{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T05:20:19Z","timestamp":1792646419108,"version":"4.5.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2004,8]]},"DOI":"10.1097\/01.fpc.0000114761.78957.7e","type":"journal-article","created":{"date-parts":[[2004,7,28]],"date-time":"2004-07-28T04:01:55Z","timestamp":1090987315000},"page":"557-567","source":"Crossref","is-referenced-by-count":71,"title":["A substrate specific functional polymorphism of human \u03b3-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells"],"prefix":"10.1097","volume":"14","author":[{"given":"Qing","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bainan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo","family":"Kager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Carl","family":"Panetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Hon","family":"Pui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary V","family":"Relling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-9-20210213","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1172\/JCI112088","article-title":"Polyglutamation of methotrexate. Is methotrexate a prodrug?","volume":"76","author":"Chabner","year":"1985","journal-title":"J Clin Invest"},{"key":"R2-9-20210213","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1056\/NEJM199610033351408","article-title":"Intrinsic and acquired resistance to methotrexate in acute leukemia.","volume":"335","author":"Gorlick","year":"1996","journal-title":"N Engl J Med"},{"key":"R3-9-20210213","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1200\/JCO.1993.11.1.5","article-title":"Karnofsky memorial lecture. Ode to methotrexate.","volume":"11","author":"Bertino","year":"1993","journal-title":"J Clin Oncol"},{"key":"R4-9-20210213","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1200\/JCO.1994.12.7.1383","article-title":"Intensive intravenous methotrexate and mercaptopurine treatment of higher-risk non-T, non-B acute lymphocytic leukemia: A Pediatric Oncology Group study.","volume":"12","author":"Camitta","year":"1994","journal-title":"J Clin Oncol"},{"key":"R5-9-20210213","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1200\/JCO.1994.12.4.740","article-title":"Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber Cancer Institute\/Children's Hospital Acute Lymphoblastic Leukemia Consortium Protocol 85-01.","volume":"12","author":"Schorin","year":"1994","journal-title":"J Clin Oncol"},{"key":"R6-9-20210213","doi-asserted-by":"crossref","first-page":"2514","DOI":"10.1182\/blood.V78.10.2514.2514","article-title":"Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (Protocol 81-01 update).","volume":"78","author":"Niemeyer","year":"1991","journal-title":"Blood"},{"key":"R7-9-20210213","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1200\/JCO.1998.16.1.246","article-title":"Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial.","volume":"16","author":"Mahoney","year":"1998","journal-title":"J Clin Oncol"},{"key":"R8-9-20210213","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1056\/NEJM199802193380803","article-title":"Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia.","volume":"338","author":"Evans","year":"1998","journal-title":"N Engl J Med"},{"key":"R9-9-20210213","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1056\/NEJM199808273390907","article-title":"Acute lymphoblastic leukemia.","volume":"339","author":"Pui","year":"1998","journal-title":"N Engl J Med"},{"key":"R10-9-20210213","doi-asserted-by":"crossref","first-page":"5007","DOI":"10.1016\/S0021-9258(18)91984-8","article-title":"Carrier-mediated transport of the folic acid analogue, methotrexate, in the L1210 leukemia cell.","volume":"243","author":"Goldman","year":"1968","journal-title":"J Biol Chem"},{"key":"R11-9-20210213","doi-asserted-by":"crossref","first-page":"7431","DOI":"10.1038\/sj.onc.1206946","article-title":"Resistance to antifolates.","volume":"22","author":"Zhao","year":"2003","journal-title":"Oncogene"},{"key":"R12-9-20210213","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S0083-6729(08)60397-0","article-title":"Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism.","volume":"45","author":"Shane","year":"1989","journal-title":"Vitam Horm"},{"key":"R13-9-20210213","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1172\/JCI118409","article-title":"Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high-dose methotrexate.","volume":"97","author":"Masson","year":"1996","journal-title":"J Clin Invest"},{"key":"R14-9-20210213","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1182\/blood.V76.1.44.44","article-title":"Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis.","volume":"76","author":"Whitehead","year":"1990","journal-title":"Blood"},{"key":"R15-9-20210213","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1172\/JCI117552","article-title":"Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia.","volume":"94","author":"Synold","year":"1994","journal-title":"J Clin