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- Title
The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl-DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis.
- Authors
Keil, Andreas; Frese‐Schaper, Manuela; Steiner, Selina K.; Körner, Meike; Schmid, Ralph A.; Frese, Steffen
- 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. 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.
- Subjects
SYSTEMIC lupus erythematosus treatment; AGAR; ANALYSIS of variance; ANIMAL experimentation; BIOLOGICAL models; ELECTROPHORESIS; ENZYME-linked immunosorbent assay; FLOW cytometry; MICE; RESEARCH funding; STATISTICS; SYSTEMIC lupus erythematosus; T-test (Statistics); DATA analysis; DATA analysis software; LOG-rank test
- Publication
Arthritis & Rheumatology, 2015, Vol 67, Issue 7, p1858
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.39119