 34984431)
56. Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, et al. Transport of methotrexate, methotrexate polyglutamates, and 17betaestradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res 2003; 63:4048-4054. (Pubitemid 36917926)
57. Sharma S, Das M, Kumar A, Marwaha V, Shankar S, Singh P, et al. Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among north Indians. Pharmacogenet Genomics 2009; 19:823-828.
58. Merrill JT, Shen C, Schreibman D, Coffey D, Zakharenko O, Fisher R, et al. Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis. Arthritis Rheum 1997; 40:1308-1315. (Pubitemid 27430143)
59. Hider SL, Thomson W, Mack LF, Armstrong DJ, Shadforth M, Bruce IN. Polymorphisms within the adenosine receptor 2a gene are associated with adverse events in RA patients treated with MTX. Rheumatology (Oxford) 2008; 47:1156-1159. (Pubitemid 352038219)
60. Varani K, Massara A, Vincenzi F, Tosi A, Padovan M, Trotta F, et al. Normalization of A2A and A3 adenosine receptor upregulation in rheumatoid arthritis patients by treatment with anti-tumor necrosis factor alpha but not methotrexate. Arthritis Rheum 2009; 60:2880-2891.
61. Bar-Yehuda S, Silverman MH, Kerns WD, Ochaion A, Cohen S, Fishman P. The anti-inflammatory effect of A3 adenosine receptor agonists: a novel targeted therapy for rheumatoid arthritis. Expert Opin Investig Drugs 2007; 16:1601-1613. (Pubitemid 350028410)
62. Wessels JAM, Kooloos WM, De Jonge R, de Vries-Bouwstra JK, Allaart CF, Linssen A, et al. Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 2006; 54:2830-2839. (Pubitemid 44497761)
63. Lee YC, Cui J, Costenbader KH, Shadick NA, Weinblatt ME, Karlson EW. Investigation of candidate polymorphisms and disease activity in rheumatoid arthritis patients on methotrexate. Rheumatology (Oxford) 2009; 48:613-617.
64. Krajinovic M, Robaey P, Chiasson S, Lemieux-Blanchard E, Rouillard M, Primeau M, et al. Polymorphisms of genes controlling homocysteine levels and IQ score following the treatment for childhood ALL. Pharmacogenomics 2005; 6:293-302. (Pubitemid 40601632)
65. Al-Shakfa F, Dulucq S, Brukner I, Milacic I, Ansari M, Beaulieu P, et al. DNA variants in region for noncoding interfering transcript of dihydrofolate reductase gene and outcome in childhood acute lymphoblastic leukemia. Clin Cancer Res 2009; 15:6931-6938.
66. Lievers KJ, Kluijtmans LA, Boers GH, Verhoef P, den Heijer M, Trijbels FJ, et al. Influence of a glutamate carboxypeptidase II (GCPII) polymorphism (1561C-> T) on plasma homocysteine, folate and vitamin B(12) levels and its relationship to cardiovascular disease risk. Atherosclerosis 2002; 164:269-273. (Pubitemid 35223076)
67. Sanchez-del-Campo L, Montenegro MF, Cabezas-Herrera J, Rodriguez-Lopez JN. The critical role of alpha-folate receptor in the resistance of melanoma to methotrexate. Pigment Cell Melanoma Res 2009; 22:588-600.
68. Zaza G, Yang W, Kager L, Cheok M, Downing J, Pui CH, et al. Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis. Blood 2004; 104:1435-1441. (Pubitemid 39166522)
69. Garcia-Bournissen F, Moghrabi A, Krajinovic M. Therapeutic responses in childhood acute lymphoblastic leukemia (ALL) and haplotypes of gamma glutamyl hydrolase (GGH) gene. Leuk Res 2007; 31:1023-1025. (Pubitemid 46856715)
70. Dervieux T, Kremer J, Lein DO, Capps R, Barham R, Meyer G, et al. Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics 2004; 14:733-739. (Pubitemid 39552788)
71. Van der Straaten RJ, Wessels JA, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Allaart CF, Bogaartz J, et al. Exploratory analysis of four polymorphisms in human GGH and FPGS genes and their effect in methotrexate-treated rheumatoid arthritis patients. Pharmacogenomics 2007; 8:141-150.
