Beneficial effects of a polyamine biosynthesis inhibitor on lupus in MRL-lpr/lpr mice.
Difluoromethylornithine (DFMO), an experimental drug that inactivates ornithine decarboxylase and thus reduces the production of polyamines has a beneficial effect on the mean survival time and the clinical and laboratory manifestations of murine lupus in female MRL-lpr/lpr mice. DFMO-treated mice showed a 29% increase in the mean survival time compared with age- and sex-matched control mice of the same strain. Lymphadenopathy was evident in untreated mice at 14 weeks of age, but was delayed until 19 weeks of age in DFMO-treated mice. In addition, the sera of DFMO-treated mice contained a significantly lower concentration of anti-DNA antibodies compared with untreated mice. These results open the possibility of development of a new class of therapeutic agents based on polyamine biosynthesis inhibitors for the treatment of human autoimmune disease. Possible mechanisms for the action of DFMO include its inhibitory action on cell proliferation as well as its ability to prevent DNA from assuming an immunogenic left-handed Z-DNA conformation.
Thomas
T J
TJ
Department of Medicine, University of Minnesota, Minneapolis, USA.
Messner
R P
RP
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D015317:Biogenic Polyamines / Q000096:biosynthesis*; D004247:DNA / Q000276:immunology; D000518:Eflornithine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008206:Lymphatic Diseases / Q000517:prevention & control; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009690:Nucleic Acid Conformation / Q000187:drug effects; D065108:Ornithine Decarboxylase Inhibitors
D000974:Antibodies, Antinuclear; D015317:Biogenic Polyamines; D004791:Enzyme Inhibitors; D007136:Immunoglobulins; D065108:Ornithine Decarboxylase Inhibitors; D004247:DNA; D000518:Eflornithine