10 - Antivascular therapy in gynaecological cancers

Summary

The great majority of women with advanced ovarian cancer will relapse and die from their disease. There is therefore a great need for new agents that can extend remission and prolong survival. One approach is to introduce agents that target the vasculature that maintains a tumour's ability to survive and grow. These can be divided into agents that act against established blood vessels (vascular disrupting agents or VDAs) or inhibit the formation of new blood vessels (anti-angiogenic drugs). Angiogenesis inhibitors are considered to be cytostatic in nature, in contrast to VDAs, which are thought to be cytotoxic, but there is considerable overlap between the two groups, with agents classified according to their primary site of action (Box 10.1).

Angiogenesis is under dynamic regulation by stimulatory pro-angiogenic factors released by tumour and host cells, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), interleukin 8 (IL-8), matrix metalloproteinases (MMPs) and inhibitory anti-angiogenic factors (tumour necrosis factor [TNF], 5-HT, angiostatin, endostatin). Diffusion of nutrients and oxygen from nearby capillaries beyond a tumour size of 2 mm is insufficient to sustain cell function. An imbalance of pro- and anti-angiogenic factors stimulates an angiogenic switch so that the tumour develops an angiogenic phenotype to grow and metastasise. Several process are thereafter involved, such as endothelial cell proliferation, proteolytic degradation of the extracellular matrix and migration of endothelial cells, leading to the formation of a functioning vessel with a lumen.