The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl-DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis

Arthritis Rheumatol. 2015 Jul;67(7):1858-67. doi: 10.1002/art.39119.


Objective: The treatment of lupus nephritis is still an unmet medical need requiring new therapeutic approaches. Our group found recently that irinotecan, an inhibitor of topoisomerase I (topo I), reversed proteinuria and prolonged survival in mice with advanced lupus nephritis. While irinotecan is known to stabilize the complex of topo I and DNA, the enzyme tyrosyl-DNA phosphodiesterase 1 (TDP-1) functions in an opposing manner by releasing topo I from DNA. Therefore, we undertook this study to test whether the TDP-1 inhibitor furamidine has an additional effect on lupus nephritis when used in combination with irinotecan.

Methods: NZB/NZW mice were treated with low-dose irinotecan and furamidine either alone or in combination beginning at age 26 weeks. DNA relaxation was visualized using gel electrophoresis. Binding of anti-double-stranded DNA (anti-dsDNA) antibodies to DNA modified by topo I, TDP-1, and the topo I inhibitor camptothecin was determined by enzyme-linked immunosorbent assay.

Results: Compared to treatment with either agent alone, simultaneous treatment with low-dose irinotecan and furamidine significantly improved survival of NZB/NZW mice. Similar to what has been previously shown for irinotecan alone, the combination treatment did not change the levels of anti-dsDNA antibodies. In vitro, recombinant TDP-1 increased topo I-mediated DNA relaxation, resulting in enhanced binding of anti-dsDNA antibodies. In combination with topo I and camptothecin, TDP-1 reversed the inhibitory effects of camptothecin on DNA relaxation and anti-dsDNA binding.

Conclusion: Affecting DNA relaxation by the enzymes topo I and TDP-1 and their inhibitors may be a promising approach for the development of new targeted therapies for systemic lupus erythematosus.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamidines / therapeutic use*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Drug Therapy, Combination
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Immunomodulation
  • Irinotecan
  • Lupus Nephritis / drug therapy*
  • Lupus Nephritis / immunology
  • Mice
  • Mice, Inbred NZB
  • Phosphoric Diester Hydrolases / drug effects*
  • Topoisomerase I Inhibitors / therapeutic use*
  • Treatment Outcome


  • Benzamidines
  • Enzyme Inhibitors
  • Topoisomerase I Inhibitors
  • furamidine
  • Irinotecan
  • Phosphoric Diester Hydrolases
  • Tdp1 protein, mouse
  • Camptothecin