Biochem Pharmacol 2011 Dec;82 (12): 1832-42. [IF:4.889]
Effects of the novel vascular targeting agent MDS-11P on tumor vascularity and its antitumor activity.
Deng ZT , Feng T , Wang P , Qi X , Chen XH , Li YX , Song CL , Geng MY , Li J .
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yu-Shan Road, Qingdao 266003, China.
中国海洋大学海洋药物教育部重点实验室
Abstract
Vascular disrupting agents show selective effects on tumor established vasculature, and achieve encouraging results in both pre-clinical and clinical experiments. In the present study, we investigated the effects of a new CA4 derivative MDS-11 and its prodrug MDS-11P on vascular disrupting activity in vitro and in vivo. Surface plasmon resonance (SPR) and tubulin polymerization assay showed that MDS-11 interacted with tubulin directly and inhibited tubulin polymerization in a cell free system, and western blot assay further confirmed the action in the cellular level. MDS-11 was found to significantly disrupt the microtubulin skeleton in proliferating HUVECs than quiescent ones determined by confocal microscopy. Furthermore, MDS-11 was found to damage the HUVEC-formed tube quickly, but did not influence structures of microvessels from aortic ring possessing pericytes and smooth muscle cells until 3h treatment. In A549 xenograft mice, immunohistochemistry staining of tumor sections revealed that a single dose of MDS-11P led to large areas of necrosis within tumor and reduced the number of tumor vessels, which was consolidated by perfused vascular volume assay. Pharmacokinetic studies of MDS-11P indicated that MDS-11P rapidly converted to the active form, MDS-11, and exhibited a much faster elimination in mice. The antitumor analysis using H22 and A549 mice xenograft models revealed that the growth inhibition rates of MDS-11P at 50mg/kg (twice a day for three weeks) reached 59.4%, 60.5% respectively without obvious weight loss. Taken together, these results suggest that MDS-11 is a potential vascular disrupting agent for further development of antitumor drug.
摘要：
血管破坏剂对肿瘤血管有选择性作用，并在临床前和临床试验中均取得了令人鼓舞的结果。在本研究中，我们分析了一个新的CA4衍生物MDS-11及其磷酸盐MDS-11-P在体外和体内的血管破坏活性作用效果。表面等离子体共振（SPR）和微管蛋白聚合实验表明，MDS-11与微管蛋白有较高的亲和力,并且可以剂量依赖的抑制无细胞体系的微管蛋白聚合。免疫印迹实验进一步在细胞水平上印证这一活性。激光共聚焦观察结果显示，MDS-11可以显著破坏增生人脐静脉内皮细胞（HUVEC）的微管蛋白骨架。而且，MDS-11可以迅速破坏HUVEC形成的管腔，但直至处理3h，对控制血管壁周细胞和平滑肌细胞的主动脉环微血管结构并未造成影响。对A549移植瘤小鼠肿瘤部分进行免疫组织化学染色，发现单剂量 MDS-11P处理，导致肿瘤内部大面积坏死，减少肿瘤血管的数量，这一结论通过血管灌注量检测得到进一步巩固。MDS-11P的药代动力学研究表明，MDS-11P迅速转换MDS-11活动形式，在小鼠体内消除较快。使用H22和A549异种移植小鼠模型的抗肿瘤分析结果显示， 在使用MDS-11P 50mg/kg剂量处理（每天两次持续三个星期）后，生长抑制率分别为59.4％，60.5％，没有明显的体重减轻。上述结果表明，MDS-11是一个值得进一步研究开发的抗肿瘤化合物。
