PHASE-I STUDY OF 5-DAY CONTINUOUS-INFUSION FLUORODEOXYURIDINE AND HIGH-DOSE FOLINIC ACID WITH ORAL HYDROXYUREA

Fluorodeoxyuridine (FUdR), the deoxynucleoside metabolite of 5-fluorou racil (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 hypothe sized that the simultaneous administration of FUdR, leucov orin, and hydroxyurea might afford more effective inhibition of TS. Th irty-six patients with neoplastic disease Considered refractory to sta ndard therapy were entered into this phase I protocol. Treatment was a dministered on days 1 through 5 of a 28-day cycle and consisted of fol inic 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. in fusion, and hydroxyurea given p.o. once per day at doses ranging from 0 to 2500 mg in 500-mg increments. The hydroxyurea and FUdR levels wer e escalated in a sequential fashion. The majority of patients had refr actory breast or lung cancer. Dose-limiting toxicities were mucositis and diarrhea at the maximally tolerated dose of 0.15 mg/kg FUdR and 20 00 mg hydroxyurea per day in conjunction with high-dose folinic acid. Hematological toxicity was minor. Of the is patients in whom response could be evaluated, none had evidence of objective disease regression. Mucositis and diarrhea are the dose-limiting toxicities when continuo us 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.