Comparison of dideoxynucleoside drugs (DDI and zidovudine) and induction of hematopoietic toxicity using normal human bone marrow cells in vitro

The drug zidovudine (AZT), a synthetic thymidine analog, has been used in the treatment of acquired immunodeficiency syndrome (AIDS). Clinical use of zidovudine has induced hematopoietic toxicity manifested by anemia, neutropenia and on occasion thrombocytopenia. Such toxicity has stimulated the development of alternative dideoxynucleoside drugs capable of exerting anti-viral potency while minimizing the risk for inducing organ toxicities. One such alternative dideoxynucleoside drug is 2′,3′-dideoxyinosine (ddI). Recent therapeutic anti-viral strategy, now undergoing clinical trial, is the evaluation of combined zidovudine ddI treatment. Unfortunately a complete assessment of their potential toxicity using this drug regimen has not been thoroughly examined. We report here the results of studies comparing the toxicity profile of zidovudine versus ddI on their ability to influence several classes of hematopoietic progenitor stem cells, e.g. granulocyte-macrophage (CFU-GM), megakaryocyte (CFU-Meg) and erythroid (CFU-E/BFU-E) following in vitro co-culture with normal human bone marrow. Since the main clinical toxicity associated with zidovudine in vitro is the development of anemia, additional in vitro studies compared the dose-escalation effect of erythropoietin in the presence of combined zidovudine and ddI. CFU-GM, CFU-Meg, CFU-E and BFU-E were all reduced ( P