title: Phase I and pharmacologic study of i.v. hydroxyurea infusion given with i.p. 5-fluoro-2'-deoxyuridine and leucovorin.
abstract: Preclinical data suggests that the action of fluoropyrimidines may be enhanced by the addition of hydroxyurea. We developed a phase I trial to determine the maximum tolerated dose and pharmacokinetics of i.v. hydroxyurea (HU) in combination with i.p. 5-fluoro-2'-deoxyuridine (FUdR) and leucovorin (LV). Eligible patients had metastatic carcinoma confined mostly to the peritoneal cavity, and adequate hepatic, renal and bone marrow function. Patients were treated with a fixed dose of FUdR (3 g) and LV (640 mg) administered on days 1--3. HU was administered as a 72-h infusion starting simultaneously with i.p. therapy on day 1. The following dose levels were studied: 2.0, 2.5, 3.0 and 3.6 g/m(2)/day. Pharmacokinetics were studied in blood and peritoneal fluid. Twenty-eight patients were accrued. Steady-state plasma and peritoneal fluid HU levels increased with increasing dose, and steady state was achieved within 12 h of continuous dosing. The steady-state HU plasma:peritoneal fluid concentration ratio ranged from 1.06 x 10(3) to 1.25 x 10(3) and the plasma HU clearance ranged from 4.63 to 5.81 l/h/m(2). Peritoneal fluid AUC = 137,639 +/- 43,914 microg/ml x min, t(1/2) = 100.9 +/- 56.4 min and Cl = 25.29 +/- 10.88 ml/min. Neutropenia represented the dose-limiting toxicity. We conclude that i.p. FUdR and LV in combination with i.v. HU is well tolerated. The addition of systemic HU increased the incidence of myelosuppression.
authors.affiliation: 1University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Garcia
authors.forename: F M
authors.initials: FM
authors.lastname: Muggia
authors.forename: C P
authors.initials: CP
authors.lastname: Spears
authors.forename: S
authors.initials: S
authors.lastname: Jeffers
authors.forename: H
authors.initials: H
authors.lastname: Silberman
authors.forename: M
authors.initials: M
authors.lastname: Pujari
authors.forename: R T
authors.initials: RT
authors.lastname: Koda
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage*; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D005467:Floxuridine; D002955:Leucovorin; D006918:Hydroxyurea