Drug Insight: vascular disrupting agents and angiogenesis—novel approaches for drug delivery

Vascular disrupting agents (VDAs) are designed to disrupt the already established abnormal vasculature, and induce rapid shutdown of tumor blood supply causing subsequent tumor death from hypoxia and nutrient deprivation. The authors discuss the strategies to improve drug delivery, and suggest that further clinical trials need to evaluate novel treatment strategies that combine VDAs with radiotherapy, cytotoxic drugs, anti-angiogenic agents, and other novel targeted therapies. Close attention to the cardiovascular side effect profile of these agents is also imperative during their clinical development. Vascular disrupting agents (VDAs), or endothelial disrupting agents, attempt to exploit the vascular endothelium that supplies rapidly dividing neoplasms. Unlike antiangiogenesis agents (e.g. the monoclonal antibody bevacizumab; and tyrosine kinase inhibitors sorafenib and sunitinib) that disrupt endothelial cell survival mechanisms and the development of a new tumor blood supply, VDAs are designed to disrupt the already established abnormal vasculature that supports tumors, by targeting their dysmorphic endothelial cells. Tumor vascular endothelium is characterized by its increased permeability, abnormal morphology, disorganized vascular networks, and variable density. VDAs induce rapid shutdown of tumor blood supply, causing subsequent tumor death from hypoxia and nutrient deprivation. The safety profile of this class of compounds is more indicative of agents that are indeed 'vascularly' active. For example, VDAs can cause: acute coronary and other thrombophlebitic syndromes; alterations in blood pressure, heart rate, and ventricular conduction; transient flush and hot flashes; neuropathy; and tumor pain. Despite these cardiovascular concerns some patients have benefited from VDAs in early clinical trials. Further drug development of VDAs must include the combination of these agents with other novel biological agents, cytotoxic chemotherapy, and radiotherapy. Close monitoring of patients receiving VDAs for any cardiovascular toxicity is imperative. Key Points Vascular disrupting agents (VDAs), or endothelial disrupting agents, attempt to exploit the vascular endothelium that supplies rapidly dividing neoplasms The safety profile for this class of compounds is more indicative of agents that are vascularly active, including: acute coronary syndromes; alterations in blood pressure, heart rate, and ventricular conduction; transient hot flashes; neuropathy; and