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