title: [Phase I study of 5-fluorouracil and l-leucovorin].
abstract: Leucovorin, given usually by i.v. injection or orally changes to 5, 10-methylene tetrahydrofolate in tumor as well as normal cells. And in normal FdUMP, an active metabolite of 5-FU, binds tightly to thymidylate synthase in the presence of cofactor, 5, 10-methylene tetrahydrofolate. This interaction leads to potentiate the cytotoxic effect of 5-FU by prolonged inhibition of thymidylate synthase. Phase I study using l-leucovorin (l-LV), an active form of leucovorin, combined with 5-FU, was conducted. In the weekly schedule, 5-FU was fixed to 600mg/m2, and l-LV dose was escalated from 125 mg/m2 to 250mg/m2, if toxicity was acceptable. On the other hand, in the five consecutive-day schedule, 5-FU was fixed to 370mg/m2 and l-LV was escalated from 25mg/m2 to 50mg/m2, 100mg/m2 and 200 mg/m2. l-LV 10mg/m2 was tested as reference. On weekly schedule of l-LV 250mg/m2, grade III diarrhea was seen in 2 cases and grade IV leucopenia was seen in one. In five consecutive-day schedule, at each dose of l-LV, stomatitis, nausea plus vomiting, anorexia, anemia and leucopenia were seen. However, the increase of toxicities were not seen by dose escalation of l-LV. Then, we have been conducted a randomized early phase II study using 250 mg/m2 of l-LV weekly (arm A) and 100mg/m2 (arm B) or 10mg/m2 (arm C) of l-LV for 5 consecutive days in gastric and colorectal cancer by multicenter cooperative study. Plasma concentrations of l-LV were maintained > 10(-5) mol/L for over 5 hrs. after 2 hrs. infusion of 250 mg/m2 of l-LV and for over one hr. after a rapid injection of 100mg/m2 of l-LV.
authors.affiliation: Dept. of Chemotherapy, Tokyo Metropolitan Komagome Hospital.
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.forename: K
authors.initials: K
authors.lastname: Ota
authors.forename: A
authors.initials: A
authors.lastname: Wakui
authors.forename: S
authors.initials: S
authors.lastname: Akazawa
authors.forename: M
authors.initials: M
authors.lastname: Ogawa
authors.forename: Y
authors.initials: Y
authors.lastname: Ariyoshi
authors.forename: J
authors.initials: J
authors.lastname: Yura
authors.forename: J
authors.initials: J
authors.lastname: Inagaki
authors.forename: A
authors.initials: A
authors.lastname: Hoshino
authors.forename: T
authors.initials: T
authors.lastname: Abe
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000097:blood; D008297:Male; D008875:Middle Aged; D012004:Rectal Neoplasms / Q000097:blood / Q000188:drug therapy*; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy*
chemical_list: D002955:Leucovorin; D005472:Fluorouracil