Effective use of ribonucleotide reductase inhibitors (Didox and Trimidox) alone or in combination with didanosine (ddI) to suppress disease progression 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-trihydroxybenzohydroxamidoxime (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 peripheral lymphadenopathy and splenomegaly. Efficacy of treatment with these drugs was based upon their ability to influence survival and disease pathophysiology by monitoring the development of splenomegaly. Toxicity was determined by changes in body weight, total peripheral white blood cell count and hematocrit. Didox or trimidox monotherapy was associated 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 trimidox, didox or ddI alone. These results demonstrate RRIs have potent activity in reversing the disease manifestations characteristic of MAIDS. Further studies are warranted to determine human clinical efficacy.
Mayhew
C
C
Department of Clinical Sciences, Chandler Medical Center, University of Kentucky, Lexington 40536, USA.
Oakley
O
O
Piper
J
J
Hughes
N K
NK
Phillips
J
J
Birch
N J
NJ
Elford
H L
HL
Gallicchio
V S
VS
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001550:Benzamidines / Q000494:pharmacology; D015415:Biomarkers; D016049:Didanosine / Q000494:pharmacology; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D006877:Hydroxamic Acids / Q000494:pharmacology; D009052:Leukemia Virus, Murine / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology / Q000821:virology; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015996:Survival Rate
C074761:3,4,5-trihydroxybenzamidoxime; D000998:Antiviral Agents; D001550:Benzamidines; D015415:Biomarkers; D006877:Hydroxamic Acids; D012264:Ribonucleotide Reductases; D016049:Didanosine; C035419:3,4-dihydroxybenzohydroxamic acid