AEGiS-15IAC: Combination of inhibitors of lymphocyte activation (Hydroxyurea, Trimidox and Didox) and reverse transcriptase (Abacavir, Didanosine and Tenofovir) suppresses development of murine retrovirus-induced lymphoproliferative disease.

15th International AIDS Conference


Bangkok, Thailand - July 11-16, 2004

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Combination of inhibitors of lymphocyte activation (Hydroxyurea, Trimidox and Didox) and reverse transcriptase (Abacavir, Didanosine and Tenofovir) suppresses development of murine retrovirus-induced lymphoproliferative disease.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. A10230)

Gallicchio VS, Mayhew CN, Sumpter LN, Inayat MS, Cibull ML, Elford HL
University of Kentucky, Lexington, United States

BACKGROUND: To ascertain novel drugs that inhibit ribonucleotide reductase (RRI)[didox (DX) and trimidox (TX)] compared to hydroxyurea (HU) will enhance antiviral activity of NRTIs (abacavir, ddI and tenofovir) when tested in murine retrovirus-induced lymphoproliferative disease.

METHODS: Immune deficient animals were treated with or without mono- or combination therapy with RRIs and NRTIs. They were treated for a period of 8-weeks post-viral infection. Animals were examined for changes in proviral DNA, activated B-cells, hypergammaglobulinemia, splenomegaly, loss of splenic architecture, and blood toxicity.

RESULTS: Combination RRIs and NRTIs were extremely effective (DX>TX>HU) in inhibiting development of retrovirus-induced immunodeficiency disease, reduced levels of proviral DNA, activated B-cells, hypergammaglobulinemia, splenomegaly, and loss of splenic architecture. Numbers of bone marrow derived stem cells and peripheral blood cell indices revealed DX and TX in combination with NRTIs were well tolerated; however, HU plus NRTIs induced acute myelosuppression.

CONCLUSIONS: These data demonstrate novel RRIs in combination with NRTIs provide significant inhibition against retroviral disease when tested in murine AIDS.

Keywords: AEGIS, Didanosine, Benzamidines, Dideoxynucleosides, Hydroxyurea, Adenine, Hydroxamic Acids, Organophosphorus Compounds, RNA-Directed DNA Polymerase, Ribonucleotide Reductases, Antiviral Agents, Lymphoproliferative Disorders, Murine Acquired Immunodeficiency Syndrome, Retroviridae Infections, Spleen, Splenomegaly, Bone Marrow, 3,4,5-trihydroxybenzamidoxime, abacavir, tenofovir, 3,4-dihydroxybenzohydroxamic acid, Animal, antagonists & inhibitors

040711
A10230

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