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    Combination of inhibitors of lymphocyte activation (hydroxyurea, trimidox, and didox) and reverse transcriptase (didanosine) suppresses development of murine retrovirus-induced lymphoproliferative disease.

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    Authors
    Mayhew, Christopher N.
    Sumpter, Ryan
    Inayat, Mohammed
    Cibull, Michael
    Phillips, Jonathan D.
    Elford, Howard L.
    Gallicchio, Vincent S.
    Issue Date
    2005
    
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    Abstract
    The ribonucleotide reductase inhibitor hydroxyurea (HU) has demonstrated some benefit as a component of drug cocktails for the treatment of HIV-1 infection. However, HU is notoriously myelosuppressive and often administered only as salvage therapy to patients with late-stage disease, potentially exacerbating the bone marrow toxicity of HU. In this report we have compared the antiviral effects of HU and two novel RR inhibitors trimidox (3,4,5-trihydroxybenzamidoxime) and didox (3,4-dihydroxybenzohydroxamic acid) in combination with didanosine (2,3-didoxyinosine; ddI) in the LPBM5 MuLV retrovirus model (murine AIDS). We also evaluated the effects of these drug combinations on the hematopoietic tissues of LPBM5 MuLV-infected animals. The combination of RR inhibitors and ddI was extremely effective (DX>TX>HU) in inhibiting development of retrovirus-induced disease (splenomegaly, hypergammaglobulinemia, activated B-splenocytes and loss of splenic architecture). In addition, relative levels of proviral DNA were significantly lower in combination drug-treated animals compared to infected controls. Evaluation of femur cellularity, numbers of marrow-derived myeloid progenitor cells (CFU-GM and BFU-E) and peripheral blood indices revealed that TX and DX in combination with ddI were well-tolerated. However, treatment with HU and ddI induced moderate myelosuppression. These data demonstrate that RR inhibitors in combination with ddI provide significant protection against retroviral disease in murine AIDS. Moreover, the novel RR inhibitors TX and DX appear to be more effective and less myelosuppressive than HU when administered with ddI in this model.
    Citation
    Antiviral Research, 65(1): 13-22
    Publisher
    Elsevier Science Direct
    Journal
    Antiviral Research
    URI
    http://hdl.handle.net/2436/29451
    DOI
    10.1016/j.antiviral.2004.09.003
    PubMed ID
    15652967
    Additional Links
    http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T2H-4DS7NWT-2&_user=1644469&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000054077&_version=1&_urlVersion=0&_userid=1644469&md5=3a5c40ddbe951fb57d602aa5fdfd6316
    Type
    Journal article
    Language
    en
    ISSN
    0166-3542
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.antiviral.2004.09.003
    Scopus Count
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    Research Institute in Healthcare Science

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    Related articles

    • Suppression of retrovirus-induced immunodeficiency disease (murine AIDS) by trimidox and didox: novel ribonucleotide reductase inhibitors with less bone marrow toxicity than hydroxyurea.
    • Authors: Mayhew CN, Mampuru LJ, Chendil D, Ahmed MM, Phillips JD, Greenberg RN, Elford HL, Gallicchio VS
    • Issue date: 2002 Nov
    • In vivo examination of hydroxyurea and the novel ribonucleotide reductase inhibitors trimidox and didox in combination with the reverse transcriptase inhibitor abacavir: suppression of retrovirus-induced immunodeficiency disease.
    • Authors: Sumpter LR, Inayat MS, Yost EE, Duvall W, Hagan E, Mayhew CN, Elford HL, Gallicchio VS
    • Issue date: 2004 Jun
    • In vivo and in vitro comparison of the short-term hematopoietic toxicity between hydroxyurea and trimidox or didox, novel ribonucleotide reductase inhibitors with potential anti-HIV-1 activity.
    • Authors: Mayhew CN, Phillips JD, Greenberg RN, Birch NJ, Elford HL, Gallicchio VS
    • Issue date: 1999
    • Short-term treatment with novel ribonucleotide reductase inhibitors Trimidox and Didox reverses late-stage murine retrovirus-induced lymphoproliferative disease with less bone marrow toxicity than hydroxyurea.
    • Authors: Mayhew CN, Phillips JD, Cibull ML, Elford HL, Gallicchio VS
    • Issue date: 2002 Sep
    • Effective use of ribonucleotide reductase inhibitors (Didox and Trimidox) alone or in combination with didanosine (ddI) to suppress disease progression and increase survival in murine acquired immunodeficiency syndrome (MAIDS).
    • Authors: Mayhew C, Oakley O, Piper J, Hughes NK, Phillips J, Birch NJ, Elford HL, Gallicchio VS
    • Issue date: 1997 Nov
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