Inhibitory effect of azidothymidine, 2'-3'-dideoxyadenosine, and 2'-3'-dideoxycytidine on in vitro growth of hematopoietic progenitor cells from normal persons and from patients with AIDS.
Therapy of patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) with azidothymidine (AZT) and 2'-3'-dideoxycytidine (ddC) is complicated by severe anemia, neutropenia, and thrombocytopenia, the cause of which is unknown. We therefore tested the effect of AZT, ddC, and an additional 2'-3'-dideoxynucleoside analogue, 2'-3'-dideoxyadenosine (ddA), on the hematopoietic progenitor cells derived from the bone marrow of normal persons and patients with AIDS/ARC. All three substances dose-dependently inhibited the in vitro colony formation of the pluripotent (CFU-GEMM), as well as the erythroid (BFU-E) and granulocyte-macrophage progenitor cells (CFU-GM). The 50% inhibition of normal progenitors by AZT occurred at 0.13 microM for CFU-GEMM, 0.32 microM for BFU-E, and 1.9 microM for CFU-GM, by ddA at 15 microM for CFU-GEMM, 40 microM for BFU-E, and 140 microM for CFU-GM. ddC was the most toxic agent and already inhibited 71% +/- 16% (mean +/- standard error of the mean [SEM]) of CFU-GEMM and 52% +/- 22% of BFU-E at 0.1 microM, whereas the 50% inhibition of CFU-GM was reached at 0.3 microM. Hematotoxicity occurred at concentrations lower than necessary to inhibit the human immunodeficiency virus (HIV), except for ddA, which is 100 times less toxic than AZT whereas its antiviral effect is only 10 times less. The inhibition of progenitor cells from AIDS patients by the 2'-3'-dideoxynucleosides was comparable to normal progenitors, except for a higher sensitivity of AIDS-derived CFU-GEMM and BFU-E to AZT.
Ganser
A
A
Department of Hematology, University of Frankfurt, FRG.
Greher
J
J
Völkers
B
B
Staszewski
S
S
Hoelzer
D
D
D000386:AIDS-Related Complex / Q000473:pathology; D000163:Acquired Immunodeficiency Syndrome / Q000473:pathology*; D001853:Bone Marrow / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003853:Deoxyribonucleosides / Q000633:toxicity*; D016048:Dideoxyadenosine; D015224:Dideoxynucleosides / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000633:toxicity*; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D016047:Zalcitabine; D015215:Zidovudine / Q000633:toxicity
D003853:Deoxyribonucleosides; D015224:Dideoxynucleosides; D006131:Growth Inhibitors; D015215:Zidovudine; D016048:Dideoxyadenosine; D016047:Zalcitabine