Angiogenesis refers to the formation of new blood vessels from an existing vasculature and is recognised as a necessary requirement for most tumours to grow beyond 1-2 mm in diameter. Factors established as playing a role in angiogenesis may be divided into two principal groups: (a) those that stimulate endothelial cell proliferation and/or elongation, migration and vascular morphogenesis including
vascular endothelial growth factor (
VEGF),
basic fibroblast growth factor (bFGF),
platelet derived endothelial cell growth factor (
PD-ECGF) and the tie and tek receptors, and (b)
proteases and their receptors involved in the breakdown of basement membranes and the extracellular matrix (ECM) including the
matrix metalloproteinases (
MMPs),
cathepsins and those involved in the
plasmin cascade. Angiogenesis has been identified as a potential target for development of
anticancer agents. The discovery of a range of naturally-occurring factors which negatively regulate angiogenesis, including the
thrombospondins,
angiostatin and
endostatin, and the tissue inhibitors of
MMPs (TIMPs), has given added impetus to this approach. Synthetic anti-angiogenic compounds have been developed, including
TNP-470,
carboxyamidotriazole,
VEGF-
tyrosine kinase inhibitors and
MMP inhibitors (MMPI) which, like the naturally-occurring anti-angiogenic factors, inhibit angiogenesis in vitro and in vivo, and tumour development, growth and
metastasis in vivo. Anti-angiogenic agents also enhance the antitumour activity of many conventional cytotoxic chemotherapeutic agents. Such combinations may have a particular role as adjuvant
therapies following surgical resection of primary tumours. Unlike tumour cells, tumour associated endothelial cells do not develop resistance to anti-angiogenic agents. Furthermore, anti-angiogenic agents are generally
cytostatic rather than cytotoxic. As such, these agents are, in general, likely to be administered over long periods of time. Therefore, as well as having proven antitumour efficacy, an anti-angiogenic compound will need to be well-tolerated if it is to become established in the clinical management of patients with malignant disease.