Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models

Abstract

Our results show the ability of sorafenib to potently inhibit the growth of both ectopically- and orthotopically-implanted Renca and 786-O tumors. The observed tumor growth inhibition and tumor stasis or stabilization correlated strongly with decreased tumor angiogenesis, which was due, at least in part, to inhibition of VEGF and PDGF-mediated endothelial cell and pericyte survival. Finally, sorafenib-mediated inhibition of tumor growth and angiogenesis occurred at concentrations equivalent to those achieved in patients in the clinic.

Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

“…2; refs. 48,49). In the 786-O xenograft model, a dose of 15 mg/kg produced 28% tumor growth inhibition, whereas treatment with 30, 60, or 90 mg/kg dose resulted in 80% tumor growth inhibition; tumor stabilization occurred at doses of 60 or 90 mg/kg (49).…”

“…48,49). In the 786-O xenograft model, a dose of 15 mg/kg produced 28% tumor growth inhibition, whereas treatment with 30, 60, or 90 mg/kg dose resulted in 80% tumor growth inhibition; tumor stabilization occurred at doses of 60 or 90 mg/kg (49). Similarly, in the Renca tumor model, a dose of 15 mg/kg produced 53% tumor growth inhibition, whereas treatment with a 60 or 90 mg/kg dose produced 82% inhibition and resulted in tumor stabilization during treatment (48,49).…”

“…The effect of sorafenib on angiogenesis was assessed by measuring the level of CD31 endothelial marker in the tumor (48,49). A significant reduction in 786-O tumor vasculature was evident within 3 days of sorafenib treatment at the 15, 30, or 60 mg/kg dose level.…”

Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation

“…The median survival time (MST) of advanced HCC in China is only 3 to 6 months, and a slightly longer MST of 6 to 9 months in Europe and the United States. Sorafenib (Nexavar, Bayer Pharmaceuticals) is a small molecule that can inhibit tumor cell proliferation and tumor angiogenesis as well as increase the rate of apoptosis in a wide range of tumor models [14,15] . Sorafenib works by inhibiting the serine/threonine kinases Raf-1, B-Raf, the receptor tyrosine kinase activity of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3 and platelet-derived growth factor receptor β (PDGFR-β) [14,15] .…”

“…Sorafenib (Nexavar, Bayer Pharmaceuticals) is a small molecule that can inhibit tumor cell proliferation and tumor angiogenesis as well as increase the rate of apoptosis in a wide range of tumor models [14,15] . Sorafenib works by inhibiting the serine/threonine kinases Raf-1, B-Raf, the receptor tyrosine kinase activity of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3 and platelet-derived growth factor receptor β (PDGFR-β) [14,15] . Cellular signaling pathways mediated by Raf-1 and vascular endothelial growth factor (VEGF) have been implicated in the molecular pathogenesis of HCC [16][17][18][19] , providing a rationale for investigating sorafenib for this indication.…”