Invest"},{"key":"R16-9-20210213","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1182\/blood.V80.5.1316.1316","article-title":"Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (greater than 50 chromosomes) B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group study.","volume":"80","author":"Whitehead","year":"1992","journal-title":"Blood"},{"key":"R17-9-20210213","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1182\/blood.V84.2.564.564","article-title":"Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia.","volume":"84","author":"Barredo","year":"1994","journal-title":"Blood"},{"key":"R18-9-20210213","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1182\/blood.V93.5.1643","article-title":"Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation.","volume":"93","author":"Belkov","year":"1999","journal-title":"Blood"},{"key":"R19-9-20210213","first-page":"33","article-title":"Glutamyl hydrolase: properties and pharmacologic impact.","volume":"26","author":"Galivan","year":"1999","journal-title":"Semin Oncol"},{"key":"R20-9-20210213","first-page":"1040","article-title":"Characterization of human cellular gamma-glutamyl hydrolase.","volume":"53","author":"Rhee","year":"1998","journal-title":"Mol Pharmacol"},{"key":"R21-9-20210213","first-page":"2423","article-title":"Methotrexate intracellular disposition in acute lymphoblastic leukemia: a mathematical model of gamma-glutamyl hydrolase activity.","volume":"8","author":"Panetta","year":"2002","journal-title":"Clin Cancer Res"},{"key":"R22-9-20210213","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S0378-1119(99)00362-5","article-title":"Structural organization of the human gamma-glutamyl hydrolase gene.","volume":"238","author":"Yin","year":"1999","journal-title":"Gene"},{"key":"R23-9-20210213","doi-asserted-by":"crossref","first-page":"24522","DOI":"10.1074\/jbc.M202020200","article-title":"Three-dimensional structure of human gamma-glutamyl hydrolase. A class I glatamine amidotransferase adapted for a complex substrate.","volume":"277","author":"Li","year":"2002","journal-title":"J Biol Chem"},{"key":"R24-9-20210213","doi-asserted-by":"crossref","first-page":"40365","DOI":"10.1074\/jbc.M007908200","article-title":"Molecular modeling and site-directed mutagenesis define the catalytic motif in human gamma-glutamyl hydrolase.","volume":"275","author":"Chave","year":"2000","journal-title":"J Biol Chem"},{"key":"R25-9-20210213","doi-asserted-by":"crossref","first-page":"6364","DOI":"10.1016\/S0021-9258(20)82150-4","article-title":"Isolation and characterization of pteroylpolyglutamate hydrolase from rat intestinal mucosa.","volume":"259","author":"Elsenhans","year":"1984","journal-title":"J Biol Chem"},{"key":"R26-9-20210213","first-page":"2230","article-title":"Hydrolytic cleavage of methotrexate gamma-polyglutamates by folylpolyglutamyl hydrolase derived from various tumors and normal tissues of the mouse.","volume":"46","author":"Samuels","year":"1986","journal-title":"Cancer Res"},{"key":"R27-9-20210213","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1093\/jn\/120.5.467","article-title":"Properties of pteroylpolyglutamate hydrolase in pancreatic juice of the pig.","volume":"120","author":"Bhandari","year":"1990","journal-title":"J Nutr"},{"key":"R28-9-20210213","doi-asserted-by":"crossref","first-page":"10134","DOI":"10.1073\/pnas.93.19.10134","article-title":"Human gamma-glutamyl hydrolase: cloning and characterization of the enzyme expressed in vitro.","volume":"93","author":"Yao","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"issue":"suppl 1","key":"R29-9-20210213","first-page":"S124","article-title":"Rational and design of total therapy study XV for newly diagnosed acute lymphoblastic leukemia.","volume":"83","author":"Pui","year":"2004","journal-title":"Annal Hematol"},{"key":"R30-9-20210213","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/ng1151","article-title":"Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells.","volume":"34","author":"Cheok","year":"2003","journal-title":"Nature Genet"},{"key":"R31-9-20210213","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S1535-6108(02)00032-6","article-title":"Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling.","volume":"1","author":"Yeoh","year":"2002","journal-title":"Cancer Cell"},{"key":"R32-9-20210213","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1006\/jmbi.1996.0477","article-title":"A fast flexible docking method using an incremental construction algorithm.","volume":"261","author":"Rarey","year":"1996","journal-title":"J Mol Biol"},{"key":"R33-9-20210213","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1002\/jcc.540100804","article-title":"Validation of the general-purpose Tripos 5.2 force-field.","volume":"10","author":"Clark","year":"1989","journal-title":"J Comput Chem"},{"key":"R34-9-20210213","first-page":"694","article-title":"Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians.","volume":"58","author":"Tai","year":"1996","journal-title":"Am