Abstract
Angiogenesis is crucial for tumour growth and the formation of metastases. Various classes of angiogenesis inhibitors that are each able to inhibit one of the various steps of this complex process can be distinguished. Results from clinical studies with these agents are summarised. In general, it has been shown that most angiogenesis inhibitors can be safely administered, but that tumour regressions are rare. Combining angiogenesis inhibitors with cytotoxic chemotherapy can enhance anticancer activity. Recently, some promising data with regard to clinical efficacy have been presented. While performing clinical studies with angiogenesis inhibitors, defining biological activity is crucial, but thus far no validated techniques are available. It is conceivable that in the near future various classes of angiogenesis inhibitors will be combined in an attempt to further improve antiangiogenic and anticancer activity.
Highlights
Tumour-related angiogenesis is a multistep process that is initiated through the activity of various proangiogenic factors or stimuli that are secreted by tumour cells and host components such as macrophages, lymphocytes and kidney cells (Klagsbrun and D’ Amore, 1996)
Besides vascular endothelial growth factor (VEGF), basic fibroblast growth factor, plateletderived growth factor (PDGF), interleukin-8 and insulin-like growth factor (IGF) are factors involved in angiogenesis, and these factors have their own endothelial cell receptors
Phase I studies exploring different intravenous (i.v.) administration schedules showed that the agent, given as single agent or in combination with various cytotoxic agents, was safe and did not cause dose-limiting toxicity (DLT) when given at predefined doses
Summary
Receptor tyrosine kinase inhibitors SU5416 SU6668 SU11248 c-Kit, Flt-3 PTK787/ZK22854 ZD6474 CP-547,632. Sugen/Pharmacia Sugen/Pharmacia Sugen/Pharmacia Phase I Schering/Novartis Astra Zeneca Pfizer. VEGFR-2 VEGFR-2, bFGFR, PDGFR VEGFR-2, PDGFR, VEGFR-1, VEGFR-2 VEGFR-2, EGFR VEGFR-2, EGFR, PDGFR. Inhibitors of endothelial cell proliferation ABT-510 Angiostatin Endostatin TNP-470 Thalidomide
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