72. Van Ede AE, Laan RF, De Abreu RA, Stegeman AB, Van de Putte LB. Purine enzymes in patients with rheumatoid arthritis treated with methotrexate. Ann Rheum Dis 2002; 61:1060-1064. (Pubitemid 35397351)
73. Rizzo R, Rubini M, Govoni M, Padovan M, Melchiorri L, Stignani M, et al. HLA-G 14-bp polymorphism regulates the methotrexate response in rheumatoid arthritis. Pharmacogenet Genomics 2006; 16:615-623. (Pubitemid 44223073)
74. Baricordi OR, Govoni M, Rizzo R, Trotta F. In rheumatoid arthritis, a polymorphism in the HLA-G gene concurs in the clinical response to methotrexate treatment. Ann Rheum Dis 2007; 66:1125-1126. (Pubitemid 47122334)
75. Stamp LK, O'Donnell JL, Chapman PT, Barclay ML, Kennedy MA, Frampton CM, et al. Lack of association between HLA-G 14 bp insertion/deletion polymorphism and response to long-term therapy with methotrexate response in rheumatoid arthritis. Ann Rheum Dis 2009; 68:154-155.
76. Wessels JAM, Van der Kooij SM, le Cessie S, Kievit W, Barerra P, Allaart CF, et al. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum 2007; 56:1765-1775. (Pubitemid 47110376)
77. De Jonge R, Hooijberg JH, Van Zelst BD, Jansen G, Van Zantwijk CH, Kaspers GJ, et al. Effect of polymorphisms in folate-related genes on in-vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia. Blood 2005; 106:717-720. (Pubitemid 40981271)
78. Bertrand R, MacKenzie RE, Jolivet J. Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutamate substrates. Biochim Biophys Acta 1987; 911:154-161. (Pubitemid 17232160)
79. Patino-Garcia A, Zalacain M, Marrodan L, San-Julian M, Sierrasesumaga L. Methotrexate in pediatric osteosarcoma: response and toxicity in relation to genetic polymorphisms and dihydrofolate reductase and reduced folate carrier 1 expression. J Pediatr 2009; 154:688-693.
80. Linnebank M, Malessa S, Moskau S, Semmler A, Pels H, Klockgether T, et al. Acute methotrexate-induced encephalopathy-causal relation to homozygous allelic state for MTR c.2756A >G (D919G)? J Chemother 2007; 19:455-457. (Pubitemid 47236526)
81. Berkun Y, Abou Atta I, Rubinow A, Orbach H, Levartovsky D, Aamar S, et al. 2756GG genotype of methionine synthase reductase gene is more prevalent in rheumatoid arthritis patients treated with methotrexate and is associated with methotrexate-induced nodulosis. J Rheumatol 2007; 34:1664-1669. (Pubitemid 47267607)
82. McGuire JJ. Anticancer antifolates: current status and future directions. Curr Pharm Des 2003; 9:2593-2613. (Pubitemid 37456011)
83. Sun W, Wu RR, Van Poelje PD, Erion MD. Isolation of a family of organic anion transporters from human liver and kidney. Biochem Biophys Res Commun 2001; 283:417-422. (Pubitemid 32924708)
84. Uwai Y, Iwamoto K. Transport of aminopterin by human organic anion transporters hOAT1 and hOAT3: comparison with methotrexate. Drug Metab Pharmacokinet 2010; 25:163-169.
85. Unal ES, Zhao R, Goldman ID. Role of the glutamate 185 residue in proton translocation mediated by the proton-coupled folate transporter SLC46A1. Am J Physiol Cell Physiol 2009; 297:C66-C74.
86. Badagnani I, Castro RA, Taylor TR, Brett CM, Huang CC, Stryke D, et al. Interaction of methotrexate with organic anion transporting polypeptide 1A2 and its genetic variants. J Pharmacol Exp Ther 2006; 318:521-529. (Pubitemid 44061225)
87. Krajinovic M, Costea I, Primeau M, Dulucq S, Moghrabi A. Combining several polymorphisms of thymidylate synthase gene for pharmacogenetic analysis. Pharmacogenomics J 2005; 5:374-380.
