Microtubule depolymerizing vascular disrupting agents: novel therapeutic agents for oncology and other pathologies.
Vascular disrupting agents (VDAs) are a relatively new group of 'vascular targeting' agents that exhibit selective activity against established tumour vascular networks, causing severe interruption of tumour blood flow and necrosis to the tumour mass. Microtubule depolymerizing agents form by far the largest group of small molecular weight VDAs many of which, including lead compound disodium combretastatin A-4 3-O-phosphate (CA-4-P), are under clinical development for cancer. Although distinct from the angiogenesis inhibitors, VDAs can also interfere with angiogenesis and therefore constitute a potential group of novel drugs for the treatment of pathological conditions characterized by excessive angiogenesis, in addition to cancer. The endothelial cytoskeleton is the primary cellular target of this family of drugs, and some progress in understanding the molecular and signalling mechanisms associated with their endothelial disrupting activity has been made in the last few years. Susceptibility of tumour vessels to VDA damage is ascribed to their immature pericyte-defective nature, although the exact molecular mechanisms involved have not been clearly defined. Despite causing profound damage to tumours, VDAs fail to halt tumour growth unless used together with conventional treatments. This failure is attributed to resistance mechanisms, primarily associated with cells that remain viable within the tumour rim, and enhanced angiogenesis. The focus is now to understand mechanisms of susceptibility and resistance to identify novel molecular targets and develop strategies that are more effective.
Kanthou
Chryso
C
Cancer Research-UK Tumour Microcirculation Group, Section of Oncology, School of Medicine & Biomedical Sciences, University of Sheffield, Sheffield, UK.
Tozer
Gillian M
GM
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D001632:Bibenzyls / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D050257:Tubulin Modulators / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D050257:Tubulin Modulators; C040105:combretastatin