INHIBITION OF LYMPHOMA USING RIBONUCLEOTIDE REDUCTASE INHIBITORS DIDOX OR TRIMIDOX IN THE MURINE IMMUNODEFICIENCY MAIDS MODEL

Abstract

Listen

Translate article

Background: To obtain additional in vivo experimental evidence to determine whether a new series of ribonucleotide reductase inhibitors (RRI), 3,4-dihydroxybenzohydroxamic acid (Didox) and 3,4,5-trihydroxybenzamidoxime(Trimidox) can inhibit retrovirus replication by depriving virus of its source of the deoxynucleotides obligatory for the synthesis of the proviral DNA intermediate of retrovirus replication in the murine model of AIDS (MAIDS). C57BL6 female mice were inoculated i.p. with LP-BM5 MuLV. Non-infected and infected mice were treated (M-F) with either Didox or Trimidox i.p., alone or in combination with didanosine (ddI, s.c.) beginning 1-day or 1-week post-viral infection. Controls consisted of virally infected mice not receiving RRIs or ddI. Mice were monitored for disease progression via: survival, presence of splenomegaly, lymphadenopathy, hypergammaglobulinemia, blood and bone marrow toxicity, reverse transcriptase activity, and flow cytometric analysis of infected PBMCs exhibiting viralgag 12 envelope glycoprotein expression. Results: Infected mice receiving either Didox (300, 460 mg/kg/bw) or Trimidox(150, 220 mg/kg/bw) either alone or in combination with ddI (600 mg/kg/bw) demonstrated increased survival compared to viral controls with reduced splenomegaly, lymphadenopathy, hypergammaglobulinemia, reverse transcriptase activitiy from lymph tissue and viral infected PBMCs. This antiviral effect was enhanced with ddI; however, ddI alone had only marginal antiviral activity. No sign of lymphoma or blood or marrow toxicity was observed following >50 weeks post-viral infection compared to infected control animals not receiving drugs. Conclusions: These results demonstrate RRIs are potent antiviral agents capable of increasing survival and reducing several markers of immunodeficiency disease, in particular, the inductiona and presence of lymphoma using the MAIDS model. Further studies are justified in order to elucidate the role of RRIs as antiviral agents in animal models and warrant initiation of clinical trials to examine their antiviral potential in patients infected with HIV.