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a School of Health Sciences, University of Wolverhampton, Wolverhampton, United Kingdom;
b Departments of Clinical Sciences and
c Infectious Diseases, and
d Markey Cancer Center, University of Kentucky Medical Center, Lexington, Kentucky, USA;
e Academic Consulting Services Ltd., Codsall, United Kingdom; eMolecules for Health Inc., Richmond, Virginia, USA
Key Words. Bone marrow • Burst-forming unit–erythroid • Colony-forming unit-granulocyte-macrophage • Didox • Hematopoiesis • HIV-1 • Hydroxyurea • Ribonucleotide reductase inhibitors • Toxicity • Trimidox
Dr. Vincent S. Gallicchio, University of Kentucky, CAHP, Room 220, 121 Washington Avenue, Lexington, Kentucky 40536-0003, USA.
Inhibitors of the cellular enzyme ribonucleotide reductase (hydroxyurea, [HU]) have been proposed as a new therapeutic strategy for the treatment of HIV type-1 (HIV-1) infection. However, HU use may be limited by the frequent development of hematopoietic toxicity. We report here short-term hematopoietic toxicity in mice receiving HU when compared to either of two more potent 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. Effects on hematopoiesis were established by quantitating peripheral blood indices (hematocrit, hemoglobin, mean corpuscular volume, mean cell hemoglobin, mean corpuscular hemoglobin concentration, RBC, and WBC) and numbers of colony-forming units-granulocyte-macrophage (CFU-GM) and BFU-E from bone marrow and spleen. HU produced rapid induction of a macrocytic hypochromic anemia and altered white blood cell kinetics associated with myelosuppression defined as reduced marrow organ cellularity and induction of splenic extramedullary hematopoiesis. Compared to HU, TX and DX induced fewer changes in peripheral blood indices and CFU-GM and BFU-E per hematopoietic organ. In vitro 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 200 µM). HU inhibited colony formation more than either DX or TX. These in vivo and in vitro studies suggest that novel ribonucleotide reductase inhibitors TX and DX may provide an effective alternative to HU in HIV-1 therapy because they demonstrate reduced hematopoietic toxicity.
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