88. Goode EL, Potter JD, Bigler J, Ulrich CM. Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 2004; 13:157-162. (Pubitemid 38116635)
89. Rau T, Erney B, Gores R, Eschenhagen T, Beck J, Langer T. High-dose methotrexate in pediatric acute lymphoblastic leukemia: impact of ABCC2 polymorphisms on plasma concentrations. Clin Pharmacol Ther 2006; 80:468-476. (Pubitemid 44737489)
90. Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 2006; 127:917-928. (Pubitemid 44792250)
91. Gradhand U, Kim RB. Pharmacogenomics of MRP transporters (ABCC1-5) and BCRP (ABCG2). Drug Metab Rev 2008; 40:317-354. (Pubitemid 352000949)
92. Kruh GD, Belinsky MG, Gallo JM, Lee K. Physiological and pharmacological functions of Mrp2, Mrp3 and Mrp4 as determined from recent studies on gene-disrupted mice. Cancer Metastasis Rev 2007; 26:5-14. (Pubitemid 46452179)
93. Chan L, Lowes S, Hirst BH. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci 2004; 21:25-51. (Pubitemid 38050202)
94. El-Sheikh AA, Van den Heuvel JJ, Koenderink JB, Russel FG. Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/A. J Pharmacol Exp Ther 2007; 320:229-235.
95. Hulot JS, Villard E, Maguy A, Morel V, Mir L, Tostivint I, et al. A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination. Pharmacogenet Genomics 2005; 15:277-285. (Pubitemid 40676548)
96. Uwai Y, Taniguchi R, Motohashi H, Saito H, Okuda M, Inui K. Methotrexateloxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3. Drug Metab Pharmacokinet 2004; 19:369-374.
97. Van Aubel RA, Smeets PH, Peters JG, Bindels RJ, Russel FG. The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J Am Soc Nephrol 2002; 13:595-603. (Pubitemid 34183923)
98. Vanwert AL, Sweet DH. Impaired clearance of methotrexate in organic anion transporter 3 (Slc22a8) knockout mice: a gender-specific impact of reduced folates. Pharm Res 2008; 25:453-462. (Pubitemid 351257979)
99. Abe T, Kakyo M, Tokui T, Nakagomi R, Nishio T, Nakai D, et al. Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J Biol Chem 1999; 274:17159-17163.
100. Abe T, Unno M, Onogawa T, Tokui T, Kondo TN, Nakagomi R, et al. LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology 2001; 120: 1689-1699. (Pubitemid 32523487)
101. Van de SE, Van der Kruijssen CM,Wagenaar E, Burggraaff JE, Mesman E, Kenworthy KE, et al. Methotrexate pharmacokinetics in transgenic mice with liver-specific expression of human OATP1B1 (SLCO1B1). Drug Metab Dispos 2009; 37:277-281.
102. Kitamura Y, Hirouchi M, Kusuhara H, Schuetz JD, Sugiyama Y. Increasing systemic exposure of methotrexate by active efflux mediated by multidrug resistance-associated protein 3 (Mrp3/Abcc3). J Pharmacol Exp Ther 2008; 27:465-473.
103. Vlaming ML, Mohrmann K, Wagenaar E, de Waart DR, Elferink RP, Lagas JS, et al. Carcinogen and anticancer drug transport by Mrp2 in vivo: studies using Mrp2 (Abcc2) knockout mice. J Pharmacol Exp Ther 2006; 318:319-327.
104. Vlaming ML, Pala Z, Van EA, Wagenaar E, Van TO, de Waart DR, et al. Impact of Abcc2 (Mrp2) and Abcc3 (Mrp3) on the in-vivo elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate. Clin Cancer Res 2008; 14:8152-8160.
105. Vlaming ML, Pala Z, Van EA, Wagenaar E, de Waart DR, Van de WK, et al. Functionally overlapping roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate in vivo. Clin Cancer Res 2009; 15: 3084-3093.
106. L̂scher W, Potschka H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 2005; 76:22-76. (Pubitemid 41033402)
107. Schmiegelow K. Advances in individual prediction of methotrexate toxicity: a review. Br J Haematol 2009; 146:489-503.
