02 BOOK OF ABSTRACTS .indd

Progress in tumour vascular targeting
Gillian M. Tozer
Tumour Microcirculation Group, Academic Unit of Surgical Oncology, University
of Sheffield, K Floor Royal Hallamshire Hospital, Sheffield, S10 2JF, UK
The blood supply of solid tumours influences the outcome of treatment via its
influence on the microenvironment of tumour cells and its critical role in drug
delivery. In addition, tumour blood vessels are an important target for cancer therapy
because of the reliance of tumour cells on their blood supply for proliferation and
survival. Over the past thirty years, major advances have been made in understanding
the molecular processes associated with tumour angiogenesis, the main process
by which tumours vascularize, culminating in 2004 in bevacizumab (Avastin TM ),
a monoclonal antibody against vascular endothelial growth factor (VEGF), being
accepted into clinical practice in the USA for the treatment of metastatic colorectal
cancer, in combination with conventional chemotherapy.
Current research into new vascular targeting strategies can be divided into antiangiogenic
and anti-vascular approaches. Anti-angiogenic approaches aim to prevent
the neo-vascularization processes in tumours, whereas anti-vascular approaches aim
to cause a rapid and selective shut-down of the established tumour vasculature,
leading to secondary tumour cell death. Drugs with anti-vascular properties are often
known as vascular damaging agents or VDAs. Not withstanding this discrimination,
individual agents may possess both anti-angiogenic and anti-vascular (vascular
disrupting) actions.
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The colchicine-related tubulin-binding/microtubule-depolymerizing agents, predominantly
the combretastatins, constitute the largest group of low molecular
weight drugs currently in clinical trial as tumour anti-vascular agents (Tozer et al.,
2005, Nat Rev Cancer 5: 423-435). Their potency and selectivity for the tumour
vasculature is now well established and clinical trials are concentrating on their
potential in combination with conventional radio- and chemo-therapy. The basis for
their selective action against tumour blood vessels is now urgently sought to provide
a basis for further drug development in this area.
Mouse fibrosarcoma cell lines, expressing only single VEGF isoforms (VEGF 120
,
VEGF 164
or VEGF 188
) or all the isoforms (w/t), were developed from embryonal
fibroblasts isolated from corresponding transgenic mice, in order to determine the
influence of the different isoforms on tumour angiogenesis, vascular morphology
and function and the corresponding vascular response to the lead combretastatin,
CA-4-P. Results showed that VEGF 188
plays a significant role in the maturation phase
of tumour angiogenesis, leading to the development of mature vascular walls and
vessel networks. In addition, the vascular response to combretastatin A-4-P (CA-4-P)
was greater in the VEGF 120
than in the VEGF 188
tumours. This work has helped
identify the vascular characteristics that influence tumour susceptibility to CA-4-P.
Supported by Cancer Research UK