EFFECTIVE USE OF RIBONUCLEOTIDE REDUCTASE INHIBITORS (DIDOX AND TRIMIDOX) ALONE OR IN COMBINATION WITH DIDANOSINE (DDI) TO SUPPRESS DISEASEPROGRESSION AND INCREASE SURVIVAL IN MURINE ACQUIRED-IMMUNODEFICIENCY-SYNDROME (MAIDS)

Ribonucleotide reductase inhibitors (RRIs) have been recently shown to inhibit retroviral replication. We examined a new series of RRIs, 3,4 -dihydroxybenzohydroxamic acid (Didox) and 3,4,5-trihydroxybenzohydrox amidoxime (Trimidox) for their ability to alter disease progression in murine acquired immunodeficiency syndrome (MAIDS), both alone and in combination with 2',3'-dideoxyinosine (ddI). MAIDS disease was induced by inoculation of female C57BL/6 mice with the LP-BM5 murine leukemia virus (MuLV) and disease progression characterized by extensive perip heral lymphadenopathy and splenomegaly. Efficacy of treatment with the se drugs was based upon their ability to influence survival and diseas e pathophysiology by monitoring the development of splenomegaly. Toxic ity was determined by changes in body weight, total peripheral white b lood cell count and hematocrit. Didox or trimidox monotherapy was asso ciated with increased survival and decreased disease pathophysiology, with no apparent toxicity. Combined with ddI, their ability to reduce development of viral induced splenomegaly was enhanced compared to tri midox, didox or ddI alone. These results demonstrate RRIs have potent activity in reversing the disease manifestations characteristic of MAI DS. Further studies are warranted to determine human clinical efficacy .