AVE8062: a new combretastatin derivative vascular disrupting agent

Angiogenesis has an essential role in promoting and supporting tumor growth and it is an important therapeutic target. The tumor vascular network is the result of pro-angiogenic and inhibitory factors as well as of the interaction between endothelial cells and extracellular matrix. Different antiangiogenic therapeutics have been developed to improve tumor control through vascular-targeting agents (VTA). VTAs can be divided into two groups: antiangiogenic agents and vascular-disrupting agents (VDAs). VTAs inhibit specific factors required to induce and direct the angiogenic process, with major activity against small tumor masses and at the tumor periphery, encompassing monoclonal antibodies and small molecules inhibitors of the tyrosine kinase domain of the VEGF receptor. VDAs specifically target and destroy well-established tumor vessels with ischemia and destruction of large masses with central hemorrhagic necrosis and survival of a thin peripheral tumor layer. VDAs can be divided into biologics, such as ligand-based, and small-molecule agents; this second group includes small-molecule VDAs like flavonoids, such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA), and microtubule-destabilizing agents. In this review we will discuss the mechanism of action, as well as the preclinical and clinical results, of one of the most promising antitubulin agents: the combretastatin A4-phosphate derivative, AVE8062A.

[1]  G. Yancopoulos,et al.  VEGF-Trap: A VEGF blocker with potent antitumor effects , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Stephen L. Brown,et al.  Vascular targeting therapies for treatment of malignant disease , 2005, Cancer.

[3]  G. Tozer,et al.  Determinants of anti-vascular action by combretastatin A-4 phosphate: role of nitric oxide , 2000, British Journal of Cancer.

[4]  G Mchedlishvili,et al.  Red blood cell behavior at low flow rate in microvessels. , 1999, Microvascular research.

[5]  G. Tozer,et al.  Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. , 1997, Cancer research.

[6]  C. Kanthou,et al.  The vascular targeting agent combretastatin A-4-phosphate induces neutrophil recruitment to endothelial cells in vitro. , 2003, Anticancer research.

[7]  M. Stratford,et al.  The vascular response of tumor and normal tissues in the rat to the vascular targeting agent, combretastatin A-4-phosphate, at clinically relevant doses. , 2002, International journal of oncology.

[8]  S. Fox,et al.  Relationship of vascular maturation in breast cancer blood vessels to vascular density and metastasis, assessed by expression of a novel basement membrane component, LH39 , 2000, British Journal of Cancer.

[9]  Chryso Kanthou,et al.  Disrupting tumour blood vessels , 2005, Nature Reviews Cancer.

[10]  C. Kanthou,et al.  The tumor vascular targeting agent combretastatin A-4-phosphate induces reorganization of the actin cytoskeleton and early membrane blebbing in human endothelial cells. , 2002, Blood.

[11]  J. Alexander,et al.  Serotonin induced actin polymerization and association with cytoskeletal elements in cultured bovine aortic endothelium. , 1987, Biochemical and biophysical research communications.

[12]  K. Hori,et al.  Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis , 2003, British Journal of Cancer.

[13]  A. Fyles,et al.  The relationship between elevated interstitial fluid pressure and blood flow in tumors: a bioengineering analysis. , 1999, International journal of radiation oncology, biology, physics.

[14]  B. Curry,et al.  ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. , 2002, Cancer research.

[15]  B Vojnovic,et al.  Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability. , 2001, Cancer research.

[16]  A. Wozniak,et al.  Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors , 2008, Investigational New Drugs.

[17]  M A Konerding,et al.  3D microvascular architecture of pre-cancerous lesions and invasive carcinomas of the colon , 2001, British Journal of Cancer.

[18]  E. Voest,et al.  Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  T. Tsuruo,et al.  A Novel Combretastatin A‐4 Derivative, AC‐7700, Shows Marked Antitumor Activity against Advanced Solid Tumors and Orthotopically Transplanted Tumors , 1999, Japanese journal of cancer research : Gann.

[20]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[21]  F. Eskens,et al.  Vascular disrupting agents in clinical development , 2007, British Journal of Cancer.

[22]  Yasufumi Sato,et al.  Antitumor Effects due to Irreversible Stoppage of Tumor Tissue Blood Flow: Evaluation of a Novel Combretastatin A‐4 Derivative, AC7700 , 1999, Japanese journal of cancer research : Gann.

[23]  P. Vrignaud,et al.  Early Quantitative Evaluation of a Tumor Vasculature Disruptive Agent AVE8062 Using Dynamic Contrast-Enhanced Ultrasonography , 2008, Investigative radiology.

[24]  P. LoRusso,et al.  Differentiation and definition of vascular-targeted therapies. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[25]  P. Thorpe.  Vascular Targeting Agents as Cancer Therapeutics , 2004, Clinical Cancer Research.

[26]  P. Vrignaud,et al.  Evaluation of tissue perfusion (tumor, spleen, heart) in mice after administration of AVE8062, a tumor vascular-targeting agent , 2004 .

[27]  Liz Y. Han,et al.  Antitumor and antivascular effects of AVE8062 in ovarian carcinoma. , 2007, Cancer research.