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

Inhibitors of the cellular enzyme ribonucleotide reductase (hydroxyurea, [H U]) have been proposed as a new therapeutic strategy for the treatment of H IV type-1 (HIV-1) infection. However, HU use may be limited by the frequent development of hematopoietic toxicity. We report here short-term hematopoi etic toxicity in mice receiving HCT when compared to either of two more pot ent enzyme inhibitors, didox (DX) and trimidox (TX). High dose HU, DX, and TX monotherapy (500, 460, and 220 mg/kg/day respectively) was administered by daily i.p. injection (Monday-Friday) to C57BL/6 mice for 10 weeks. Effec ts on hematopoiesis were established by quantitating peripheral blood indic es (hematocrit, hemoglobin, mean corpuscular volume, mean cell hemoglobin, mean corpuscular hemoglobin concentration, RBC, and WBC) and numbers of col ony-forming units-granulocyte-macrophage (CFU-GM) and BFU-E from bone marro w and spleen. HU produced rapid induction of a macrocytic hypochromic anemi a and altered white blood cell kinetics associated with myelosuppression de fined as reduced marrow organ cellularity and induction of splenic extramed ullary hematopoiesis. Compared to HU, TX and DX induced fewer changes in pe ripheral blood indices and CFU-GM and BFU-E per hematopoietic organ. In vit ro human and murine marrow CFU-GM and BFU-E colony formations were assayed in the presence of dose escalation HU, DX, or TX (0, 1, 10, 50, 100, and 20 0 mu M). HU inhibited colony formation more than either DX or TX. These in vivo and in vitro studies suggest that novel ribonucleotide reductase inhib itors TX and DX may provide an effective alternative to HU in HIV-1 therapy because they demonstrate reduced hematopoietic toxicity.