{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:58:18Z","timestamp":1760317098893,"version":"build-2065373602"},"reference-count":42,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2015,8,4]],"date-time":"2015-08-04T00:00:00Z","timestamp":1438646400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"National Comprehensive Cancer Network \/ Allos Pharmaceuticals","award":["36-19-5-2177-001"],"award-info":[{"award-number":["36-19-5-2177-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5\u2010fluorouracil (5\u2010FU).<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Twenty\u2010seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg\/m<jats:sup>2<\/jats:sup> on day 1 followed 24 hours later by 5\u2010FU at a dose of 3000 mg\/m<jats:sup>2<\/jats:sup>\/48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Mucositis was the most common dose\u2010limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression\u2010free survival (PFS) was 112 days (range, 28\u2010588 days). Seven patients (26%) had a PFS of &gt;180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non\u2010small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>The recommended dose of PDX was 148 mg\/m<jats:sup>2<\/jats:sup>. A subset of heavily pretreated patients had PFS durations of \u22656 months with this regimen. <jats:bold><jats:italic>Cancer<\/jats:italic> 2015;121:3862\u20133868.<\/jats:bold> \u00a9 <jats:italic>2015 American Cancer Society<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.29504","type":"journal-article","created":{"date-parts":[[2015,8,4]],"date-time":"2015-08-04T11:02:25Z","timestamp":1438686145000},"page":"3862-3868","source":"Crossref","is-referenced-by-count":3,"title":["A phase 1 clinical trial of sequential pralatrexate followed by a 48\u2010hour infusion of 5\u2010fluorouracil given every other week in adult patients with solid tumors"],"prefix":"10.1002","volume":"121","author":[{"given":"Jean L.","family":"Grem","sequence":"first","affiliation":[{"name":"Section of Oncology\/Hematology, Department of Internal Medicine University of Nebraska Medical Center Omaha Nebraska"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary E.","family":"Kos","sequence":"additional","affiliation":[{"name":"Early Clinical Trials Unit, Eppley Cancer Institute University of Nebraska Medical Center Omaha Nebraska"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruby E.","family":"Evande","sequence":"additional","affiliation":[{"name":"Section of Oncology\/Hematology, Department of Internal Medicine University of Nebraska Medical Center Omaha Nebraska"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane L.","family":"Meza","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, College of Public Health University of Nebraska Medical Center Omaha Nebraska"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James K.","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Section of Oncology\/Hematology, Department of Internal Medicine University of Nebraska Medical Center Omaha Nebraska"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,8,4]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"139","volume-title":"Cancer Chemotherapy and Biotherapy: Principles and Practice","author":"Grem JL","year":"2011"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.472732"},{"key":"e_1_2_7_4_1","first-page":"327","article-title":"Schedule\u2010dependent antitumor effects of methotrexate and 5\u2010fluorouracil","volume":"37","author":"Bertino JR","year":"1977","journal-title":"Cancer Res"},{"key":"e_1_2_7_5_1","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1200\/JCO.1984.2.4.311","article-title":"Activity of sequential low\u2010dose methotrexate and fluorouracil in advanced colorectal carcinoma. Attempt at correlation with tissue and blood levels of phosphoribosylpyrophosphate","volume":"2","author":"Kemeny N","year":"1984","journal-title":"J Clin Oncol"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1991.9.3.371"},{"key":"e_1_2_7_7_1","first-page":"960","article-title":"Advanced Colorectal Cancer Meta\u2010Analysis Project","volume":"12","author":"Meta\u2010analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer","year":"1994","journal-title":"J Clin Oncol"},{"key":"e_1_2_7_8_1","first-page":"551","article-title":"New folate analogs of the 10\u2010deaza\u2010aminopterin series: markedly increased antitumor activity of the 10\u2010ethyl analog compared to the parent compound and methotrexate against some human tumor xenografts in nude mice","volume":"69","author":"Schmid FA","year":"1985","journal-title":"Cancer Treat Rep"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00255903"},{"key":"e_1_2_7_10_1","first-page":"26","article-title":"New folate analogs of the 10\u2010deaza\u2010aminopterin series. Further evidence for markedly increased antitumor efficacy compared with methotrexate in ascitic and solid murine tumor models","volume":"12","author":"Sirotnak FM","year":"1984","journal-title":"Cancer Chemother Pharmacol"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/1042819031000077124"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002800050823"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-009-0954-4"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-2251"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-0331"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6606063"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-1214"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.29.9024"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.JTO.0000263715.84567.5f"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.20.8470"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0b013e31822adb19"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.21.9220"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.23.4344"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-2439"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.12.004"},{"key":"e_1_2_7_26_1","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1158\/1055-9965.2268.13.12","article-title":"MTHFR polymorphisms and risk of chronic lymphocytic leukemia","volume":"13","author":"Rudd MF","year":"2004","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1247\/csf.20.191"},{"key":"e_1_2_7_28_1","first-page":"3249","article-title":"Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers","volume":"19","author":"Kawakami K","year":"1999","journal-title":"Anticancer Res"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.14.617"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-0425"},{"key":"e_1_2_7_31_1","first-page":"1265","article-title":"Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil toxicity","volume":"23","author":"Jakobsen A","year":"2006","journal-title":"J Clin Oncol"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2002.09.091"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.tpj.6500012"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2001.2007"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2001.19.6.1779"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s003840100358"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-005-4021-7"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22235"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604555"},{"key":"e_1_2_7_40_1","first-page":"201","article-title":"Thymidylate synthase polymorphisms and mRNA expression are independent chemotherapy predictive markers in esophageal adenocarcinoma patients","volume":"32","author":"Kuamocki H","year":"2008","journal-title":"Int J Oncol"},{"key":"e_1_2_7_41_1","first-page":"109","volume-title":"Cancer Chemotherapy and Biotherapy: Principles and Practice","author":"Chabner BA","year":"2011"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2013.779688"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-014-2441-9"}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcncr.29504","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcncr.29504","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.29504","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T20:50:56Z","timestamp":1760302256000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.29504"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,4]]},"references-count":42,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2015,11]]}},"alternative-id":["10.1002\/cncr.29504"],"URL":"https:\/\/doi.org\/10.1002\/cncr.29504","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"type":"print","value":"0008-543X"},{"type":"electronic","value":"1097-0142"}],"subject":[],"published":{"date-parts":[[2015,8,4]]}}}