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dc.contributor.authorMayhew, Christopher N.
dc.contributor.authorMampuru, Leseilane J.
dc.contributor.authorChendil, Damodoran
dc.contributor.authorAhmed, Mansoor M.
dc.contributor.authorPhillips, Jonathan D.
dc.contributor.authorGreenberg, Richard N.
dc.contributor.authorElford, Howard L.
dc.contributor.authorGallicchio, Vincent S.
dc.date.accessioned2008-06-04T11:09:30Z
dc.date.available2008-06-04T11:09:30Z
dc.date.issued2002
dc.identifier.citationAntiviral Research, 56(2): 167-181
dc.identifier.issn0166-3542
dc.identifier.pmid12367722
dc.identifier.doi10.1016/S0166-3542(02)00108-0
dc.identifier.urihttp://hdl.handle.net/2436/29472
dc.description.abstractRecently, 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.
dc.language.isoen
dc.publisherElsevier Science Direct
dc.relation.urlhttp://www.ingentaconnect.com/content/els/01663542/2002/00000056/00000002/art00108?token=005015399702c275c277b422c496773487834702c556e59592f653b2a2d3a7c4e724770bb3f9837c
dc.subjectMurine AIDS
dc.subjectBone marrow toxicity
dc.subjectHydroxyurea
dc.subjectDidox
dc.subjectTrimidox
dc.subject.meshAnimals
dc.subject.meshBenzamidines
dc.subject.meshBone Marrow Cells
dc.subject.meshDNA, Viral
dc.subject.meshFemale
dc.subject.meshFemur
dc.subject.meshFree Radical Scavengers
dc.subject.meshHematopoietic Stem Cells
dc.subject.meshHydroxamic Acids
dc.subject.meshHydroxyurea
dc.subject.meshHypergammaglobulinemia
dc.subject.meshLeukemia Virus, Murine
dc.subject.meshLeukemia, Experimental
dc.subject.meshMice
dc.subject.meshMice, Inbred C57BL
dc.subject.meshMurine Acquired Immunodeficiency Syndrome
dc.subject.meshProviruses
dc.subject.meshRetroviridae Infections
dc.subject.meshRibonucleotide Reductases
dc.subject.meshSpleen
dc.subject.meshSplenomegaly
dc.subject.meshTumor Virus Infections
dc.titleSuppression of retrovirus-induced immunodeficiency disease (murine AIDS) by trimidox and didox: novel ribonucleotide reductase inhibitors with less bone marrow toxicity than hydroxyurea.
dc.typeJournal article
dc.identifier.journalAntiviral Research
html.description.abstractRecently, 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.


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