The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl-DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis
| Autor: | Steffen Frese, Ralph A. Schmid, Selina Steiner, Manuela Frese-Schaper, Meike Körner, Andreas Keil |
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| Rok vydání: | 2015 |
| Předmět: |
Immunology
Lupus nephritis Topoisomerase-I Inhibitor Biology Pharmacology law.invention 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Rheumatology immune system diseases law medicine Immunology and Allergy skin and connective tissue diseases 030304 developmental biology 030203 arthritis & rheumatology 0303 health sciences Topoisomerase Tyrosyl-DNA Phosphodiesterase 1 medicine.disease 3. Good health Irinotecan chemistry Recombinant DNA biology.protein DNA Camptothecin medicine.drug |
| Zdroj: | Arthritis & Rheumatology. 67:1858-1867 |
| ISSN: | 2326-5191 |
| DOI: | 10.1002/art.39119 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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