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

Zhi Ting Deng, Teng Feng, Peng Wang, Xin Qi, Xue Hong Chen, Ying Xia Li, Chun Li Song, Mei Yu Geng, Jing Li

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish
Pages (from-to)1832-1842
Number of pages11
JournalBiochemical Pharmacology
Volume82
Issue number12
DOIs
StatePublished - 15 Dec 2011
Externally publishedYes

Keywords

  • Antitumor
  • CA4 derivative
  • MDS-11P
  • Vascular disrupting agents
  • Vascularity

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