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

2.50
Hdl Handle:
http://hdl.handle.net/2436/29451
Title:
Combination of inhibitors of lymphocyte activation (hydroxyurea, trimidox, and didox) and reverse transcriptase (didanosine) suppresses development of murine retrovirus-induced lymphoproliferative disease.
Authors:
Mayhew, Christopher N.; Sumpter, Ryan; Inayat, Mohammed; Cibull, Michael; Phillips, Jonathan D.; Elford, Howard L.; Gallicchio, Vincent S.
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
Issue Date:
2005
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:
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.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): 13-22en
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.en
dc.language.isoenen
dc.publisherElsevier Science Directen
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 diseaseen
dc.subject.meshAnimalsen
dc.subject.meshAntiviral Agentsen
dc.subject.meshB-Lymphocytesen
dc.subject.meshBenzamidinesen
dc.subject.meshDidanosineen
dc.subject.meshDrug Therapy, Combinationen
dc.subject.meshEnzyme Inhibitorsen
dc.subject.meshFemaleen
dc.subject.meshHydroxamic Acidsen
dc.subject.meshHydroxyureaen
dc.subject.meshLeukemia Virus, Murineen
dc.subject.meshLeukemia, Experimentalen
dc.subject.meshLymphocyte Activationen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshMurine Acquired Immunodeficiency Syndromeen
dc.subject.meshRetroviridae Infectionsen
dc.subject.meshReverse Transcriptase Inhibitorsen
dc.subject.meshRibonucleotide Reductasesen
dc.subject.meshTreatment Outcomeen
dc.subject.meshTumor Virus Infectionsen
dc.titleCombination of inhibitors of lymphocyte activation (hydroxyurea, trimidox, and didox) and reverse transcriptase (didanosine) suppresses development of murine retrovirus-induced lymphoproliferative disease.en
dc.typeArticleen
dc.identifier.journalAntiviral Researchen

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