2'3'-DIDEOXYCYTIDINE-INDUCED THYMIC LYMPHOMA CORRELATES WITH SPECIES-SPECIFIC SUPPRESSION OF A SUBPOPULATION OF PRIMITIVE HEMATOPOIETIC PROGENITOR CELLS IN MOUSE BUT NOT RAT OR HUMAN BONE-MARROW

The nucleoside analogue, 2',3'-dideoxycytidine (ddC), is a potent inhi bitor of HIV replication, and AIDS patients receiving ddC experience c linical improvement without significant hematologic toxicity. Repeated ddC administration (1,000 mg/kg per day) for 13 wk produces an increa sed incidence of thymic lymphoma in B6C3F1 mice. Previous studies reve al a common link between chemically induced and genetically associated models of mouse thymic lymphoma that involves a defect in a subpopula tion of primitive hematopoietic progenitor cells. This defect is chara cterized by suppression of a subpopulation of IL-3-responsive cells an d ablation of stem cell factor synergy with GM-CSF. The present study was undertaken to ascertain whether ddC produces the same pattern of b one marrow toxicity in mice, and whether this effect is observed in ra t and human bone marrow. ddC exposure in vivo and in vitro produced a select suppression of murine CFU identical to that previously describe d for other models of mouse thymic lymphoma. In contrast, this selecti ve CFU suppression was not observed in rat and human bone marrow or in CD34+ cells. These studies suggest that the mouse may not be a good p redictive model for ddC hematotoxicity in humans and that susceptibili ty to the development of thymic lymphoma may be unique to the mouse.