359 POSTER Pharmacokinetic and pharmacodynamic effects of MN-029, a novel vascular disrupting agent (VDA), in patients (pts) with advanced solid tumors

Abstract

To provide a comprehensive overview of the current state of development of a novel class of anti-cancer drugs, the vascular disrupting agents (VDAs), previously known as vascular targeting agents (VTAs).A comprehensive review, analysis and commentary of the published medical literature on VDAs was performed.Tumour vascular targeting therapy exploits known differences between normal and tumour blood vessels. VDAs target the pre-existing vessels of tumours (cf anti-angiogenics), and cause vascular shutdown leading to tumour cell death and rapid haemorrhagic necrosis within hours. It is becoming clear that VDAs have overlapping activity with anti-angiogenic drugs, which prevent the formation of new blood vessels. There are two types of VDA. First, biological or ligand-directed VDAs use antibodies, peptides or growth factors to target toxins or pro-coagulants to the tumour endothelium. In contrast, small molecule VDAs work either as tubulin-binding agents or through induction of local cytokine production. VDAs can kill tumour cells resistant to conventional chemotherapy and radiotherapy, and work best on cells in the poorly perfused hypoxic core of tumours, leaving a viable rim of well-perfused tumour tissue at the periphery, which rapidly regrows. Consequently, responses of tumours to VDAs given as single agents have been poor; however, combination therapy with cytotoxic chemotherapy, external-beam radiotherapy, and radioimmunotherapy, which target the peripheral tumour cells, has produced some excellent responses in animal tumours. VDAs are generally well tolerated with different side-effect profiles to current oncological therapies. Dynamic magnetic resonance imaging is most frequently used to obtain a pharmacodynamic end point to determine whether the VDA is acting on its intended target.VDAs are a promising new class of drug, which offer the attractive possibility of inducing responses in all tumour types with combination therapy.