Selective depletion of DNA precursors: an evolving strategy for potentiation of dideoxynucleoside activity against human immunodeficiency virus.
Human immunodeficiency virus type 1 (HIV-1) is wholly dependent on its host cell for a variety of essential metabolites. Among the latter are the deoxynucleoside-5'-triphosphates (dNTPs) required for reverse transcription of the single-stranded RNA viral genome into double-stranded viral DNA. Since viral DNA synthesis has an absolute requirement for all four dNTPs, restriction of a single one of these is sufficient to inhibit HIV-1 replication. To date, this therapeutic strategy has been most successful when depletion of the individual dNTP is coupled with exposure to its corresponding chain-terminating dideoxynucleoside (ddN). While several examples of such combined therapy have been defined and studied in vitro, that which has been investigated most extensively at both the laboratory and the clinical level is ddATP exposure combined with dATP depletion [with dATP restriction being induced by the ribonucleotide reductase inhibitor hydroxyurea (HU) and ddATP generated from its prodrug 2',3'-dideoxyinosine (ddI)]. Several long-term clinical trials of the hydroxyurea/2',3'-dideoxyinosine combination have been completed, with plasma viral RNA being reduced to undetectable levels in a substantial fraction (one-third to one-half) of the patients treated. The major advantages of this and analogous combinations discussed in this review are their low cost relative to other current multiple drug protocols and their potential for retention of activity against drug-resistant HIV mutants.
Johns
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DG
Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. johnsd@dc37a.nci.nih.gov
Gao
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D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D015224:Dideoxynucleosides / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D015215:Zidovudine / Q000008:administration & dosage / Q000494:pharmacology
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D004791:Enzyme Inhibitors; D015215:Zidovudine; D012264:Ribonucleotide Reductases; D006918:Hydroxyurea