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

Rahul P. Bakshi, Fayez Hamzeh, Ian Frank, Joseph J. Eron, Ronald J. Bosch, Susan L. Rosenkranz, Yoninah S. Cramer, Michael Ussery, Charles Flexner

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1360-1365
Number of pages6
JournalAIDS research and human retroviruses
Volume23
Issue number11
DOIs
StatePublished - Nov 1 2007

ASJC Scopus subject areas

  • Immunology
  • Virology
  • Infectious Diseases

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