Effects of the novel vascular targeting agent MDS-11P on tumor vascularity and its antitumor activity

doi:10.1016/j.bcp.2011.08.024

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Effects of the novel vascular targeting agent MDS-11P on tumor vascularity and its antitumor activity
	Deng, Zhi-Ting 1; Feng, Teng 1; Wang, Peng 1; Qi, Xin 1; Chen, Xue-Hong 1; Li, Ying-Xia 1; Song, Chun-Li 1; Geng, Mei-Yu2 ; Li, Jing1
刊名	BIOCHEMICAL PHARMACOLOGY
	2011-12-15
卷号	82 期号:12 页码:1832-1842
关键词	Vascular disrupting agents MDS-11P Antitumor CA4 derivative Vascularity
ISSN号	0006-2952
DOI	10.1016/j.bcp.2011.08.024
文献子类	Article
英文摘要	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 rnicrovessels from aortic ring possessing pericytes and smooth muscle cells until 3 h 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 50 mg/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. (C) 2011 Elsevier Inc. All rights reserved.
资助项目	National High-tech R&D Program of China[2007AA09Z405] ; Program for Changjiang Scholars and Innovative Research Team in University[IRT0944]
WOS关键词	COMBRETASTATIN A4 PHOSPHATE ; ANGIOGENESIS IN-VITRO ; DISRUPTING AGENTS ; ENDOTHELIAL-CELLS ; A-4 ; VIVO ; CANCER ; CYTOSKELETON ; THERAPIES ; SCHEDULE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000297142000004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278304]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Li, Jing
作者单位	1.Ocean Univ China, Key Lab Marine Drugs, Minist Educ, Sch Med & Pharm, Qingdao 266003, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Deng, Zhi-Ting,Feng, Teng,Wang, Peng,et al. Effects of the novel vascular targeting agent MDS-11P on tumor vascularity and its antitumor activity[J]. BIOCHEMICAL PHARMACOLOGY,2011,82(12):1832-1842.
APA	Deng, Zhi-Ting.,Feng, Teng.,Wang, Peng.,Qi, Xin.,Chen, Xue-Hong.,...&Li, Jing.(2011).Effects of the novel vascular targeting agent MDS-11P on tumor vascularity and its antitumor activity.BIOCHEMICAL PHARMACOLOGY,82(12),1832-1842.
MLA	Deng, Zhi-Ting,et al."Effects of the novel vascular targeting agent MDS-11P on tumor vascularity and its antitumor activity".BIOCHEMICAL PHARMACOLOGY 82.12(2011):1832-1842.