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Phytochemistry Reviews

, Volume 13, Issue 1, pp 191–206 | Cite as

Plant-derived vascular disrupting agents: compounds, actions, and clinical trials

  • Verena K. Kretzschmann
  • Robert Fürst
Article

Abstract

The tumor vasculature of solid tumors offers unique characteristics compared to the normal vasculature and, therefore, represents an attractive target in anti-cancer therapy. Besides the classic anti-angiogenic agents, which inhibit tumor neovascularization, a novel promising class of anti-tumor drugs has emerged in the last years, the vascular-disrupting agents (VDAs). In contrast to angiogenesis inhibitors, VDAs act on already established tumor blood vessels of large solid tumors and induce a vascular shutdown by targeting tumor endothelial cells. This results in extensive necrotic tumor cell death. The sources of VDAs are quite divers, however, the plant-derived compounds represent the largest and most prominent class. Plant-derived VDAs have undergone extensive preclinical investigations and are now tested in several advanced clinical trials. In this review we summarize preclinical data, including drug-target relationships as well as functional in vitro and in vivo assays, discuss their molecular way of action, and update the clinical status of the most prominent plant-derived VDAs: FAA/DMXAA, CA-4-P, OXi4503, AVE8062, and ZD6126. All these data emphasize the value of secondary plant metabolites and their (semi-)synthetic derivatives for current drug discovery.

Keywords

Anti-vascular therapy Cancer Combretastatin DMXAA Tubulin-binding drugs 

Abbreviations

AI

Angiogenesis inhibitor

ATC

Anaplastic thyroid cancer

CA-4

Combretastatin A-4

CA-4-P

Combretastatin A-4 3-O-phosphate

DCE-MRI

Dynamic contrast-enhanced magnetic resonance imaging

DLT

Dose-limiting toxicity

DMXAA

5, 6-Dimethylxanthenone-4-acetic acid

FAA

Flavone acetic acid

GEF

Guanine nucleotide exchange factor

HMVEC

Human lung microvascular endothelial cells

HNLD

Highest non-lethal dose

HUVEC

Human umbilical vein endothelial cells

IKK

IκB kinase

IκB

Inhibitor of NFκB

MLC

Myosin light chain

MTD

Maximum tolerated dose

NAC

N-acetylcolchinol

NFκB

Nuclear factor κB

NSCLC

Non-small cell lung cancer

PD

Pharmacodynamics

PET

Positron emission tomography

PK

Pharmacokinetics

RD

Recommended dose

ROCK

Rho kinase

TNF

Tumor necrosis factor

VDA

Vascular-disrupting agent

Notes

Acknowledgments

We are thankful to Dr. Ilse Zündorf (Goethe-University Frankfurt/Main, Germany) for her help with preparing the figures.

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Pharmacy, Center for Drug Research, Pharmaceutical BiologyUniversity of MunichMunichGermany
  2. 2.Institute of Pharmaceutical Biology, BiocenterGoethe-University Franfurt/MainFrankfurt/MainGermany

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