Benzylacyclouridine reverses azidothymidine-induced marrow suppression
without impairment of anti-human immunodeficiency virus activity
P Calabresi, A Falcone, MH St Clair, MC Wiemann, SH Chu and JW Darnowski
Department of Medicine, Roger Williams General Hospital, Providence, RI
02908.
Increased extracellular concentrations of uridine (Urd) have been reported
to reduce, in vitro, azidothymidine (AZT)-induced inhibition of human
granulocyte-macrophage progenitor cells without impairment of its antihuman
immunodeficiency virus (HIV) activity. Because of the clinical toxicities
associated with chronic Urd administration, the ability of
benzylacyclouridine (BAU) to effect, in vivo, AZT-induced anemia and
leukopenia was assessed. This agent inhibits Urd catabolism and, in vivo,
increases the plasma concentration of Urd in a dose- dependent manner,
without Urd-related toxicity. In mice rendered anemic and leukopenic by the
administration of AZT for 28 days in drinking water (1.5 mg/mL), the
continued administration of AZT plus daily BAU (300 mg/kg, orally)
partially reversed AZT-induced anemia and leukopenia (P less than .05),
increased peripheral reticulocytes (to 4.9%, P less than .01), increased
cellularity in the marrow, and improved megaloblastosis. When
coadministered with AZT from the onset of drug administration, BAU reduced
AZT-induced marrow toxicity. In vitro, at a concentration of 100 mumol/L,
BAU possesses minimal anti- HIV activity and has no effect on the ability
of AZT to reverse the HIV- induced cytopathic effect in MT4 cells. The
clinical and biochemical implications of these findings are discussed.
Volume 76,
Issue 11,
pp. 2210-2215,
12/01/1990
Copyright © 1990 by The American Society of Hematology
