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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AuthorsMayhew, Christopher N.
Phillips, Jonathan D.
Elford, Howard L.
Gallicchio, Vincent S.
MetadataShow full item record
AbstractThe 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.
CitationAntiviral Research, 65(1): 13-22
PublisherElsevier Science Direct
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- 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
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- Authors: Mayhew C, Oakley O, Piper J, Hughes NK, Phillips J, Birch NJ, Elford HL, Gallicchio VS
- Issue date: 1997 Nov