Rationale for the use of hydroxyurea as an anti-human immunodeficiency virus drug

Hydroxyurea has been extensively used in medical practice, mainly for treat ing chronic myelogenous leukemia, sickle cell anemia, and other diseases. I n light of its ability to inhibit DNA synthesis and to induce cell cycle ar rest through inhibition of ribonucleotide reductase, the effects of hydroxy urea on replication of human immunodeficiency virus type 1 (HIV-1) have bee n investigated. In vitro hydroxyurea has been shown to block HIV-1 reverse transcription and/or replication in quiescent peripheral blood mononuclear cells (PBMC) and macrophages, Hydroxyurea was also found to be synergistic with the nucleoside reverse transcriptase inhibitor didanosine and to inhib it HIV-1 replication ill activated PBMC; this inhibition may be due to a re duction in deoxynucleoside triphosphate pool sizes. Finally, hydroxyurea ha s been shown to sensitize didanosine-resistant mutants, Hydroxyurea may the refore be useful for limiting the spread of didanosine-resistant HIV-1 vari ants. The favorable toxicity profile of hydroxyurea and the lack of signifi cant overlapping toxicities with some of the nucleoside reverse transcripta se inhibitors, as well als their distinct mechanisms of action, have provid ed further rationale for use of these agents in combination therapies.