Reversal of Established Lupus Nephritis and Prolonged Survival of New Zealand Black × New Zealand White Mice Treated with the Topoisomerase I Inhibitor Irinotecan
Reversal of Established Lupus Nephritis and Prolonged Survival of New Zealand Black × New Zealand White Mice Treated with the Topoisomerase I Inhibitor Irinotecan
复制标题
用拓扑异构酶 I 抑制剂伊立替康治疗后，新西兰黑×新西兰白小鼠的狼疮性肾炎得到逆转并延长了生存期
作者：
M. Frese‐Schaper;J. Zbaeren;M. Gugger;M. Monestier;S. Frese
系统性红斑狼疮是一种慢性自身免疫性疾病，主要影响育龄妇女。狼疮相关性肾小球肾炎是这些患者死亡的主要原因。目前系统性红斑狼疮的治疗方案包括环磷酰胺、泼尼松龙、硫唑嘌呤和吗替麦考酚酯。然而，在小鼠中，这些药物单独或联合使用均未显示出逆转已建立的蛋白尿。使用新西兰黑×新西兰白色F1小鼠，我们报告说，从第13周开始给予拓扑异构酶I抑制剂伊立替康完全防止了蛋白尿的发生，并延长了生存期至少90周，没有可检测到的副作用。此外，根据中位年龄35周，对已确诊狼疮肾炎的小鼠（如3+级（≥300 mg/dl）和4+级（≥2000 mg/dl）蛋白尿所示）应用伊立替康，缓解率分别为75%和55%。与对照组动物的40周相比，73周（3+级和4+级合并）的生存期显著延长。尽管伊立替康治疗小鼠血清中的总IgG和抗dsDNA抗体以及肾脏中的系膜IgG沉积物未减少，但内皮下免疫沉积物显著减少，表明可预防肾小球基底膜破坏。该效应伴随ssDNA断裂速率增加和肾细胞凋亡抑制，与已知的伊立替康抗癌治疗不同。总之，我们的数据提供的证据表明，伊立替康可能代表了一个全新的策略，用于治疗系统性红斑狼疮。
Systemic lupus erythematosus is a chronic autoimmune disorder that predominantly affects women of childbearing age. Lupus-associated glomerulonephritis is a major cause of mortality in these patients. Current treatment protocols for systemic lupus erythematosus include cyclophosphamide, prednisolone, azathioprine, and mycophenolate mofetil. However, in mice none of these agents alone or in combination were shown to reverse established proteinuria. Using New Zealand Black × New Zealand White F1 mice, we report that administration of the topoisomerase I inhibitor irinotecan from week 13 completely prevented the onset of proteinuria and prolonged survival up to at least 90 wk without detectable side effects. Furthermore, application of irinotecan to mice with established lupus nephritis, as indicated by grade 3+ (≥300 mg/dl) and grade 4+ (≥2000 mg/dl) proteinuria and, according to a median age of 35 wk, resulted in remission rates of 75% and 55%, respectively. Survival was significantly prolonged with 73 wk (grade 3+ and 4+ combined) versus 40 wk for control animals. Although total IgG and anti-dsDNA Abs in the serum and mesangial IgG deposits in the kidneys were not reduced in irinotecan-treated mice, subendothelial immune deposits were considerably diminished, suggesting a prevention of glomerular basement membrane disruption. This effect was accompanied by increased rates of ssDNA breaks and inhibition of renal cell apoptosis being different to what is known about irinotecan in anticancer therapy. In conclusion, our data provide evidence that irinotecan might represent an entirely new strategy for the treatment of systemic lupus erythematosus.
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影响因子：
11.2
作者：
Y. Hsiang;M. G. Lihou;Leroy F. Liu
通讯作者：
Y. Hsiang;M. G. Lihou;Leroy F. Liu
影响因子：
82.9
作者：
Neubert, Kirsten;Meister, Silke;Voll, Reinhard E.
通讯作者：
Voll, Reinhard E.
影响因子：
--
作者：
Tao, Xuelian;Fan, Fred;Lipsky, Peter E.
通讯作者：
Lipsky, Peter E.
影响因子：
5
作者：
A. Borchers;A. Ansari;T. Hsu;D. Kono;M. Gershwin
通讯作者：
A. Borchers;A. Ansari;T. Hsu;D. Kono;M. Gershwin
用烷化剂处理的细胞中 DNA 的稳定性降低。
影响因子：
3.7
作者：
Frankfurt,OS
通讯作者：
Frankfurt,OS