Different effect of benzylacyclouridine on the toxic and therapeutic
effects of azidothymidine in mice
A Falcone, JW Darnowski, RM Ruprecht, SH Chu, I Brunetti and P Calabresi
Department of Medicine, Roger Williams General Hospital, Boston, MA.
It has been reported that in vitro uridine (Urd) can reverse azidothymidine
(AZT) cytotoxicity without decreasing anti-human immunodeficiency virus
(HIV) activity. Our studies in mice have shown that daily oral doses of
benzylacyclouridine (BAU), an inhibitor of Urd breakdown, also reduces AZT
hematologic toxicity, presumably by elevating the plasma concentration of
Urd. We now extend these murine studies and report the effect of various
doses of exogenous Urd, various doses of BAU, or the combination of BAU and
Urd, administered daily, on AZT-induced toxicity. In mice receiving
concomitant AZT, daily doses of Urd of 1,000 to 2,000 mg/kg increase
peripheral reticulocytes and slightly reduce AZT-induced hematologic
toxicity. However, the range of effective doses is narrow, and higher doses
of Urd (greater than 3,000 mg/kg/d) significantly enhance hematologic
toxicity. At its most effective dose, (2,000 mg/kg/d), Urd produces 28%
mortality. In contrast, BAU doses up to 300 mg/kg/d reduced AZT-related
hematologic toxicity in a dose-dependent manner without mortality. Higher
daily doses of BAU and the combination of BAU with low doses of Urd were
not more effective. Studies conducted in mice infected with the Rauscher
murine leukemia virus (RLV) indicate that BAU does not impair the
antiretroviral effect of AZT when administered at doses that reduce
AZT-induced anemia and leukopenia. These findings may be significant for
the treatment of patients with acquired immunodeficiency syndrome (AIDS)
and AIDS-related complex.
Volume 76,
Issue 11,
pp. 2216-2221,
12/01/1990
Copyright © 1990 by The American Society of Hematology
