Recent Advances in Angiogenesis and ... - Bentham Science

Tumor Vascular Disrupting Agents Recent Advances in Angiogenesis and Antiangiogenesis, 2009 103
blood flow rate (ml / g / min)
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Fig. (1). Blood flow rate in the P22 rat sarcoma versus normal tissues of the BDIX rat in control (0h) and CA-4-P (30 mg/kg)
treated (6h) rats. Blood flow rate was estimated from tissue uptake of intravenously administered, radiolabelled iodoantipyrine.
prevents cell aggregation and induces apoptosis [25].
The peptide N-cadherin inhibitor, ADH-1, developed
by Adherex, entered clinical trial in 2006 and is now
in Phase II development, with evidence of
haemorrhage in treated tumors (http:
//www.adherex.com/). Low molecular weight
antagonists are currently under development.
5. CELLULAR EVENTS
tumour brain heart kidney
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The hall-mark of VDAs is their very rapid effects on
tumor blood vessels. For instance, CA-4-P and
DMXAA cause a significant decrease in tumor blood
flow within minutes of drug exposure, with maximum
effects between 1 and 6 hours [26, 27]. For CA-4-P,
these rapid effects are paralleled in vitro, by remodeling
of the endothelial cytoskeleton, triggered by
disruption of interphase microtubules [28]. Endothelial
cells are particularly sensitive to CA-4-P and similar
compounds. Effects predominantly consist of
increased development of actin stress fibers,
actinomyosin contractility, rounding up of cells,
formation of focal adhesions, disruption of cell-cell
junctions involving both VE- and N-cadherin, and
increase in monolayer permeability [28, 29].
Additionally, in a sub-population of cells, F-actin
accumulates around the surface of severely contracted
cells in the form of surface blebs. Signalling pathways
associated with these changes involve the small GTPase,
RhoA, and Rho kinase and stress-activated protein
kinase-2/p38 (SAPK/p38) [28, 30]. We have recently
confirmed the importance of Rho kinase in vivo by
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time after drug administration (h)
using a small molecule inhibitor, which blocked CA-4-
P-induced necrosis in a colorectal xenografted tumor
model (unpublished data).
The primary target of DMXAA is unknown.
Cytoskeletal effects in endothelial cells are confined to
the actin skeleton, involving partial dissolution of actin
filaments [31]. Unlike CA-4-P, DMXAA causes
significant intratumoral increases in the activity of
tumor necrosis factor alpha (TNF) [32]. However, the
time-course of blood flow shut-down in animal models
was not consistent with TNF induction, leading to the
concept that DMXAA causes its vascular effects by
both indirect action via induced cytokines and direct
action on tumor endothelial cells. This theory was
substantiated on discovering that tumor vascular
damage was attenuated but not blocked, in tumors
growing in TNF receptor-1-deficient mice, following
DMXAA treatment [33]. In vitro studies have strongly
suggested that DMXAA induces TNF in conjunction
with a co-stimulator [34]. TNF acts as a vascular
disrupting agent in its own right [35], and modifies the
actin cytoskeleton and permeability through the
Rho/Rac pathway [36]. DMXAA directly stimulates
various signaling pathways in vitro, including the
SAPK/p38 pathway, inhibition of which prevents
some of the in vitro effects of the drug [37]. In
addition, DMXAA has been shown to directly
stimulate mouse dendritic cells in vitro, with
subsequent proinflammatory cytokine release [38].
Dendritic cells, especially tumor-associated
macrophages, are a likely important source of
increased levels of TNF and nitric oxide (NO) in
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