Hydroxyurea

Hydroxyurea is an inhibitor of ribonucleoside diphosphate reductase with IC40, IC70 and IC90 values of 1.5 × 10^-3 M, 3 × 10^-3 M, and 10^-2 M, respectively [1].

Ribonucleoside diphosphate reductase is the rate-limiting enzyme responsible for the conversion of ribonucleotides to deoxyribonucleotides which are essential for DNA synthesis. Thus, inhibition of the enzyme has cellular division arrested in the S phase [2].

In activated peripheral blood mononuclear cells (PBMCs), Hydroxyurea inhibited HIV-1 replication with IC90 value of 0.4 mM [2]. In erythroid cells obtained from β-thalassemia/hemoglobin E (β-Thal/HbE) patients, treatment of 30 μM Hydroxyurea for 96 h significantly increased the fractional fetal hemoglobin (HbF) content [3].

In a mouse xenograft model with SW620 tumors, mice received the combination treatment of Ganciclovir (100 mg/kg, i.p.) and Hydroxyurea (1500 mg/kg, i.p.) for 5 consecutive days showed greater delay on tumor growth compared with Ganciclovir treatment alone, with many of the tumors actually decreasing below their initial sizes. Compared with Ganciclovir treatment alone, addition of Hydroxyurea resulted in increased DNA synthesis inhibition and delayed progression through S phase following removal of drug [4].

References:

[1]. Krakoff I H, Brown N C, Reichard P. Inhibition of ribonucleoside diphosphate reductase by hydroxyurea. Cancer Research, 1968, 28(8): 1559-1565.

[2]. Lori F, Lisziewicz J. Rationale for the use of hydroxyurea as an anti-human immunodeficiency virus drug. Clinical Infectious Diseases, 2000, 30(2): S193-S197.

[3]. Watanapokasin Y, Chuncharunee S, Sanmund D, et al. In vivo and in vitro studies of fetal hemoglobin induction by hydroxyurea in beta-thalassemia/hemoglobin E patients. Gene therapy, 2002, 9(15): 1023-1030.

[4]. Boucher P D, Ostruszka L J, Murphy P J, et al. Hydroxyurea significantly enhances tumor growth delay in vivo with herpes simplex virus thymidine kinase/ganciclovir gene therapy. Gene therapy, 2002, 9(15): 1023-1030.