J Hum Genet"},{"key":"R35-9-20210213","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0378-1119(03)00807-2","article-title":"Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms.","volume":"319","author":"Chave","year":"2003","journal-title":"Gene"},{"key":"R36-9-20210213","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1056\/NEJMra020526","article-title":"Pharmacogenomics - drug disposition, drug targets, and side effects.","volume":"348","author":"Evans","year":"2003","journal-title":"N Engl J Med"},{"key":"R37-9-20210213","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1126\/science.286.5439.487","article-title":"Pharmacogenomics: translating functional genomics into rational therapeutics.","volume":"286","author":"Evans","year":"1999","journal-title":"Science"},{"key":"R38-9-20210213","first-page":"567","article-title":"Pharmacogenomics of childhood acute lymphoblastic leukemia.","volume":"6","author":"Brenner","year":"2002","journal-title":"Curr Opin Mol Ther"},{"key":"R39-9-20210213","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1001\/jama.290.15.2001","article-title":"Results of therapy for acute lymphoblastic leukemia in black and white children.","volume":"290","author":"Pui","year":"2003","journal-title":"JAMA"},{"key":"R40-9-20210213","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1001\/jama.290.15.2008","article-title":"Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia.","volume":"290","author":"Kadan-Lottick","year":"2003","journal-title":"JAMA"},{"key":"R41-9-20210213","doi-asserted-by":"crossref","first-page":"3832","DOI":"10.1182\/blood.V100.10.3832","article-title":"Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia.","volume":"100","author":"Laverdiere","year":"2002","journal-title":"Blood"},{"key":"R42-9-20210213","first-page":"3416","article-title":"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.","volume":"7","author":"Whetstine","year":"2001","journal-title":"Clin Cancer Res"},{"key":"R43-9-20210213","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1097\/00008571-200204000-00002","article-title":"Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses.","volume":"12","author":"Urano","year":"2002","journal-title":"Pharmacogenetics"},{"key":"R44-9-20210213","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/ng0595-111","article-title":"A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.","volume":"10","author":"Frosst","year":"1995","journal-title":"Nature Genet"},{"key":"R45-9-20210213","doi-asserted-by":"crossref","first-page":"13217","DOI":"10.1073\/pnas.95.22.13217","article-title":"A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells.","volume":"95","author":"Bagley","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"R46-9-20210213","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1006\/mgme.1998.2714","article-title":"A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity.","volume":"64","author":"Weisberg","year":"1998","journal-title":"Mol Genet Metab"},{"key":"R47-9-20210213","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1182\/blood.V98.1.231","article-title":"Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism.","volume":"98","author":"Ulrich","year":"2001","journal-title":"Blood"},{"key":"R48-9-20210213","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1097\/00008571-200204000-00001","article-title":"Differing effects of methylenetetrahydrofolate reductase single nucleotide polymorphisms on methotrexate efficacy and toxicity in rheumatoid arthritis.","volume":"12","author":"Evans","year":"2002","journal-title":"Pharmacogenetics"},{"key":"R49-9-20210213","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1086\/301825","article-title":"A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?","volume":"62","author":"van der Put","year":"1998","journal-title":"Am J Hum Genet"},{"key":"R50-9-20210213","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S0140-6736(02)08065-0","article-title":"Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukaemia.","volume":"359","author":"Krajinovic","year":"2002","journal-title":"Lancet"},{"key":"R51-9-20210213","first-page":"2898","article-title":"A novel single nucleotide polymorphism within the 5 tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity.","volume":"63","author":"Mandola","year":"2003","journal-title":"Cancer Res"}],"container-title":["Pharmacogenetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.1097\/01.fpc.0000114761.78957.7e","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T19:22:45Z","timestamp":1785784965000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/00008571-200408000-00009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,8]]},"references-count":51,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2004]]}},"URL":"https:\/\/doi.org\/10.1097\/01.fpc.0000114761.78957.7e","relation":{},"ISSN":["0960-314X"],"issn-type":[{"value":"0960-314X","type":"print"}],"subject":[],"published":{"date-parts":[[2004,8]]}}}