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

2.50
Hdl Handle:
http://hdl.handle.net/2436/29472
Title:
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, Christopher N.; Mampuru, Leseilane J.; Chendil, Damodoran; Ahmed, Mansoor M.; Phillips, Jonathan D.; Greenberg, Richard N.; Elford, Howard L.; Gallicchio, Vincent S.
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
Issue Date:
2002
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:
Article
Language:
en
ISSN:
0166-3542
Appears in Collections:
Diabetes, Physiology and Molecular Medicine Research Group

Full metadata record

DC FieldValue Language
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): 167-181en
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.en
dc.language.isoenen
dc.publisherElsevier Science Directen
dc.relation.urlhttp://www.ingentaconnect.com/content/els/01663542/2002/00000056/00000002/art00108?token=005015399702c275c277b422c496773487834702c556e59592f653b2a2d3a7c4e724770bb3f9837cen
dc.subjectMurine AIDSen
dc.subjectBone marrow toxicityen
dc.subjectHydroxyureaen
dc.subjectDidoxen
dc.subjectTrimidoxen
dc.subject.meshAnimalsen
dc.subject.meshBenzamidinesen
dc.subject.meshBone Marrow Cellsen
dc.subject.meshDNA, Viralen
dc.subject.meshFemaleen
dc.subject.meshFemuren
dc.subject.meshFree Radical Scavengersen
dc.subject.meshHematopoietic Stem Cellsen
dc.subject.meshHydroxamic Acidsen
dc.subject.meshHydroxyureaen
dc.subject.meshHypergammaglobulinemiaen
dc.subject.meshLeukemia Virus, Murineen
dc.subject.meshLeukemia, Experimentalen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshMurine Acquired Immunodeficiency Syndromeen
dc.subject.meshProvirusesen
dc.subject.meshRetroviridae Infectionsen
dc.subject.meshRibonucleotide Reductasesen
dc.subject.meshSpleenen
dc.subject.meshSplenomegalyen
dc.subject.meshTumor Virus Infectionsen
dc.titleSuppression of retrovirus-induced immunodeficiency disease (murine AIDS) by trimidox and didox: novel ribonucleotide reductase inhibitors with less bone marrow toxicity than hydroxyurea.en
dc.typeArticleen
dc.identifier.journalAntiviral Researchen

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