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dc.contributor.authorMayhew, Christopher N.
dc.contributor.authorSumpter, Ryan
dc.contributor.authorInayat, Mohammed
dc.contributor.authorCibull, Michael
dc.contributor.authorPhillips, Jonathan D.
dc.contributor.authorElford, Howard L.
dc.contributor.authorGallicchio, Vincent S.
dc.date.accessioned2008-06-04T11:02:25Z
dc.date.available2008-06-04T11:02:25Z
dc.date.issued2005
dc.identifier.citationAntiviral Research, 65(1): 13-22
dc.identifier.issn0166-3542
dc.identifier.pmid15652967
dc.identifier.doi10.1016/j.antiviral.2004.09.003
dc.identifier.urihttp://hdl.handle.net/2436/29451
dc.description.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.
dc.language.isoen
dc.publisherElsevier Science Direct
dc.relation.urlhttp://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
dc.subjectLymphoproliferative disease
dc.subject.meshAnimals
dc.subject.meshAntiviral Agents
dc.subject.meshB-Lymphocytes
dc.subject.meshBenzamidines
dc.subject.meshDidanosine
dc.subject.meshDrug Therapy, Combination
dc.subject.meshEnzyme Inhibitors
dc.subject.meshFemale
dc.subject.meshHydroxamic Acids
dc.subject.meshHydroxyurea
dc.subject.meshLeukemia Virus, Murine
dc.subject.meshLeukemia, Experimental
dc.subject.meshLymphocyte Activation
dc.subject.meshMice
dc.subject.meshMice, Inbred C57BL
dc.subject.meshMurine Acquired Immunodeficiency Syndrome
dc.subject.meshRetroviridae Infections
dc.subject.meshReverse Transcriptase Inhibitors
dc.subject.meshRibonucleotide Reductases
dc.subject.meshTreatment Outcome
dc.subject.meshTumor Virus Infections
dc.titleCombination of inhibitors of lymphocyte activation (hydroxyurea, trimidox, and didox) and reverse transcriptase (didanosine) suppresses development of murine retrovirus-induced lymphoproliferative disease.
dc.typeJournal article
dc.identifier.journalAntiviral Research
html.description.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.


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