title: Oral zidovudine, continuous-infusion fluorouracil, and oral leucovorin calcium: a phase I study.
abstract: A phase I clinical, pharmacologic, and biochemical evaluation of escalating oral zidovudine (AZT) given over 2 days with a fixed dose of continuous-infusion fluorouracil (800 mg/m2 per day X 3 days) and oral leucovorin calcium was performed. Eighteen patients were treated with doses of AZT ranging from 1.0 to 9.0 g/m2 per day. Nausea and vomiting were dose limiting, with a maximally tolerated dose of 7.5 g/m2 per day. Rash and mucositis occurred but were not dose limiting. A dose-related increase in peak plasma levels of AZT was observed, and the alpha half-life of AZT in plasma (75 min) was unaffected by these high doses. At doses above 4.0 g/m2 per day, trough levels significantly increased, perhaps reflecting prolonged absorption from the gut. No responses were observed; however, a significant increase in DNA single-strand breaks was observed in peripheral blood cells after a threshold dose of 4.0 g/m2 per day, confirming a biological effect of AZT in this regimen. Further trials with an intravenous formulation capable of maintaining plasma levels and circumventing dose-limiting toxicity are warranted.
authors.affiliation: Department of Medicine, Roger Williams General Hospital, Providence, RI 02908.
authors.forename: M R
authors.initials: MR
authors.lastname: Posner
authors.forename: J W
authors.initials: JW
authors.lastname: Darnowski
authors.forename: P
authors.initials: P
authors.lastname: Calabresi
authors.forename: I
authors.initials: I
authors.lastname: Brunetti
authors.forename: D
authors.initials: D
authors.lastname: Corvese
authors.forename: G
authors.initials: G
authors.lastname: Curt
authors.forename: F J
authors.initials: FJ
authors.lastname: Cummings
authors.forename: J
authors.initials: J
authors.lastname: Clark
authors.forename: M J
authors.initials: MJ
authors.lastname: Browne
authors.forename: J
authors.initials: J
authors.lastname: Beitz
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004247:DNA / Q000097:blood; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D015215:Zidovudine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D015215:Zidovudine; D004247:DNA; D002955:Leucovorin; D005472:Fluorouracil