Department of Biochemistry, University of Wisconsin-Madison, Madison, WI.
Transl Oncol. 2013 Aug 1;6(4):392-7. doi: 10.1593/tlo.13253. Print 2013 Aug.
Human pancreatic ribonuclease (RNase 1) is a small secretory protein that catalyzes the cleavage of RNA. This highly cationic enzyme can enter human cells spontaneously but is removed rapidly from circulation by glomerular filtration. Here, this shortcoming is addressed by attaching a poly(ethylene glycol) (PEG) moiety to RNase 1. The pendant has no effect on ribonucleolytic activity but does increase persistence in circulation. The RNase 1-PEG conjugates inhibit the growth of tumors in a xenograft mouse model of human lung cancer. Both retention in circulation and tumor growth inhibition correlate with the size of the pendant PEG. A weekly dose of the 60-kDa conjugate at 1 µmol/kg inhibited nearly all tumor growth without affecting body weight. Its molecular efficacy is ∼5000-fold greater than that of erlotinib, which is a small molecule in clinical use for the treatment of lung cancer. These data demonstrate that the addition of a PEG moiety can enhance the in vivo efficacy of human proteins that act within cells and highlight a simple means of converting an endogenous human enzyme into a cytotoxin with potential clinical utility.
人胰腺核糖核酸酶（RNase 1）是一种小的分泌蛋白，能催化 RNA 的切割。这种高度阳离子的酶能自发进入人体细胞，但很快会被肾小球滤过清除出循环。在这里，通过将聚乙二醇（PEG）片段连接到 RNase 1 上来解决这个缺点。侧链对核糖核酸酶活性没有影响，但会增加在循环中的持久性。RNase 1-PEG 缀合物在人肺癌异种移植小鼠模型中抑制肿瘤生长。循环中的保留时间和肿瘤生长抑制与侧链 PEG 的大小相关。每周以 1 µmol/kg 的剂量给予 60 kDa 缀合物，可抑制几乎所有肿瘤生长，而不影响体重。其分子效力比厄洛替尼高约 5000 倍，厄洛替尼是一种用于治疗肺癌的临床小分子药物。这些数据表明，添加 PEG 片段可以增强在细胞内起作用的人蛋白的体内疗效，并突出了一种将内源性人酶转化为具有潜在临床应用的细胞毒素的简单方法。
