ABSTRACT
Graduate School o f Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan
INTRODUCTION
In adults, angiogenesis is strictly restricted to processes associated with wound healing and the female reproductive cycle. When a balance between angiogenic and angiostatic factors is disrupted, however, uncontrolled angiogenic factors are released from tumor cells. These factors go on to stimulate endothelial cell (EC) proliferation, and newly formed endothelial cells break down the extracellular matrix, migrate to cancer cells, and eventually begin to form a lumen. Tumor angiogenesis is well known to play a key role in tumor growth and metastasis. The potential regulators of angiogenesis have been identified, i.e., basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), methionine aminopeptidase2 (MetAP-2), thymidine phosphorylase (TP), and plasminogen activator (PA). VEGF and bFGF stimulate endothelial cell proliferation. MMPs digest the extracellular matrix (ECM) and are responsible for the invasion and metastasis. TP is expressed at higher levels in a wide variety of solid tumors than in the adjacent nonneoplastic tissues. PA is promoted by VEGF and activates the invasion of ECs. Angiogenesis is observed in tumor growth and angiogenesis-dependent diseases such as diabetic retinopathy and arthritis. Moreover, it is known that tumor growth is dependent on a blood supply, i.e., oxygen and nutrients. Consequently, angiogenesis inhibitors may potentially be used as new therapeutic agents
for cancer treatment (Folkman 1995). Several angiogenesis inhibitors, such as TNP-470 (Ingber et al. 1990), marimastat (Gore et al. 1996), and SU5416 (Fong et al. 1999), have been developed for targeting endothelial cell proliferation, invasion, and VEGFR signaling pathways, respectively.
