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ZD6474, a VEGF-2 receptor antagonist for the treatment of cancer Between 1970 and 1994, cancer claimed the lives of about 123 million Americans. According to the most recent statistics, it is estimated that 1.3 million new cases of cancer will be diagnosed and 555,500 people will die from cancer in the United States in the year 2002. Inhibitors of angiogenesis have received considerable attention because of their anti-cancer opportunities and the market for this therapeutic class is anticipated to reach $1.75 billion by 2006. Although there are multiple opportunities for the development of anti-angiogenic molecules, the most advanced targets are the growth factors. The principal growth factors driving angiogenesis are VEGF, bFGF, and hepatocyte growth factor/scatter factor. Discovered in the 1980's, VEGF is one of the archetypal angiogenic growth factors and has received considerable attention. VEGF is a homodimeric 45kDa glycoprotein that specifically acts on endothelial cells binding to a growing number of endothelial tyrosine kinase receptors including Flt-1 (VEGFR-1), KDR/flk-1 (VEGFR-2) and VEGFR-3/Flt-4. VEGFR-2 is exclusively expressed in endothelial cells and appears to play a pivotal role in endothelial cell differentiation and vasculogenesis. Like all cytokine receptors, VEGF receptor binding activates intracellular mechanisms through receptor dimerization, which in the case of VEGF receptors increases receptor tyrosine kinase activity. VEGFR-2 receptor activation induces angiogenesis, endothelial cell proliferation and the elongation, network formation, and branching of nonproliferating endothelial cells. AstraZeneca have recently published data characterizing a novel orally active VEGF-2 receptor antagonist, ZD6474. This therapeutic candidate selectively inhibits VEGF-2 tyrosine kinase activity with nanomolar potency. Over a similar concentration range, this produces inhibition of VEGF-stimulated endothelial cell proliferation. Administration of 50 mg/kg/day ZD6474 also inhibited neovascularization of A459 xenografts and inhibited the growth of a wide range of other tumors with a minimally active dose of at least 25 mg/kg in each case. ZD6474 is currently in Phase I clinical development and preliminary data show that diarrhea is the dose limiting event with other events including rash and asymptomatic QTc prolongation Entry date October, 2002 Adapted from Wedge et al, Cancer Res 2002 Aug 15;62(16):4645-55
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