Effect of hydroxyurea and dideoxyinosine on intracellular 3'-deoxyadenosine-5'-triphosphate concentrations in HIV-infected patients.

TitleEffect of hydroxyurea and dideoxyinosine on intracellular 3'-deoxyadenosine-5'-triphosphate concentrations in HIV-infected patients.
Publication TypeJournal Article
Year of Publication2007
AuthorsBakshi RP, Hamzeh F, Frank I, Eron JJ, Bosch RJ, Rosenkranz SL, Cramer YS, Ussery M, Flexner C
JournalAIDS Res Hum Retroviruses
Volume23
Issue11
Pagination1360-5
Date Published2007 Nov
ISSN0889-2229
KeywordsAnti-HIV Agents, Cytosol, Deoxyadenine Nucleotides, Didanosine, Double-Blind Method, Drug Therapy, Combination, HIV Infections, Humans, Hydroxyurea, Leukocytes, Mononuclear
Abstract

Hydroxyurea (HU) significantly enhances the antiretroviral effects of the adenosine analog reverse transcriptase inhibitor dideoxyinosine (ddI). This is believed to be due to a reduction in intracellular de-oxyadenosine triphosphate (dATP) concentrations resulting from HU-mediated inhibition of ribonucleotide reductase (RnR). The effect of combined HU-ddI treatment on intracellular dATP pools in vivo has not been examined. We measured intracellular dATP concentrations in peripheral blood mononuclear cells (PBMCs) from 69 HIV-infected patients receiving 1000 or 1500 mg HU daily for 14 days, 200 mg ddI twice daily for 14 days, or a combination of the two drugs. Median intracellular dATP concentrations decreased from base-line to day 14 by 46% in the ddI + 1000 mg HU arm and by 62% in the ddI + 1500 mg HU arm. When compared to the HU monotherapy arms, these changes proved statistically significant (p = 0.018; stratified Wilcoxon rank-sum test). These findings support reduced intracellular dATP as the mechanism of ddI-HU synergistic activity, and indicate that changes in intracellular nucleotides contribute to HU activity and toxicity in patients. Since a significant reduction in dATP was measurable only when ddI was combined with HU, the antiretroviral activity of ddI may be more complex than previously assumed.

DOI10.1089/aid.2007.0078
Alternate JournalAIDS Res. Hum. Retroviruses
PubMed ID18184078
Grant ListAI-25868 / AI / NIAID NIH HHS / United States
AI-27668 / AI / NIAID NIH HHS / United States
AI-38855 / AI / NIAID NIH HHS / United States
AI-38858 / AI / NIAID NIH HHS / United States
RR-00046 / RR / NCRR NIH HHS / United States
RR-00052 / RR / NCRR NIH HHS / United States
U01 AI025868 / AI / NIAID NIH HHS / United States
U01 AI069423 / AI / NIAID NIH HHS / United States