{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T16:25:15Z","timestamp":1774542315122,"version":"3.50.1"},"reference-count":19,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2000,4,8]]},"abstract":"<jats:p> PURPOSE: Multitargeted antifolate (MTA) is an investigational agent that, like gemcitabine, exhibits broad activity in solid tumors. A phase I trial of MTA and gemcitabine was undertaken, based on the demonstration of preclinical cytotoxic synergy. <\/jats:p><jats:p> PATIENTS AND METHODS: Thirty-five patients (group I) received 164 courses (median, four; range, one to 14 courses) of treatment of gemcitabine at doses of 1,000 and 1,250 mg\/m<jats:sup>2<\/jats:sup> on days 1 and 8 and MTA at doses of 200, 300, 400, 500, and 600 mg\/m<jats:sup>2<\/jats:sup>, given 90 minutes after gemcitabine on day 1. Courses were repeated every 3 weeks. Because the day 8 dose of gemcitabine was reduced or omitted in 57% of courses due to neutropenia, 21 patients (group II) were treated on an alternate schedule, with MTA administered on day 8 rather than day 1. This group received 85 treatment courses (median, four; range, one to 10 courses). <\/jats:p><jats:p> RESULTS: The most common and dose-limiting toxicity was neutropenia. Other toxicities included nausea, fatigue, rash, and elevated hepatic transaminases. The maximum-tolerated dose was gemcitabine\/MTA 1,000\/500 mg\/m<jats:sup>2<\/jats:sup> for group I and 1,250\/500 mg\/m<jats:sup>2<\/jats:sup> for group II. Thirteen objective responses were documented (colorectal cancer, n = 3; non\u2013small-cell lung cancer, n = 3; cholangiocarcinoma, n = 2; ovarian carcinoma, n = 2; mesothelioma, n = 1; breast cancer, n = 1; and adenocarcinoma of unknown primary site, n = 1). Gemcitabine had no effect on the disposition of MTA. <\/jats:p><jats:p> CONCLUSION: The gemcitabine\/MTA combination is broadly active and warrants further evaluation. The sequence of gemcitabine administered on days 1 and 8 with MTA administered on day 8 is better tolerated and is recommended for further study at doses of gemcitabine\/MTA 1,250\/500 mg\/m<jats:sup>2<\/jats:sup>. <\/jats:p>","DOI":"10.1200\/jco.2000.18.8.1748","type":"journal-article","created":{"date-parts":[[2017,2,24]],"date-time":"2017-02-24T07:18:30Z","timestamp":1487920710000},"page":"1748-1757","source":"Crossref","is-referenced-by-count":83,"title":["Phase I and Pharmacologic Study of Sequences of Gemcitabine and the Multitargeted Antifolate Agent in Patients With Advanced Solid Tumors"],"prefix":"10.1200","volume":"18","author":[{"given":"Alex A.","family":"Adjei","sequence":"first","affiliation":[{"name":"From the Department of OncologyMayo Clinic and Foundation, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Erlichman","sequence":"additional","affiliation":[{"name":"From the Department of OncologyMayo Clinic and Foundation, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff A.","family":"Sloan","sequence":"additional","affiliation":[{"name":"From the Department of OncologyMayo Clinic and Foundation, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel M.","family":"Reid","sequence":"additional","affiliation":[{"name":"From the Department of OncologyMayo Clinic and Foundation, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry C.","family":"Pitot","sequence":"additional","affiliation":[{"name":"From the Department of OncologyMayo Clinic and Foundation, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard M.","family":"Goldberg","sequence":"additional","affiliation":[{"name":"From the Department of OncologyMayo Clinic and Foundation, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prema","family":"Peethambaram","sequence":"additional","affiliation":[{"name":"From the Department of OncologyMayo Clinic and Foundation, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pamela","family":"Atherton","sequence":"additional","affiliation":[{"name":"From the Department of OncologyMayo Clinic and Foundation, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorelei J.","family":"Hanson","sequence":"additional","affiliation":[{"name":"From the Department of OncologyMayo Clinic and Foundation, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven R.","family":"Alberts","sequence":"additional","affiliation":[{"name":"From the Department of OncologyMayo Clinic and Foundation, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Jett","sequence":"additional","affiliation":[{"name":"From the Department of OncologyMayo Clinic and Foundation, Rochester, MN."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"233","reference":[{"key":"R1-0237","unstructured":"Plunkett  W,  Huang  P,  Xu  YZ, et al:  Gemcitabine:  metabolism, mechanisms of action, and self-potentiation. 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