National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, Beijing 100176, China.
National Engineering Laboratory for Anti-tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Regul Toxicol Pharmacol. 2018 Jun;95:190-197. doi: 10.1016/j.yrtph.2018.03.017. Epub 2018 Mar 24.
PEGylated recombinant human endostatin (MES) exhibited prolonged serum half-life and enhanced antitumor activity when compared with endostatin. A pre-clinical study was performed to evaluate the safety of MES in rats. After intravenous (IV) infusions of MES at a dose level of 3, 15 and 75 mg/kg in Sprague Dawley (SD) rats, MES was well tolerated in animals, with no observable changes in clinical observation, body weight, food consumption, urine analysis, hematology and serum biochemical analysis. The increase of kidney weights, and slight to severe vacuolation and necrosis of proximal tubule epithelial cells in kidney were observed in 15 and 75 mg/kg MES groups, but this adverse-effect was reversible. In summary, the major toxicity target organ of MES might be kidney, and the no observed adverse effect level (NOAEL) of MES in rats was 3 mg/kg in this study. These pre-clinical safety data contribute to the initiation of the ongoing clinical study.
聚乙二醇化重组人血管内皮抑制素（MES）与血管内皮抑制素相比，具有延长血清半衰期和增强抗肿瘤活性的作用。进行了一项临床前研究，以评估 MES 在大鼠中的安全性。在 Sprague Dawley（SD）大鼠中以 3、15 和 75mg/kg 的剂量水平静脉（IV）输注 MES 后，MES 在动物中耐受良好，临床观察、体重、食物消耗、尿液分析、血液学和血清生化分析均无明显变化。在 15 和 75mg/kg MES 组中观察到肾脏重量增加，以及肾脏近端肾小管上皮细胞的轻微至严重空泡和坏死，但这种不良反应是可逆的。总之，MES 的主要毒性靶器官可能是肾脏，在这项研究中，MES 在大鼠中的无观察不良效应水平（NOAEL）为 3mg/kg。这些临床前安全性数据为正在进行的临床研究的启动提供了依据。
