, Volume 57, Issue 3, pp 126-134
Date: 28 Feb 2008

Topoisomerase inhibitors as anti-arthritic agents

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Abstract.

Introduction:

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.

Method:

The topoisomerase I inhibitors camptothecin and β-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 β-laperchone) but inhibited angiogenesis and collagenase expression to a lesser degree than camptothecin.

Conclusion:

These studies support the explorative use of topoisomerase I (particularly camptothecin) and II inhibitors as potential agents for use against RA.

Received 23 August 2007; returned for revision 27 September 2007; accepted by J. Di Battista 19 November 2007