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AB0161 The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl-DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis
  1. A. Keil1,
  2. M. Frese-Schaper1,
  3. S.K. Steiner1,
  4. M. Körner2,
  5. R.A. Schmid1,
  6. S. Frese1
  1. 1Department of Clinical Research and Division of General Thoracic Surgery, University Hospital Bern
  2. 2Insitute of Pathology, University Bern, Bern, Switzerland

Abstract

Background The treatment of lupus nephritis is still an unmet medical need requiring new therapeutic approaches. Our group found recently that irinotecan, a camptothecin derivate and inhibitor of topoisomerase I (topo I), reversed proteinuria and prolonged survival in mice with advanced lupus nephritis. Irinotecan stabilizes the complex of topo I and DNA and is shown to decrease the binding of lupus-typical anti-dsDNA autoantibodies. The enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) functions opposite to irinotecan by releasing topo I from DNA.

Objectives We tested whether the TDP1 inhibitor furamidine has an additional effect in suppressing murine lupus nephritis when used in combination with the topo I inhibitor irinotecan. Furthermore, we investigated if TDP1 increases the binding of anti-dsDNA antibodies.

Methods NZB/NZW mice were treated with low-dose irinotecan and furamidine either alone or in combination beginning at 26 weeks of age. DNA relaxation was visualized by gel electrophoresis. Binding of anti-dsDNA antibodies to DNA modified by topo I, TDP1 and the topo I inhibitor camptothecin was determined by ELISA.

Results Compared to either agent alone, the simultaneous treatment with low-dose irinotecan and furamidine significantly improved survival of NZB/NZW mice. Similar to what has been shown before for irinotecan alone, the combinatorial treatment with low-dose irinotecan and furamidine remained the levels of anti-dsDNA antibodies unchanged. In vitro, recombinant TDP1 increased topo I-mediated DNA relaxation resulting in enhanced binding of anti-dsDNA antibodies. In combination with topo I and camptothecin, TDP1 reversed the inhibitory effects of camptothecin on DNA relaxation and anti-dsDNA binding.

Conclusions Affecting DNA relaxation by the enzymes topo I and TDP1 and its inhibitors may be a promising approach for the development of new targeted therapies for systemic lupus erythematosus.

Disclosure of Interest None declared

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