Synergistic cytotoxic effect of azidothymidine and recombinant interferon
alpha on normal human bone marrow progenitor cells
E Berman, R Duigou-Osterndorf, SE Krown, MP Fanucchi, J Chou, MS Hirsch, BD Clarkson and TC Chou
Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York 10021.
Azidothymidine (AZT) and interferon alpha (IFN-alpha) are among the drugs
showing strong in vitro activity against the human immunodeficiency virus
type-1 (HIV-1). Each drug, however, has significant toxicity against normal
marrow progenitor cells that frequently proves dose-limiting in patients.
In this study, AZT and recombinant IFN-alpha 2a (rIFN-alpha 2a) were tested
as single agents and in combination against normal myeloid (CFU-GM) and
erythroid (BFU- E) colony forming cells in a standard methylcellulose
culture assay. The data were analyzed using a quantitative computerized
analysis based on the median-effect principle and the isobologram equation
as described by Chou and Talalay (Adv Enz Regul 22:27, 1984). The ED90 for
BFU-E and CFU-GM inhibition was then compared with previously measured in
vivo plasma levels of each drug and the ED90 for the anti-HIV-1 effect in
vitro. We demonstrate that (a) the drugs are strongly synergistic in
inhibiting marrow progenitor cell growth and that this synergism occurs at
drug levels that are within the range of measured plasma levels in phase I
clinical trials, (b) BFU-E are more sensitive than CFU-GM to the inhibiting
effects of AZT, rIFN-alpha 2a or both drugs in combination, (c) the drug
concentrations in combination that synergistically inhibit bone marrow
progenitors are much higher than those required to inhibit HIV-1
replication in vitro, and (d) the anti- HIV-1 effect for the combination of
AZT and rIFN-alpha 2a was clearly superior to the effect of AZT or
rIFN-alpha 2a alone as indicated by the combination index and the
dose-reduction index. These data suggest that substantially lower doses of
AZT and rIFN-alpha than those currently being tested in clinical trials
might not only maintain a strong synergistic anti-HIV-1 effect but might
also avoid significant hematologic toxicity.
Volume 74,
Issue 4,
pp. 1281-1286,
09/01/1989
Copyright © 1989 by The American Society of Hematology
