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

Arthritis & Rheumatology
Andreas KeilSteffen Frese

Abstract

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. 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. 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 chan...Continue Reading

References

Oct 15, 1996·Proceedings of the National Academy of Sciences of the United States of America·S W YangH A Nash
Apr 3, 2001·The Journal of Biological Chemistry·M LisbyB R Knudsen
Oct 27, 2001·Lupus·B H Hahn
Jan 14, 2004·Kidney International·Jan J WeeningUNKNOWN Renal Pathology Society Working Group on the Classification of Lupus Nephritis
Mar 5, 2004·The New England Journal of Medicine·Gabriel ContrerasDavid Roth
Jun 11, 2004·The New England Journal of Medicine·Chee-Seng Yee, Caroline Gordon
Oct 21, 2004·The Journal of Biological Chemistry·Hans U BarthelmesDoris Marko
Feb 22, 2008·Clinical Journal of the American Society of Nephrology : CJASN·William F Clark, Jessica M Sontrop
Jan 20, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Manuela Frese-SchaperSteffen Frese
Aug 17, 2011·Expert Opinion on Therapeutic Patents·Shar-yin N HuangChristophe Marchand
Oct 20, 2011·Nature Reviews. Rheumatology·Steffen Frese, Betty Diamond
May 5, 2012·Arthritis Care & Research·Bevra H HahnUNKNOWN American College of Rheumatology
Dec 25, 2012·ACS Chemical Biology·Yves Pommier
Feb 16, 2013·Journal of Autoimmunity·Sasha BernatskyAnn E Clarke
Feb 8, 2014·Arthritis & Rheumatology·Richard FurieJoan T Merrill
Oct 28, 2014·World Journal of Transplantation·Sophia LionakiJohn N Boletis

❮ Previous
Next ❯

Citations


❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.