Ovarian cancer (Figure 1) is particularly sensitive to chemotherapy and about 70% to 80% of newly diagnosed patients respond to a combination of platinum and taxane chemotherapy.1,2

The growth and metastatic spread of tumours is dependent on the development of a vascular supply.3,4 A number of factors have been identified that contribute towards the homeostasis of angiogenesis. Angiogenesis stimulated by hypoxia, mechanical stress and acidosis results in proangiogenic cytokine production in endothelial cells, associated stromal cells and bone marrow. Vascular endothelial growth factor (VEGF) is the dominant proangiogenic vascular growth factor controlling blood vessel formation. Tumour growth beyond 1-2mm and the ability to metastasise require the establishment of a vascular supply through a process of angiogenesis.4

The induction of angiogenesis is a discrete component of the tumour phenotype and a potentially rate-limiting step that is an essential part of the phenotypic repertoire characterising tumour development.5 The angiogenic switch is governed by regulatory mechanisms that manage the balance between inhibitors and inducers of angiogenesis produced by tumours.

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The VEGF cytokine family consists of six glycoproteins and VEGF-A (commonly referred to as VEGF) is the most potent direct-acting angiogenic protein. VEGFs mediate angiogenic signals through high-affinity tyrosine kinase receptors. Binding of VEGF initiates a cascade of signalling events leading to endothelial mitogenesis, proliferation and survival, as well as increased vascular permeability. These receptors are present on vascular endothelium and some ovarian cancer cells, indicating a possible direct antitumour effect of anti-VEGF therapy.

Achieving VEGF inhibition
The antitumour effects of VEGF inhibition are due to a reduction in tumour microvessel density and blood flow. A temporary and paradoxical ‘normalisation’ of tumour vasculature has also been demonstrated. This results in improvement of blood flow and oxygen delivery to the tumour, with consequent enhanced delivery of chemotherapy.6

In humans, VEGF expression is upregulated in most solid tumours, including ovarian cancer.7 In epithelial ovarian cancer, angiogenesis is central to disease progression and prognosis, and the overexpression of VEGF in ovarian tumours is associated with poorer prognosis and survival.8

Experimental data have repeatedly confirmed the hypothesis that cancer growth is angiogenesis-dependent, using angiogenesis inhibitors such as anti-VEGF monoclonal antibodies or VEGF receptor small molecule kinase inhibitors.9 In murine models of epithelial cancer, blocking VEGF slows tumour progression, inhibits ascites formation10 and significantly prolongs the lifespan of the mice.11 Mice that have been inoculated with ovarian carcinoma cells that overexpress VEGF have a significantly reduced time to the formation of ascites. Blocking the effects of VEGF results in resolution of the ascites and prevents further accumulation.10 Agents that inhibit angiogenesis may have the ability to inhibit ascites formation, stop tumour progression and possibly even cause tumour regression in patients with epithelial ovarian cancer.