Phase I study of 5-day continuous infusion fluorodeoxyuridine and high-dose folinic acid with oral hydroxyurea

• Published in: Cancer chemotherapy and pharmacology 1994, Vol.35 (2), p.161-164
• Main Authors: RASCHKO, J. W, AKMAN, S. A, LEONG, L. A, MARGOLIN, K. A, MORGAN, R. J, NEWMAN, E, SOMLO, G, AHN, C, DOROSHOW, J. H
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Breast Neoplasms - drug therapy; Chemotherapy; Diarrhea - chemically induced; Drug Administration Schedule; Female; Floxuridine - administration & dosage; Humans; Hydroxyurea - administration & dosage; Hydroxyurea - adverse effects; Infusions, Intravenous; Leucovorin - administration & dosage; Lung Neoplasms - drug therapy; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Thymidylate Synthase - antagonists & inhibitors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/BF00686640

Fluorodeoxyuridine (FUdR), the deoxynucleoside metabolite of 5-fluorouracil (5-FU), can be converted in a single step to fluorodeoxyuridine monophosphate (FdUMP), which binds covalently to thymidylate synthase (TS). Ribonucleotide reductase, an obligatory enzyme in the synthesis of deoxynucleotides, can be inhibited by hydroxyurea. Recognizing the well-established synergism between 5-FU and folinic acid (leucovorin), we hypothesized that the simultaneous administration of FUdR, leucovorin, and hydroxyurea might afford more effective inhibition of TS. Thirty-six patients with neoplastic disease considered refractory to standard therapy were entered into this phase I protocol. Treatment was administered on days 1 through 5 of a 28-day cycle and consisted of folinic acid (500 mg m-2 day-1) and FUdR at escalating doses of 0.1, 0.15, or 0.2 mg kg-1 day-1 both administered by continuous i.v. infusion, and hydroxyurea given p.o. once per day at doses ranging from 0 to 250o mg in 500-mg increments. The hydroxyurea and FUdR levels were escalated in a sequential fashion. The majority of patients had refractory breast or lung cancer. Dose-limiting toxicities were mucositis and diarrhea at the maximally tolerated dose of 0.15 mg/kg FUdR and 2000 mg hydroxyurea per day in conjunction with high-dose folinic acid. Hematological toxicity was minor. Of the 18 patients in whom response could be evaluated, none had evidence of objective disease regression. Mucositis and diarrhea are the dose-limiting toxicities when continuous infusions of FUdR and high-dose folinic acid are combined with oral hydroxyurea, effects that are consistent with the observed toxicities for FUdR when administered alone or in combination with leucovorin.