In vitro myelotoxicity of 2',3'-dideoxynucleosides on human hematopoietic progenitor cells

Abstract

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.