PHASE-I EVALUATION OF TETRAHYDROURIDINE COMBINED WITH CYTOSINE-ARABINOSIDE

1 January 1979

journal article
research article

Vol. 63 (8) , 1245-1249

Abstract

In conventional clinical use, cytosine arabinoside (ara-C) is rapidly deaminated by pyrimidine nucleoside deaminase to the nontoxic compound uracil arabinoside. Tetrahydrouridine (THU) effectively inhibits this enzymatic degradation but is by itself nontoxic. Concomitant administration of THU markedly increases the myelosuppressive potency of ara-C. When 25 or 50 mg/kg of THU i.v. and 0.1-0.2 mg/kg of ara-C i.v. are given daily .times. 5 days, they produce moderate-to-severe leukopenia and mild-to-moderate thrombocytopenia. A dose of 25 mg/kg of THU with 0.1 mg/kg of ara-C i.v. daily .times. 5 days appears appropriate for phase II studies; it produces myelosuppression equivalent to that produced by 3 mg/kg per day .times. 5 days of ara-C alone. No toxicity occurred with this combination that would not have been expected from ara-C given alone in an equitoxic dose. Although THU and ara-C produced a reduction in peripheral blood and bone marrow blast cells in 8 of 9 patients with acute leukemia, bone marrow remission did not occur in any of these heavily pretreated patients.

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