Topoisomerase II inhibitors, irrespective of their chemical composition, ameliorate experimental arthritis.
OBJECTIVE
Rheumatoid arthritis (RA) is an autoimmune disease, characterized by a chronic inflammation in the joints. The model of collagen-induced arthritis (CIA) has been extensively used to elucidate the pathogenic mechanisms relevant to human RA and is widely employed for the evaluation of potential anti-rheumatic agents. Etoposide and mitoxantrone are immunosuppressive drugs, both acting by inhibiting the topoisomerase II function. We have previously demonstrated an ameliorating effect of etoposide in CIA. The aims of this study were (1) to assess the optimal ameliorating dose of etoposide and (2) to ascertain that topoisomerase II inhibition, irrespective of the chemical composition of the drug, affects the course of autoimmunity.


METHODS
Male DBA/1 mice were treated with 12.5 mg/kg body weight of etoposide five times, twice, once per week or once every second week. Mitoxantrone was administered as high dose (1 mg/kg body weight five times after immunization or after booster with collagen II) or low dose (3 microg/mouse, 5 days/week starting after collagen II immunization or after booster).


RESULTS
Treatment with 12.5 mg/kg body weight five times or twice weekly with etoposide completely inhibited development of arthritis. Low-dose treatment with mitoxantrone after collagen II immunization or high-dose treatment after collagen II booster delayed the onset of arthritis. These results were observed clinically as well as histologically. In addition, serum levels of anti-collagen II antibodies were significantly lower in mice displaying less severe arthritis.


CONCLUSIONS
Treatment of collagen-induced arthritis with topoisomerase II inhibitors ameliorates the development of disease.
Verdrengh
M
M
Department of Rheumatology and Inflammation Research, Göteborg University, Guldhedsgatan 10A, SE-413 46 Göteborg, Sweden. margareta.verdrengh@rheuma.gu.se
Isaksson
O
O
Tarkowski
A
A
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D024043:Collagen Type II / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005047:Etoposide / Q000627:therapeutic use*; D007114:Immunization / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008942:Mitoxantrone / Q000627:therapeutic use*; D019384:Nucleic Acid Synthesis Inhibitors / Q000627:therapeutic use*; D059005:Topoisomerase II Inhibitors
D024043:Collagen Type II; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D019384:Nucleic Acid Synthesis Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D008942:Mitoxantrone