Soltau Jens, Zirrgiebel Ute, Esser Norbert, Schächtele Christoph, Totzke Frank, Unger Clemens, Merfort Irmgard, Drevs Joachim
Cancer Hospital Sanafontis, Freiburg, Federal Republic of Germany.
Anticancer Res. 2008 Mar-Apr;28(2A):933-41.
Bisphosphonates have shown direct antitumoral activity in vitro, in vivo and even in clinical studies, but the exact mechanism for this has not yet been elucidated. In this study the antiangiogenic potency of zoledronic acid and clodronate were evaluated.
The effects of zoledronic acid and clodronate on the proliferation of endothelial cells and different tumor cells, and on the activity of protein kinases were investigated. Furthermore in vitro experiments were performed to evaluate the underlying antiangiogenic mechanism of action. Both bisphosphonates were examined in vivo at different doses and in daily subcutaneous application in a murine renal cell carcinoma model (RENCA). The antiangiogenic activity was evaluated by immunohistochemical staining (CD31) and by determination of mouse vascular endothelial growth factor (VEGF) serum concentration.
Zoledronic acid and clodronate inhibited proliferation of endothelial cells at lower concentrations than the different tumor cell lines did. This effect was more pronounced for zoledronic acid. The activity of almost all tested kinases was inhibited by zoledronic acid, whereas clodronate showed no effect. In the RENCA model, a significant effect of zoledronic acid on the primary tumor in a bell-shaped dose response curve with the highest efficacy between 100 Bg/kg 2xd and 200 Bg/kg 1xd, was observed. The mean vessel density (MVD) was significantly reduced by both bisphosphonates at different concentrations. This is the first report on increased mouse VEGF serum concentrations in the RENCA model.
The results indicate that these bisphosphonates, particularly zoledronic acid, possess antitumoral and antiangiogenic activity.
双膦酸盐在体外、体内甚至临床研究中均显示出直接的抗肿瘤活性，但其确切机制尚未阐明。本研究评估了唑来膦酸和氯膦酸的抗血管生成能力。
研究了唑来膦酸和氯膦酸对内皮细胞和不同肿瘤细胞增殖以及蛋白激酶活性的影响。此外，进行了体外实验以评估其潜在的抗血管生成作用机制。两种双膦酸盐均以不同剂量每日皮下注射给予小鼠肾细胞癌模型（RENCA）进行体内研究。通过免疫组织化学染色（CD31）和测定小鼠血管内皮生长因子（VEGF）血清浓度评估抗血管生成活性。
唑来膦酸和氯膦酸在比不同肿瘤细胞系更低的浓度下即可抑制内皮细胞增殖。唑来膦酸的这种作用更为明显。唑来膦酸可抑制几乎所有测试激酶的活性，而氯膦酸则无此作用。在RENCA模型中，观察到唑来膦酸对原发性肿瘤有显著作用，呈钟形剂量反应曲线，在100μg/kg 2次/天和200μg/kg 1次/天之间疗效最佳。两种双膦酸盐在不同浓度下均显著降低了平均血管密度（MVD）。这是关于RENCA模型中小鼠VEGF血清浓度升高的首次报道。
结果表明这些双膦酸盐，尤其是唑来膦酸，具有抗肿瘤和抗血管生成活性。
