Tamoxifen inhibits endothelial cell proliferation and attenuates VEGF-mediated angiogenesis and migration in vivo

Introduction: Angiogenesis is. fundamental to tumour growth and vascular en dothelial growth factor (VEGF) is one of the most potent proangiogenic cyto kines, known. We have previously demonstrated that tamoxifen reduces serum VEGF in certain cancer patients. We hypothesized that tamoxifen may attenua te the angiogenetic response to VEGF. Methods: Human dermal microvessel endothelial primary cell cultures (HMEC) were incubated with tamoxifen (1.25-5.0 mug) or vehicle. Cell proliferation was. quantified using 5-bromo-2'-deoxyuridine (BrdU) labelling endothelial cell proliferation assay. The effect of oral tamoxifen. (20 mg/day) on VEG F-mediated angiogenesis in vivo was assessed using a Matrigel angiogenesis assay in; the Sprague-Dawley rat. Results: Tamoxifen (5.0 mug/ml) significantly reduced HMEC proliferation ov er 24 h when compared with cells treated with vehicle: alone. Oral administ ration of tamoxifen in the rat (20 mg/day) significantly reduced endothelia l cell proliferation and migration in response to VEGF. Conclusion: Tamoxifen (5.0 mug/ml) reduces proliferation of a VEGF-dependen t endothelial cell line in vitro. In vivo, orally administered tamoxifen re duces VEGF-mediated angiogenesis in the rat. These findings indicate that t amoxifen may directly inhibit the effect of VEGF on the endothelial cell, i n addition to its previously described effect of reducing serum VEGF levels . This data supports a role for tamoxifen in modulation of the VEGF-depende nt angiogenic response to, surgical trauma, particularly as an adjuvant the rapy for VEGF-dependent tumours. (C) 2001 Harcourt Publishers Ltd.