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Tumor-Vascular Disrupting Agents (Tumor-VDAs)
Tumor-Vascular Disrupting Agents (Tumor-VDAs) such as ASA404 represent a distinct class of tumor
vascular-targeting therapies and provide an innovative approach to anticancer treatment.
In preclinical models, Tumor-VDAs have been shown to disrupt established tumor vasculature
causing rapid and sustained inhibition of tumor blood flow. By depriving tumors of the nutrients
necessary for growth and survival, Tumor-VDAs induce necrosis, particularly within the core of the tumor.
The potential therapeutic benefit of Tumor-VDAs may be maximized by combining them
with standard chemotherapy for cancer treatment. Standard cytotoxic therapies are commonly found to be
more active against cancer cells that are highly oxygenated and proliferating, such as those
found at the periphery of tumors, while Tumor-VDAs are particularly effective against the
internal regions of tumors, which are not readily accessible to cytotoxic agents.
Combining Tumor-VDAs with conventional chemotherapy, especially taxanes, has
demonstrated synergistic activity in preclinical models, and activity has been shown in
Phase II clinical trials. Several clinical trials are currently evaluating the therapeutic potential of
Tumor-VDAs such as ASA404 in combination with standard therapy.
Anti-angiogenic agents also target tumor vasculature and are in clinical development.
However, anti-angiogenic agents predominantly interfere with new vessel formation whereas
Tumor-VDAs cause disruption of established tumor vasculature, inhibition of tumor blood
flow and extensive tumor necrosis. Because Tumor-VDAs such as ASA404 selectively target the unique
characteristics of the tumor vasculature, they represent an exciting and promising area of cancer treatment
research and one of great clinical potential in the battle against cancer.
Tumor-VDAs cause disruption of established tumor vasculature, inhibition of tumor blood flow and extensive tumor necrosis
Tumor-VDAs
The unique features of the tumor vasculature can represent an important factor for effective
and selective cancer treatment, and these fundamental differences can be exploited
with Tumor-VDAs.1–5 The development of drug resistance may be less likely to occur with
Tumor-VDAs because tumor endothelial cells are more genetically stable than cancer cells.6 Drug delivery may also be easier because the tumor endothelium is more accessible than tumor cells.6
Proposed mechanism of action of Tumor-VDAs
Tumor-VDAs in clinical development, including ASA404, target established blood vessels within the tumor,
causing disruption of tumor vasculature, inhibition of tumor blood flow and tumor
necrosis.5, 7-9 This disruption of tumor vasculature and inhibition of tumor blood flow is
achieved via a dual mechanism of action, comprised of direct and indirect anti-vascular
activity (Figure 1).7, 10-13
Figure 1. Proposed mechanism of action of Tumor-VDAs
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Direct disruption of tumor vasculature by Tumor-VDAs may be due, at least in part, to
the induction of apoptosis in tumor vascular endothelial cells, which can be detected within
30 minutes of administration in animal models.11,14,15 Tumor endothelial cell death
causes exposure of the basement membrane, rupture of tumor blood vessels and
extravasation of erythrocytes in the surrounding tissue.11,14,15 As a result of vascular damage,
platelets accumulate within the tumor blood vessels, causing the release of serotonin
(5-HT) and of its liver metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA).7 This
direct disruption of tumor vasculature results in a rapid inhibition of tumor blood flow.7,9,16
The indirect disruption of tumor vasculature by Tumor-VDAs is associated in preclinical
models with an increase in concentrations of Tumor Necrosis Factor-α (TNF-α), nitric oxide
and other cytokines (Figure 1).7,12,15,17
The vascular damage and the intratumoral vasoactive cascade induced by Tumor-VDAs
cause inhibition of tumor blood flow by selectively targeting the abnormal and
immature nature of the tumor vasculature.4,5 In animal models, this effect continues to be
evident 24 hours after treatment.5,15,18–21
Disruption of the tumor vasculature and inhibition of tumor blood flow induced by
Tumor-VDAs deprive tumors of oxygen and nutrients necessary for tumor growth and
survival, leading to extensive tumor necrosis (Figure 2).7,22 As demonstrated in preclinical
models, extensive tumor necrosis induced by Tumor-VDAs occurs primarily within the core
of the tumor.
Figure 2. Proposed anti-tumor activity of Tumor-VDAs
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