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Combination of inhibitors of lymphocyte activation (hydroxyurea, trimidox, and didox) and reverse transcriptase (didanosine) suppresses development of murine retrovirus-induced lymphoproliferative disease.
- Source :
-
Antiviral research [Antiviral Res] 2005 Jan; Vol. 65 (1), pp. 13-22. - Publication Year :
- 2005
-
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.
- Subjects :
- Animals
Antiviral Agents administration & dosage
B-Lymphocytes immunology
Benzamidines administration & dosage
Drug Therapy, Combination
Enzyme Inhibitors administration & dosage
Enzyme Inhibitors therapeutic use
Female
Hydroxamic Acids administration & dosage
Hydroxyurea administration & dosage
Leukemia Virus, Murine drug effects
Leukemia, Experimental drug therapy
Leukemia, Experimental virology
Lymphocyte Activation drug effects
Mice
Mice, Inbred C57BL
Murine Acquired Immunodeficiency Syndrome virology
Retroviridae Infections drug therapy
Retroviridae Infections virology
Ribonucleotide Reductases antagonists & inhibitors
Treatment Outcome
Tumor Virus Infections drug therapy
Tumor Virus Infections virology
Antiviral Agents therapeutic use
Benzamidines therapeutic use
Didanosine therapeutic use
Hydroxamic Acids therapeutic use
Hydroxyurea therapeutic use
Murine Acquired Immunodeficiency Syndrome drug therapy
Reverse Transcriptase Inhibitors therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 0166-3542
- Volume :
- 65
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Antiviral research
- Publication Type :
- Academic Journal
- Accession number :
- 15652967
- Full Text :
- https://doi.org/10.1016/j.antiviral.2004.09.003