双膦酸盐在乳腺癌治疗中的抗肿瘤作用.pptVIP

* Bisphosphonates Overview * 双膦酸盐的发展历时一百年，应用于临床治疗已经40多年了，已经上市的双膦酸盐种类繁多。 首先让我们回顾一下双膦酸盐的发展过程。 不含氮的双膦酸盐:如羟乙双膦酸盐、氯曲膦酸盐和替鲁膦酸盐，大约在30年前被引入临床。这些药物具有不含氮原子的简单侧链。 含氮双膦酸盐:包括帕米膦酸盐、阿仑膦酸钠和伊班膦酸盐，具有一个含有单一氮原子的脂肪族侧链。这些药物抑制骨吸收的作用强于第一代药物。 随后又出现具有杂环结构的含氮双膦酸盐，如利塞膦酸盐、唑来膦酸盐，在作用强度和疗效方面有了进一步提高。 择泰?（唑来膦酸）是更新一代的双膦酸盐，具有一个咪唑杂环，其环状侧链含有两个氮原子，是目前作用最强的静脉输注的双膦酸盐。 * Bisphosphonates Overview * 含氮的双膦酸盐由于作用机制与不含氮的完全不同，可以更有效的抑制破坏细胞活性，增加破骨细胞凋亡。 短侧链的不含氮二磷酸盐可以和单磷酸腺苷结合，形成了ATP类似物(AppCp），由于形成的ATP类似物不能被水解, 它们在 破骨细胞内大量累积, 影响多种酶的活性, 抑制破骨细胞的骨吸收功能和导致细胞凋亡。但大量ATP类似物的累积需要大剂量氯屈膦酸才能实现。---ATP类似物不能提供能量，导致破骨细胞调亡（PCP基团和单磷酸腺苷结合，抑制了三磷酸腺苷的合成）| 含氮的双膦酸盐含氮二磷酸盐抑制骨吸收的分子机制是直接抑制甲经戊酸途径（抑制FPP合成酶）, 使得破骨细胞膜结构和功能的不完整，最终导致细胞活性降低和凋亡增加。发挥这一作用只需小剂量的双膦酸盐。（该途径的抑制，影响了类固醇、胆固醇和萜类物质的生成，萜类物质是形成活性GTP 酶的关键物质，而活性GTP酶是维持破骨细胞结构和功能的重要酶） * * DU145 prostate cancer cells were treated with zoledronic acid or vehicle (control) for 24 hours, and cellular adhesion was assessed on mineralized dentine Micrographs revealed increased adhesion of control cells (top panel) compared with cells treated with 100 μmol/L zoledronic acid (lower panel) Zoledronic acid inhibition of adhesion was dose-dependent Zoledronic acid effects were significant at the lowest dose tested (1 μmol/L), which reduced cellular adhesion by approximately 40% compared with control cells (P .05) MDA-MB-231 breast cancer cells were treated with zoledronic acid for 24 hours, and cell adhesion was assessed using non-mineralized matrices such as fibronectin and collagen I Zoledronic acid inhibition of cell adhesion was dose dependent 100 μM zoledronic acid inhibited adhesion to type I collagen (a key component of the bone matrix) by 50% versus control References Coxon JP, Oades GM, Kirby RS and Colston KW. Zoledronic acid induces apoptosis and inhibits adhesion to mineralized matrix in prostate cancer cells via inhibition of protein prenylation. BJU Inter 2004;94:164-170. Pickering LM, Mansi JL, and Colston KW. Breast cancer cell adhesion to mineralised matrices is enhanced by her2/neu amplific