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 vivo 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 < 0.05) following incubation with either zidovudine or ddI thus determining their ID50 concentrations for these classes of hematopoietic progenitors; however, the extent of toxicity associated with ddI was lower than what was observed with zidovudine. More importantly, dose-escalation of erythropoietin was effective in reversing the inhibition observed for ddI on erythroid progenitors CFU-E and BFU-E (P < 0.05), an effect not reported with zidovudine in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
Gallicchio
V S
VS
Department of Veterans Affairs, Veterans Administration Medical Center, Lexington, Kentucky.
Hughes
N K
NK
Tse
K F
KF
D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D003114:Colony-Forming Units Assay; D016049:Didanosine / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004921:Erythropoietin / Q000008:administration & dosage; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects*
D004921:Erythropoietin; D015215:Zidovudine; D016049:Didanosine