Microtubule depolymerizing vascular disrupting agents: novel therapeutic agents for oncology and other pathologies

Abstract

Summary 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.

Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents

“…In contrast to colchicine, the anti-vascular effects of 2a in vivo are apparent well below the maximum tolerated dose, offering a wide therapeutic window. 2a as well as being a potent inhibitor of colchicine binding is also shown to inhibit the growth and development of blood vessels, angiogenesis 5,[18][19][20][21] . The cis configuration only of 2a is biologically activity, with the trans form showing little or no activity 22 .…”

BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy

“…Preclinical evidence suggests that VDAs are not effective at stopping tumor growth when used as single agents but may synergize with conventional chemotherapeutics or antiangiogenic agents (7).…”

Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

“…[1][2][3] Low molecular weight microtubule depolymerizing agents represent the largest family of this class of agent, the most widely investigated of which is disodium combretastatin A-4 3-O-phosphate (CA4P). 4 CA4P, currently in Phase II/III clinical trials, 2,5 is a soluble phosphate pro-drug derivative of the natural parent compound combretastatin-A-4 (CA4) and is distantly related to colchicine.…”