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    Suppression of retrovirus-induced immunodeficiency disease (murine AIDS) by trimidox and didox: novel ribonucleotide reductase inhibitors with less bone marrow toxicity than hydroxyurea.

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    Authors
    Mayhew, Christopher N.
    Mampuru, Leseilane J.
    Chendil, Damodoran
    Ahmed, Mansoor M.
    Phillips, Jonathan D.
    Greenberg, Richard N.
    Elford, Howard L.
    Gallicchio, Vincent S.
    Issue Date
    2002
    
    Metadata
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    Abstract
    Recently, the use of the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU) in combination with nucleoside analogs has gained attention as a potential strategy for anti-HIV-1 therapy. However, appeal for the long-term use of HU in HIV-1 infection may be limited by its propensity to induce hematopoietic toxicity. We report a comparison of the efficacy and bone marrow toxicity of HU (400 and 200 mg/kg/day) with the novel RR inhibitors and free radical-scavenging compounds didox (DX; 3,4-dihydroxybenzohydroxamic acid; 350 mg/kg/day) and trimidox (TX; 3,4,5-trihydroxybenzamidoxime; 175 mg/kg/day) in the murine AIDS (LPBM5 MuLV) model of retrovirus infection. Infected mice received daily drug treatment for 8 weeks. Efficacy was determined by measuring drug effects on retroviral-induced disease progression (i.e. development of splenomegaly and hypergammaglobulinemia) and by evaluating splenic levels of proviral DNA. Bone marrow toxicity was evaluated by measuring peripheral blood indices (WBC, hematocrit and reticulocyte counts), femoral cellularity and by determining the numbers of hematopoietic progenitor cells (CFU-GM, BFU-E) per femur and spleen. Compared to infected controls receiving no drug treatment, disease progression was significantly suppressed by TX, DX and HU. However, HU was associated with mortality and induced significant hematopoietic toxicity in a time- and dose-dependent manner. Conversely, TX and DX effectively inhibited retrovirus-induced disease but did not induce hematopoietic toxicity. These results suggest that due to their reduced hematopoietic toxicity and ability to inhibit disease progression in murine AIDS, TX and DX may offer effective alternatives to HU therapy in HIV-1 infection.
    Citation
    Antiviral Research, 56(2): 167-181
    Publisher
    Elsevier Science Direct
    Journal
    Antiviral Research
    URI
    http://hdl.handle.net/2436/29472
    DOI
    10.1016/S0166-3542(02)00108-0
    PubMed ID
    12367722
    Additional Links
    http://www.ingentaconnect.com/content/els/01663542/2002/00000056/00000002/art00108?token=005015399702c275c277b422c496773487834702c556e59592f653b2a2d3a7c4e724770bb3f9837c
    Type
    Journal article
    Language
    en
    ISSN
    0166-3542
    ae974a485f413a2113503eed53cd6c53
    10.1016/S0166-3542(02)00108-0
    Scopus Count
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    Research Institute in Healthcare Science

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