Effect and Risk of AEE788, a Dual Tyrosine Kinase Inhibitor, on Regeneration in a Rat Liver Resection Model
Effect and Risk of AEE788, a Dual Tyrosine Kinase Inhibitor, on Regeneration in a Rat Liver Resection Model
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DOI：
10.1159/000275818
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发表时间：
2010-01-01
影响因子：
1.6
通讯作者：
Dahmen, U.
中科院分区：
文献类型：
--
作者：
Deng, M.;Huang, H.;Dahmen, U.
背景：AEE788是一种双酪氨酸激酶抑制剂，对多种小鼠肿瘤模型具有抗增殖作用。我们的目的是研究AEE788是否会阻碍肝脏再生并引起药物相关的副作用。方法：大鼠每2天口服50 mg/kg AEE788或溶剂，行70%肝部分切除（PH），于术后1、2、7、28天处死。采用肝脏重量与体重比、brdu染色、有丝分裂指数和增殖细胞核抗原（PCNA） PCR来评估肝脏再生。通过临床化学、组织学、银染色和免疫组织化学评估对胃肠道系统和肝脏的副作用。采用光谱法测定AEE788的血浆和肝组织水平。结果：AEE788对肝脏再生无抑制作用。没有观察到明显的药物相关的全身或肝脏副作用。即使在AEE788治疗4周后，肝脏再生过程中肝脏结构的恢复也没有明显受损。治疗1周后，PH组血浆和肝组织中AEE788浓度分别比非PH组高3倍和8倍。结论：AEE788的抗增殖特性、良好的耐受性和对肝脏再生无抑制作用，使其成为肿瘤PH临床研究的潜在候选药物，但在术后早期存在过度暴露的风险。版权所有：S. Karger AG，巴塞尔
Background: AEE788, a dual tyrosine kinase inhibitor, has antiproliferative effects on diverse tumor models in mice. We aimed to investigate whether AEE788 blocks liver regeneration and causes drug-related side effects. Methods: Rats treated orally with 50 mg/kg AEE788 or solvent every 2 days were subjected to 70% partial hepatectomy (PH) and sacrificed on postoperative days 1, 2, 7, and 28. Liver regeneration was evaluated using liver weight to body weight ratio, BrdU-staining, mitotic index, and PCR for PCNA (proliferating cell nuclear antigen). Side effects on the gastrointestinal system and liver were assessed using clinical chemistry, histology, silver staining, and immunohistochemistry. Plasma and liver tissue levels of AEE788 were measured using spectrometry. Results: AEE788 treatment did not inhibit liver regeneration. No obvious drug-related systemic or hepatic side effects were observed. Restoration of liver architecture during liver regeneration was not obviously impaired, even after 4 weeks' AEE788 treatment. After a 1-week treatment, AEE788 concentrations in plasma and liver tissue in the PH group were 3-fold and 8-fold higher than the non-PH group, respectively. Conclusion: Its antiproliferative properties, good tolerance, and lack of inhibition on liver regeneration make AEE788 a potential candidate for clinical study with oncological PH, but one that carries the risk of overexposure in the early postoperative phase. Copyright (C) 2010 S. Karger AG, Basel