In vivo examination of hydroxyurea and the novel ribonucleotide reductase inhibitors trimidox and didox in combination with the reverse transcriptase inhibitor abacavir: suppression of retrovirus-induced immunodeficiency disease.
Inhibition of ribonucleotide reductase (RR) has gained attention as a potential strategy for HIV-1 therapy through the success of hydroxyurea (HU) to potentiate the activity of the nucleoside reverse transcriptase inhibitor (NRTI) didanosine (ddI) in clinical trials. However, the use of HU has been limited by its development of hematopoietic toxicity. In this study, the novel RR inhibitors didox (DX; 3,4-dihydroxybenzohydroxamic acid), and trimidox (TX; 3,4,5-trihydroxybenzamidoxime) were evaluated along with HU for anti-retroviral efficacy in LPBM5-induced retro-viral disease (MAIDS) both as monotherapeutic regimens and in combination with the guanine containing NRTI abacavir (ABC). Anti-retroviral drug efficacy was determined by measuring inhibition of splenomegaly, hypergammaglobulinemia, and splenic levels of proviral DNA. In this study, all RRIs tested showed the ability to improve the efficacy of ABC in the MAIDS model by reducing splenomegaly, hypergammaglobulinemia, and splenic proviral DNA levels.
Sumpter
L Ryan
LR
Department of Clinical Sciences, University of Kentucky Medical Center, CHS Building, 900 South Limestone Street, Lexington, KY 40536, USA.
Inayat
Mohammed S
MS
Yost
Erin E
EE
Duvall
William
W
Hagan
Espen
E
Mayhew
Christopher N
CN
Elford
Howard L
HL
Gallicchio
Vincent S
VS
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001550:Benzamidines / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects*; D015224:Dideoxynucleosides / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006877:Hydroxamic Acids / Q000627:therapeutic use; D006918:Hydroxyurea / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000473:pathology; D013163:Splenomegaly; D000099227:Abacavir
D000998:Antiviral Agents; D001550:Benzamidines; D015224:Dideoxynucleosides; D006877:Hydroxamic Acids; D006918:Hydroxyurea; D012264:Ribonucleotide Reductases; D000099227:Abacavir; C074761:3,4,5-trihydroxybenzamidoxime; C035419:3,4-dihydroxybenzohydroxamic acid