COMPARISON OF THE ACTIONS OF HYDROXYUREA AND 9-BETA-D-ARABINOFURANOSYL-2-FLUOROADENINE ON CYTOTOXICITY AND METABOLISM OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE IN HUMAN T-CELL LEUKEMIA-CELL LINE MOLT-3

Background - The combinations of 1-beta-D-arabinofuranosylcytosine (ar a-C) and hydroxyurea (HU) or fludarabine arabinofuranosyl-2-fluoroaden ine-5'-monophosphate, F-ara-AMP) have been introduced into clinical th erapeutic regimens, because HU and F-ara-ATP inhibit RR activity and r educe dNTP level, leading to a higher rate of dCK activity and a great er accumulation of ara-CTP in cells. However, comparative studies of t he biochemical modulation of HU and F-ara-A on ara-C metabolism have n ot been precisely reported. Methods and Results - In-vitro median effe ct analyses demonstrated that HU and ara-C showed synergistic drug int eractions at concentrations more than 40 mu M of HU. con the other han d, F-ara-A and ara-C showed a synergistic effect at less than 1 mu M F -ara-A but additive or antagonistic effect at more than 1.5 mu M F-ara -A. When compared at their respective IC(50)s and IC80s, HU produced h igher intracellular ara-CTP than F-ara-A. Incorporation of radioactive ara-C or F-ara-A into cells was partially inhibited by unlabeled F-ar a-A or ara-C, respectively. Measurement of DNA polymerase activities b y the permeabilized cell method showed an additive inhibitory effect o f ara-CTP and F-ara-ATP on DNA polymerase activity under these experim ental conditions. HU and the lowest concentration of F-ara-A (3 mu M) mainly inhibited RR activity. However, higher concentrations of F-ara- A (7 and 10 mu M) showed bifunctional inhibitory effects on RR activit y and DNA synthesis, Conclusions - F-ara-A acts on the metabolism, of nucleic acids in different way depending on its concentration. This du al action of F-ara-A on RR activity and DNA synthesis should be taken into accounts when F-ara-A is used in combination with ara-C in a clin ical setting.