Combination of inhibitors of lymphocyte activation (hydroxyurea, trimidox, and didox) and reverse transcriptase (didanosine) suppresses development of murine retrovirus-induced lymphoproliferative disease.
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.
Mayhew
Christopher N
CN
Department of Clinical Sciences, University of Kentucky Medical Center, Lexington, KY, USA.
Sumpter
Ryan
R
Inayat
Mohammed
M
Cibull
Michael
M
Phillips
Jonathan D
JD
Elford
Howard L
HL
Gallicchio
Vincent S
VS
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology; D001550:Benzamidines / Q000008:administration & dosage / Q000627:therapeutic use*; D016049:Didanosine / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D006918:Hydroxyurea / Q000008:administration & dosage / Q000627:therapeutic use*; D009052:Leukemia Virus, Murine / Q000187:drug effects; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000821:virology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology; D012192:Retroviridae Infections / Q000188:drug therapy / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D014412:Tumor Virus Infections / Q000188:drug therapy / Q000821:virology
C074761:3,4,5-trihydroxybenzamidoxime; D000998:Antiviral Agents; D001550:Benzamidines; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D018894:Reverse Transcriptase Inhibitors; D012264:Ribonucleotide Reductases; D016049:Didanosine; C035419:3,4-dihydroxybenzohydroxamic acid; D006918:Hydroxyurea