Laboratory and clinical studies of biochemical modulation by hydroxyurea.

Abstract

Hydroxyurea is a potent inhibitor of the enzyme ribonucleotide reductase. Due to its effects on cellular deoxyribonucleotide pools, hydroxyurea can modulate the activity of several pyrimidine and purine antimetabolites. As an inhibitor of DNA repair, it can potentially interact with DNA-damaging agents such as alkylating agents or inhibitors of topoisomerase II. Both cytokinetic and biochemical interactions occur between hydroxyurea and cytarabine (ara-C), which account for their synergistic cytotoxicity. Inhibition of ribonucleotide reductase by hydroxyurea depletes cellular deoxycytidine triphosphate pools, thereby enhancing ara-C uptake and phosphorylation to ara-C triphosphate. In a phase II clinical trial, the combination of hydroxyurea and ara-C produced a 43% response rate in patients with refractory malignant lymphoma. Studies in murine leukemia models have demonstrated therapeutic synergy when hydroxyurea is combined with fluoropyrimidines. High levels of deoxyuridine monophosphate that have been associated with resistance to 5-fluorouracil can be suppressed by hydroxyurea, leading to greater inhibition of thymidylate synthase. Despite the strong biochemical rationale for the use of hydroxyurea and 5-fluorouracil in combination, few clinical trials have been conducted thus far. Antimetabolites and topoisomerase II inhibitors have also been shown to be synergistic in vitro. Hydroxyurea has been shown to enhance the formation of DNA strand breaks produced by amsacrine and to produce synergistic cytotoxicity with etoposide. A phase I clinical trial of these drugs has demonstrated bone marrow suppression to be the major toxicity of the combination. In summary, hydroxyurea has been shown to undergo cytokinetic and biochemical interactions with a number of established antitumor agents. Clinical trials of hydroxyurea in combination with these agents have identified doses and schedules of administration that produce acceptable levels of clinical toxicity and appear feasible for further testing.