Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
Biopolymers. 2010;94(5):626-34. doi: 10.1002/bip.21408.
Cycloviolacin O2 is a small cyclic cysteine-rich protein belonging to the group of plant proteins called cyclotides. This cyclotide has been previously shown to exert cytotoxic activity against a variety of human tumor cell lines as well as primary cultures of human tumor cells in vitro. This study is the first evaluation of its tolerability and antitumor activity in vivo. Maximal-tolerated doses were estimated to 1.5 mg/kg for single intravenous (i.v.) dosing and 0.5 mg/kg for daily repeated dosing, respectively. Two different in vivo methods were used: the hollow fiber method with single dosing (i.v., 1.0 mg/kg) and traditional xenografts with repeated dosing over 2 weeks (i.v., 0.5 mg/kg daily, 5 days a week). The human tumor cell lines used displayed dose-dependent in vitro sensitivity (including growth in hollow fibers to confirm passage of cycloviolacin O2 through the polyvinylidene fluoride fibers), with IC5o values in the micromolar range. Despite this sensitivity in vitro, no significant antitumor effects were detected in vivo, neither with single dosing in the hollow fiber method nor with repeated dosing in xenografts. In summary, the results indicate that antitumor effects are minor or absent at tolerable (sublethal) doses, and cycloviolacin O2 has a very abrupt in vivo toxicity profile, with lethality after single injection at 2 mg/kg, but no signs of discomfort to the animals at 1.5 mg/kg. Repeated dosing of 1 mg/kg gave a local-inflammatory reaction at the site of injection after 2-3 days; lower doses were without complications.
环维黄扬醇 O2 是一种小分子含半胱氨酸丰富的蛋白质，属于植物蛋白中的环肽。这种环肽先前已被证明对多种人类肿瘤细胞系以及体外人类肿瘤细胞原代培养物具有细胞毒性活性。本研究首次评估其在体内的耐受性和抗肿瘤活性。单次静脉内（i.v.）给药的最大耐受剂量估计为 1.5mg/kg，每日重复给药的最大耐受剂量估计为 0.5mg/kg。两种不同的体内方法被用于：单次给药的中空纤维法（i.v.，1.0mg/kg）和重复给药超过 2 周的传统异种移植法（i.v.，0.5mg/kg，每天一次，每周 5 天）。所使用的人类肿瘤细胞系显示出剂量依赖性的体外敏感性（包括在中空纤维中的生长以确认环维黄扬醇 O2 通过聚偏二氟乙烯纤维传递），IC50 值在微摩尔范围内。尽管体外敏感性高，但在体内未检测到明显的抗肿瘤作用，无论是在中空纤维法的单次给药还是在异种移植中的重复给药中。总之，结果表明，在可耐受（亚致死）剂量下，抗肿瘤作用较小或不存在，并且环维黄扬醇 O2 在体内具有非常突然的毒性特征，在 2mg/kg 单次注射后具有致死性，但在 1.5mg/kg 时动物没有不适迹象。1mg/kg 的重复给药在 2-3 天后在注射部位引起局部炎症反应；较低剂量无并发症。
