Effect of Hydroxyurea on Fetal Hemoglobin Synthesis in Patients With Sickle Cell Anemia

Hydroxyurea is a cell-cycle specific agent that blocks DNA synthesis by inhibiting ribonucleotide reductase, the enzyme that converts ribonucleotides to deoxyribonucleotides. Hydroxyurea has been shown to induce the production of HbF, initially in non-human primates, and now in more than fifty patients with sickle cell anemia. The majority of patients with sickle cell disease respond to the drug with a more than two-fold increase in HbF levels; in some patients the percent of HbF exceeds 10 or 15 percent. It is estimated that levels of 20 percent are required to substantially reduce the sickling propensity of red cells and to modulate disease severity. We propose now to treat several patients chronically with hydroxyurea to monitor the durability of the response, to examine for unanticipated long term sided effects and to determine hematological changes occurring longitudinally. Such patients will be candidates for protocols determining the ability of other agents to enhance HbF synthesis, especially in hydroxyurea non-responders. Finally, a series of in vitro studies are planned to attempt to develop predictors of response.