title: Phase I trial of dipyridamole with 5-fluorouracil and folinic acid.
abstract: We have performed two Phase I trials of the combination of dipyridamole, 5-fluorouracil (5-FU), and folinic acid in patients with advanced refractory malignancy, based upon in vitro evidence that dipyridamole can modulate the cytotoxicity of 5-FU. In the first trial, patients were treated every 4 wk with dipyridamole (50 mg/m2) p.o. every 6 h on Days 0 to 6, beginning 24 h prior to the i.v. administration of folinic acid (200 mg/m2) and escalating doses of i.v. 5-FU on Days 1 to 5. The maximum tolerated daily dose of 5-FU that could be given with this combination was 375 mg/m2. Because dipyridamole is extensively bound to plasma proteins, it was hypothesized that the concentrations of free dipyridamole achieved with a dose of 50 mg/m2 were inadequate to modulate the cytotoxicity of 5-FU and folinic acid. Therefore, a second Phase I trial of escalating dose of p.o. dipyridamole was performed. Folinic acid (200 mg/m2) and 5-FU (375 mg/m2) were given i.v. on Days 1 to 5 every 4 wk, beginning 24 h after the start of therapy with dipyridamole; dipyridamole was administered p.o. on Days 0 to 6 at doses of 75, 100, 125, 150, 175, or 200 mg/m2/dose to successive cohorts of patients. Dose-limiting neutropenia, mucositis, and nausea were produced at a dose of 200 mg/m2/dose; the recommended dose of dipyridamole for use in Phase II studies is 175 mg/m2 p.o. every 6 h, or 700 mg/m2/day. At this dose, a mean peak plasma concentration of total dipyridamole of 16.32 mumol and a mean peak plasma concentration of free dipyridamole of 38.30 nmol were observed. Trough concentrations of free dipyridamole averaged 60% of the peak concentrations. Objective antitumor responses were seen in a number of tumor types; five of 13 patients with breast cancer treated with high-dose p.o. dipyridamole, 5-FU, and folinic acid responded. High-dose p.o. dipyridamole can produce plasma concentrations of free dipyridamole within the range shown to modulate the cytotoxicity of 5-FU and other agents. Phase II trials of this combination are justified.
authors.affiliation: Cleveland Clinic Foundation, Ohio 44195.
authors.forename: G T
authors.initials: GT
authors.lastname: Budd
authors.forename: A
authors.initials: A
authors.lastname: Jayaraj
authors.forename: D
authors.initials: D
authors.lastname: Grabowski
authors.forename: D
authors.initials: D
authors.lastname: Adelstein
authors.forename: L
authors.initials: L
authors.lastname: Bauer
authors.forename: J
authors.initials: J
authors.lastname: Boyett
authors.forename: R
authors.initials: R
authors.lastname: Bukowski
authors.forename: S
authors.initials: S
authors.lastname: Murthy
authors.forename: J
authors.initials: J
authors.lastname: Weick
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D004176:Dipyridamole / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged
chemical_list: D004176:Dipyridamole; D002955:Leucovorin; D005472:Fluorouracil