title: Effects of the novel vascular targeting agent MDS-11P on tumor vascularity and its antitumor activity.
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 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.
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
authors.forename: Zhi-Ting
authors.initials: ZT
authors.lastname: Deng
authors.forename: Teng
authors.initials: T
authors.lastname: Feng
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
authors.forename: Xue-Hong
authors.initials: XH
authors.lastname: Chen
authors.forename: Ying-Xia
authors.initials: YX
authors.lastname: Li
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Song
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Geng
authors.forename: Jing
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects; D015251:Epirubicin / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010755:Organophosphates / Q000494:pharmacology / Q000627:therapeutic use*; D010080:Oxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011355:Prodrugs; D051381:Rats; D017207:Rats, Sprague-Dawley; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C568969:MDS 11; C568968:MDS-11P compound; D010755:Organophosphates; D010080:Oxazoles; D011355:Prodrugs; D014404:Tubulin; D015251:Epirubicin