Biol. Pharm. Bull. 27(5) 599—605 (2004)

Angiogenesis, that is the construction of new vessels from pre-existing vessels, is a crucial event in not only physiological but also pathological conditions; for example, wound healing and the female reproductive cycle are related to it in a physiological condition. On the other hand, diabetic retinopathy and chronic inflammation are closely involved in pathological angiogenesis. In particular, tumor expansion is dependent on angiogenesis because tumor cells demand oxygen and nutrients to overcome hypoxia and starvation, and metastasize to the distal organs through this angiogenic vasculature. When there is a hypoxic or starving condition in tumor tissue, tumor cells receive this signal, which is often mediated by hypoxia inducible factor-1, to promote an angiogenic switch and induce angiogenesis. Angiogenesis is regulated by numerous cytokines including pro-angiogenic factors such as vascular endothelial growth factor (VEGF), angiopoietin, basic fibroblast growth factor (bFGF), placenta-like growth factor (PlGF), platelet-derived growth factor (PDGF), and IL-8, as well as the anti-angiogenic factors angiostatin, endostatin, thrombospondin, a tissue inhibitor of metalloproteinase (TIMP), and so on. These angiogenic factors are produced in not only tumor cells but also stromal and endothelial cells. In tumor growth, pro-angiogenic factors predominantly exist in an angiogenic site and stimulate vascular endothelial cells through their receptors. These stimulated endothelial cells acquire specific characteristics to constitute new vessels. Since a close relationship between tumor growth and angiogenesis has been clarified, and since the angiogenic mechanism has subsequently been elucidated, various anti-angiogenic inhibitors for use in cancer treatment have been developed. Here, these anti-angiogenic inhibitors are collectively reviewed and their anti-angiogenic effect and subsequent anti-tumor effect estimated. Then, a novel cancer chemotherapy targeting the angiogenic vasculature, anti-neovascular therapy (ANET), is discussed which uses traditional anti-cancer agents or photosensitizer.