Recent Advances in Angiogenesis and ... - Bentham Science

Recent Advances in Angiogenesis and Antiangiogenesis, 2009, 101-111 101
Tumor Vascular Disrupting Agents
Gillan Tozer and Chyso Kanthou
Domenico Ribatti (Ed.)
All rights reserved - © 2009 Bentham Science Publishers Ltd.
CHAPTER 12
Tumor Microcirculation Group, Section of Oncology, School of Medicine & Biomedical Sciences, University of
Sheffield, Beech Hill Road, Sheffield S10 2RX, UK
Address correspondence to: Professor Gillian Tozer, Tumor Microcirculation Group, Section of Oncology,
School of Medicine & Biomedical Sciences, University of Sheffield, Beech Hill Road, Sheffield. S10 2RX, UK
Tel: +44 114 2712423; Fax: +44 114 2713314; Email: g.tozer@sheffield.ac.uk
Abstract: Tumor vascular disrupting agents (VDAs) are characterized by their ability to
produce a very rapid and selective shut-down of tumor blood flow sufficient to induce
extensive secondary tumor cell death. This effect is brought about by efficacy against
established tumor blood vessels, making their mode of action conceptually distinct from that of
the anti-angiogenic agents. Three main groups of VDAs are currently in clinical trial, consisting
of DMXAA (5, 6-dimethylxanthenone-4-acetic acid), tubulin binding agents including the
combretastatins and junctional protein inhibitors. These agents have different primary targets
but produce similar morphological and functional effects on the tumor vasculature. The
signaling pathways that mediate these effects are only partially understood but, in the case of
disodium combretastatin A-4 3-0-phosphate (CA-4-P), undoubtedly involve activation of the
small GTP-ase Rho and Rho kinase. Innate and induced resistance mechanisms need to be
investigated in order to provide new targets for improving the efficacy of VDAs, especially in
combination with conventional cancer treatments. Here, we review the developmental status of,
and mechanisms of action and resistance to, currently available VDAs.
1. INTRODUCTION
Tumor vascular disrupting agents or VDAs are
designed to target established tumor blood vessels,
with the aim of shutting down tumor blood flow and
inducing extensive secondary tumor cell death. This
approach is conceptually distinct from anti-angiogenic
therapy, which aims to prevent the development of
neovasculature, although individual agents may
possess both vascular disrupting and anti-angiogenic
properties. Distinct molecular signatures associated
with the tumor vasculature are being developed as
therapeutic targets for tumor vascular disruption [1, 2].
In addition, several classes of low molecular weight
drugs have been found to possess innate tumor
vascular disrupting properties and a number of these
are now in clinical trial. Deciphering the mechanisms
of action and bases for treatment resistance of these
agents should provide novel pathways for further drug
development in this area.
2. DMXAA
DMXAA (5, 6-dimethylxanthenone-4-acetic acid) is a
derivative of flavone-8-acetic acid that causes rapid
vascular shut-down in a range of pre-clinical tumor
models. DMXAA entered Phase I clinical trial via the
Cancer Research Campaign, now Cancer Research
UK, in 1995 [3], and is the most advanced of the
VDAs in clinical development. It is being further
developed, as ASA404, by Novartis, under license
from Antisoma plc (UK). Following a successful
randomized Phase II clinical trial of ASA404 in
combination with carboplatin and paclitaxel for
advanced previously untreated non-small cell lung
cancer, this compound is now in Phase III trial for this
condition. Results of the Phase II trial showed an
increase in patient survival from 8.8 months, for
chemotherapy alone, to 14.0 months, with the addition
of DMXAA [4]. Clinical evaluation in other tumor
types is also on-going (http: //www.novartisoncology.
com/).
3. COMBRETASTATINS AND OTHER
TUBULIN-BINDING AGENTS
Microtubule-depolymerising tubulin-binding agents
are by far the largest group of VDAs in clinical
development (Table 1).
The potent anti-cancer agents, vincristine and
vinblastine, have tumor vascular disrupting effects in
animal tumors but at doses higher than clinically
achievable [5, 6]. The combretastatins bind -tubulin
at a different site from vincristine/vinblastine and have