108. Belkov VM, Krynetski EY, Schuetz JD, Yanishevski Y, Masson E, Mathew S, et al. Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation. Blood 1999; 93:1643-1650. (Pubitemid 29102492)
109. Zhang L, Taub JW, Williamson M, Wong SC, Hukku B, Pullen J, et al. Reduced folate carrier gene expression in childhood acute lymphoblastic leukemia: relationship to immunophenotype and ploidy. Clin Cancer Res 1998; 4:2169-2177. (Pubitemid 28415664)
110. Hooijberg JH, de Vries NA, Kaspers GJ, Pieters R, Jansen G, Peters GJ. Multidrug resistance proteins and folate supplementation: therapeutic implications for antifolates and other classes of drugs in cancer treatment. Cancer Chemother Pharmacol 2006; 58:1-12.
111. Barredo JC, Synold TW, Laver J, Relling MV, Pui CH, Priest DG, et al. Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia. Blood 1994; 84:564-569. (Pubitemid 24215957)
112. Gorlick R, Goker E, Trippett T, Waltham M, Banerjee D, Bertino JR. Intrinsic and acquired resistance to methotrexate in acute leukemia. New Eng J Med 1996; 335:1041.
113. Panetta JC, Wall A, Pui CH, Relling MV, Evans WE. Methotrexate intracellular disposition in acute lymphoblastic leukemia: a mathematical model of gamma-glutamyl hydrolase activity. Clin Cancer Res 2002; 8:2423-2429. (Pubitemid 34753618)
114. Cheng Q, Yang W, Raimondi SC, Pui CH, Relling MV, Evans WE. Karyotypic abnormalities create discordance of germ line genotype and cancer cell phenotypes. Nat Genet 2005; 37:878-882. (Pubitemid 41077115)
115. Cheng Q, Cheng C, Crews KR, Ribeiro RC, Pui CH, Relling MV, et al. Epigenetic regulation of human gamma-glutamyl hydrolase activity in acute lymphoblastic leukemia cells. Am J Hum Genet 2006; 79:264-274. (Pubitemid 44141825)
116. Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M, et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum 2004; 50:2766-2774. (Pubitemid 39209513)
117. Becker ML, Gaedigk R, van Haandel L, Thomas B, Lasky A, Hoeltzel M, et al. The effect of genotype on methotrexate polyglutamate variability in juvenile idiopathic arthritis and association with drug response. Arthritis Rheum 2010 [Epub ahead of print]
118. Cheng Q,Wu B, Kager L, Panetta JC, Zheng J, Pui CH, et al. A substrate specific functional polymorphism of human [gamma]-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells. Pharmacogenet Genomics 2004; 14:557.
119. Kager L, Cheok M, Yang W, Zaza G, Cheng Q, Panetta JC, et al. Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics. J Clin Invest 2005; 115:110-117. (Pubitemid 40385511)
120. Guo W, Healey JH, Meyers PA, Ladanyi M, Huvos AG, Bertino JR, et al. Mechanisms of methotrexate resistance in osteosarcoma. Clin Cancer Res 1999; 5:621.
121. Krajinovic M, Lemieux-Blanchard E, Chiasson S, Primeau M, Costea I, Moghrabi A. Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J 2003; 4:66-72.
122. French D, Yang W, Cheng C, Raimondi SC, Mullighan CG, Downing JR, et al. Acquired variation outweighs inherited variation in whole genome analysis of methotrexate polyglutamate accumulation in leukemia. Blood 2009; 113:4512-4520.
123. Sorich MJ, Pottier N, Pei D, Yang W, Kager L, Stocco G, et al. In-vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile. PloS Med 2008; 5:e83.
124. Yang JJ, Cheng C, Yang W, Pei D, Cao X, Fan Y, et al. Genome-wide interrogation of germ line genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 2009; 301:393-403.
125. Chan ES, Cronstein BN. Molecular action of methotrexate in inflammatory diseases. Arthritis Res 2002; 4:266-273. (Pubitemid 34716307)
126. Hinks A, Moncrieffe H, Martin P, Lal SD, Ursu S, Kassoumeri L, et al. Genetic polymorphisms in key methotrexate pathway genes associated with response to MTX treatment in juvenile idiopathic arthritis. Arthritis Rheum 2009; 60 (10 Suppl):S233.