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Three nucleoside analogues, 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyinosine (ddI), and 2',3'-dideoxycytosine (ddC), were evaluated for their potential myelotoxic effects to normal human hematopoietic progenitor cells. The myeloid (granulocyte-monocyte colony-forming units, CFU-gm) and erythroid (erythroid burst-forming units, BFU-e: and erythroid colony-forming units, CFU-e) committed progenitor cells were exposed to the agents for a 1-h period prior to culture in a microcapillary assay or continuously exposed during the entire culture period. Both ddA and ddI (100 microM) were mildly toxic (less than 50% colony inhibition) to human CFU-gm, BFU-e, and CFU-e following either 1-h or continuous exposures. Marrow progenitor sensitivities to ddA and ddI were indistinguishable. Colony inhibition ranged from 47% to 67% for 1-h ddC exposure (100 microM), values that were comparable to ddA and ddI. Continuous exposure to ddC was highly myelotoxic to human hematopoietic progenitors, with concentrations of 10 and 100 microM suppressing colony formation by 79%-92% and 93%-97%, respectively. These results demonstrate that 1-h and continuous exposures to ddA and ddI were similarly myelotoxic to human hematopoietic cells, whereas a 1-h exposure to ddC was equivalent to ddA and ddI, yet continuous ddC exposure was extremely toxic to marrow cell progenitors.

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.