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

Abstract

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.

Anti-angiogenic effect of arsenic trioxide in lung cancer via inhibition of endothelial cell migration, proliferation and tube formation

“…Tumor angiogenesis is a complex process that includes multiple stages and is regulated by numerous signaling molecules that interact with one another (18). Currently, inhibition of angiogenesis has become an important target in the treatment of solid tumors, including lung cancer (31,32 Our group has previously demonstrated that As 2 O 3 exhibits anti-lung cancer activity by inhibiting angiogenesis (33). It was also demonstrated that As 2 O 3 could reduce malignant pleural effusion caused by the pleural metastasis of lung cancer by downregulating nuclear factor-κB, tumor necrosis factor-α and VEGF-A (34).…”

Phase I Clinical Trial of MPC-6827 (Azixa), a Microtubule Destabilizing Agent, in Patients with Advanced Cancer

“…In an observational study, approximately 34% of the patients with metastatic renal cell carcinoma treated with sorafenib or sunitinib developed a cardiovascular event, manifested as ECG changes, cardiac enzyme elevations, or symptoms of angina (20). The prevalence of these cardiovascular events with the use of anti-VEGF and VDAs has led to heightened awareness of potential cardiotoxicity and close monitoring of patients treated with these agents (20)(21)(22). The cardiac adverse events noted in the current study prompted planning of close monitoring for cardiac sequelae in patients treated with MPC-6827 in this and in future studies.…”

Canstatin gene electrotransfer combined with radiotherapy: preclinical trials for cancer treatment

“…4 Targeting tumor angiogenesis to control tumor growth is a widespread approach and numerous preclinical and clinical studies have focused on the development of new angiogenesis inhibitors. [4][5][6][7][8] The extracellular matrix (ECM) surrounding blood vessels plays an essential role in both the angiogenic process and the vessel morphogenesis. Although, previously, several studies highlighted the antiangiogenic activity of angiostatin, 2 a non-ECM-derived plasminogen fragment, interestingly, most naturally occurring angiogenesis inhibitors are fragments or cryptic domains from ECM-derived larger proteins that are themselves not active as angiogenesis inhibitors.…”