title: The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl-DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University Hospital Berne, Berne, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Keil
authors.affiliation: University Hospital Berne, Berne, Switzerland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Frese-Schaper
authors.affiliation: University Hospital Berne, Berne, Switzerland.
authors.forename: Selina K
authors.initials: SK
authors.lastname: Steiner
authors.affiliation: University of Berne, Berne, Switzerland.
authors.forename: Meike
authors.initials: M
authors.lastname: Körner
authors.affiliation: University Hospital Berne, Berne, Switzerland.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Schmid
authors.affiliation: University Hospital Berne, Berne, Switzerland.
authors.forename: Steffen
authors.initials: S
authors.lastname: Frese
mesh_terms: D000818:Animals; D001550:Benzamidines / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D056747:Immunomodulation; D000077146:Irinotecan; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008814:Mice, Inbred NZB; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D059004:Topoisomerase I Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D001550:Benzamidines; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; C033286:furamidine; D000077146:Irinotecan; D010727:Phosphoric Diester Hydrolases; C524959:Tdp1 protein, mouse; D002166:Camptothecin