Topoisomerase inhibitors as anti-arthritic agents.
BACKGROUND
The pathophysiology of rheumatoid arthritis (RA) includes inflammation, synoviocyte proliferation, angiogenesis, and matrix metalloproteinase-driven degradation processes. The objective of this study was to investigate a variety of structurally unrelated anticancer topoisomerase inhibiting agents as inhibitors of aspects of these disease processes involved in RA.


METHODS
The topoisomerase I inhibitors camptothecin and beta-laperchone and the topoisomerase II inhibitors, etoposide, doxorubicin, plumbagin and menadione were used in this study. Crystal induced neutrophil activation was measured by luminol dependent chemiluminescence. Synoviocyte proliferation was measured by an MTT assay using HIG 82 rabbit synoviocytes in cell culture. Angiogenesis was measured using the chorioallantoic membrane of the chick embryo. Chondrocyte (culture primary cells) expression of the matrix metalloproteinases collagenase and stromelysin was measured by Northern Blot analysis.


RESULTS
All agents inhibited synoviocyte proliferation to some degree. Camptothecin had no effect on neutrophil activation but inhibited all other processes at low (nanomolar) concentrations. Plumbagin and menadione inhibited neutrophil activation, collagenases expression and angiogenesis. The other agents had little effect on neutrophil activation (except beta-laperchone) but inhibited angiogenesis and collagenase expression to a lesser degree than camptothecin.


CONCLUSIONS
These studies support the explorative use of topoisomerase I (particularly camptothecin) and II inhibitors as potential agents for use against RA.
Jackson
J K
JK
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, B.C., V6T 1Z3, Canada.
Higo
T
T
Hunter
W L
WL
Burt
H M
HM
D000818:Animals; D018501:Antirheumatic Agents / Q000378:metabolism* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D002166:Camptothecin / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D005047:Etoposide / Q000378:metabolism / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism; D009285:Naphthoquinones / Q000378:metabolism / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000502:physiology; D011817:Rabbits; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D024483:Vitamin K 3 / Q000378:metabolism / Q000494:pharmacology
D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D009285:Naphthoquinones; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C014638:beta-lapachone; D005047:Etoposide; D024483:Vitamin K 3; D004317:Doxorubicin; D002166:Camptothecin; C014758:plumbagin