McNamara D A, Harmey J, Wang J H, Kay E, Walsh T N, Bouchier-Hayes D J
Department of Surgery, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland.
Eur J Surg Oncol. 2001 Dec;27(8):714-8. doi: 10.1053/ejso.2001.1177.
Angiogenesis is fundamental to tumour growth and vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic cytokines known. We have previously demonstrated that tamoxifen reduces serum VEGF in certain cancer patients. We hypothesized that tamoxifen may attenuate the angiogenetic response to VEGF.
Human dermal microvessel endothelial primary cell cultures (HMEC) were incubated with tamoxifen (1.25-5.0 microg) 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 VEGF-mediated angiogenesis in vivo was assessed using a Matrigel angiogenesis assay in the Sprague-Dawley rat.
Tamoxifen (5.0 microg/ml) significantly reduced HMEC proliferation over 24 h when compared with cells treated with vehicle alone. Oral administration of tamoxifen in the rat (20 mg/day) significantly reduced endothelial cell proliferation and migration in response to VEGF.
Tamoxifen (5.0 microg/ml) reduces proliferation of a VEGF-dependent endothelial cell line in vitro. In vivo, orally administered tamoxifen reduces VEGF-mediated angiogenesis in the rat. These findings indicate that tamoxifen may directly inhibit the effect of VEGF on the endothelial cell, in addition to its previously described effect of reducing serum VEGF levels. This data supports a role for tamoxifen in modulation of the VEGF-dependent angiogenic response to surgical trauma, particularly as an adjuvant therapy for VEGF-dependent tumours.
血管生成是肿瘤生长的基础，血管内皮生长因子（VEGF）是已知最有效的促血管生成细胞因子之一。我们之前已经证明，他莫昔芬可降低某些癌症患者的血清VEGF水平。我们推测他莫昔芬可能会减弱对VEGF的血管生成反应。
将人真皮微血管内皮原代细胞培养物（HMEC）与他莫昔芬（1.25 - 5.0微克）或溶剂孵育。使用5-溴-2'-脱氧尿苷（BrdU）标记内皮细胞增殖试验来定量细胞增殖。在Sprague-Dawley大鼠中使用基质胶血管生成试验评估口服他莫昔芬（20毫克/天）对体内VEGF介导的血管生成的影响。
与仅用溶剂处理的细胞相比，他莫昔芬（5.0微克/毫升）在24小时内显著降低了HMEC增殖。在大鼠中口服他莫昔芬（20毫克/天）可显著降低内皮细胞对VEGF的增殖和迁移反应。
他莫昔芬（5.0微克/毫升）在体外可降低VEGF依赖性内皮细胞系的增殖。在体内，口服他莫昔芬可降低大鼠体内VEGF介导的血管生成。这些发现表明，他莫昔芬除了其先前描述的降低血清VEGF水平的作用外，还可能直接抑制VEGF对内皮细胞的作用。该数据支持他莫昔芬在调节对手术创伤的VEGF依赖性血管生成反应中的作用，特别是作为VEGF依赖性肿瘤的辅助治疗。
