In Vivo and In Vitro Comparison of the Short-Term Hematopoietic Toxicity Between Hydroxyurea and Trimidox or Didox, Novel Ribonucleotide Reductase Inhibitors with Potential Anti-HIV-1 Activity

摘要: Inhibitors of the cellular enzyme ribonucleotide reductase (hydroxyurea, [HU]) have been proposed as a new therapeutic strategy for treatment HIV type-1 (HIV-1) infection. However, HU use may be limited by frequent development hematopoietic toxicity. We report here short-term toxicity in mice receiving when compared to either two more potent inhibitors, didox (DX) and trimidox (TX). High dose HU, DX, TX monotherapy (500, 460, 220 mg/kg/day respectively) was administered daily i.p. injection (Monday-Friday) C57BL/6 10 weeks. Effects on hematopoiesis were established quantitating peripheral blood indices (hematocrit, hemoglobin, mean corpuscular volume, cell hemoglobin concentration, RBC, WBC) numbers colony-forming units-granulocyte-macrophage (CFU-GM) BFU-E from bone marrow spleen. produced rapid induction macrocytic hypochromic anemia altered white kinetics associated with myelosuppression defined reduced organ cellularity splenic extramedullary hematopoiesis. Compared DX induced fewer changes CFU-GM per organ. In vitro human murine colony formations assayed presence escalation or (0, 1, 10, 50, 100, 200 μM). inhibited formation than TX. These vivo studies suggest that novel inhibitors provide an effective alternative HIV-1 therapy because they demonstrate