择泰唑来膦酸在乳腺癌中应用及研究进展精选文档.pptVIP

* * * 目前临床前及早期临床试验已经证实择泰可诱导肿瘤细胞凋亡,抑制肿瘤细胞增殖及其活性,减少肿瘤新生血管形成,降低肿瘤细胞黏附及向基质浸润的能力,与细胞毒药物合用产生协同效应,激活免疫系统等涉及肿瘤发生发展的多个关键环节.唑来膦酸的这些直接或间接抗肿瘤作用也奠定了其应用于实体肿瘤辅助治疗的基础. Metastasis to bone occurs via a multi-step process, and inhibition of any of these steps could prevent metastasis to bone1 The primary malignant neoplasm promotes new blood vessel formation (angiogenesis) Cancer cells must then invade the blood vessels, wherein they form multi-celled aggregates Aggregates of tumor cells form emboli that lodge in capillary beds in bone Cancer cells can adhere to vascular epithelial cells to escape the blood vessels and must extravasate through the extracellular matrices to enter the bone microenvironment As cancer cells enter the bone, they are exposed to factors in the bone microenvironment, such as growth factors released from the bone matrix during osteolysis, which may promote tumor growth Zoledronic acid can inhibit multiple steps in the metastatic process and has demonstrated direct and indirect antitumor activities in preclinical assays2 Reference Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2(8):584-593. Lipton A. Emerging role of bisphosphonates in the clinic-Antitumor activity and prevention of metastasis to bone. Cancer Treat Rev. 2008. May 15. [Epub ahead of print] * * * 8 ABCSG-12的试验设计如下:入组人群为1999-2006年收治的1803例受体阳性, III期,阳性LN10的早期绝经前乳腺癌患者,所有患者均不接受术后辅助化疗,治疗期为3年.所有患者在接受戈舍瑞林药物去势的基础上,随机进入TAM或ANA,加用或不加唑来膦酸的两两配对治疗组. * * 含氮双膦酸盐的抗肿瘤机制 NBPs, 含氮双膦酸盐 Adapted from Clézardin P, et al. Cancer Res 2019;65(12):4971-4974. NBPs NBPs NBPs的直接抗肿瘤效果 ↓肿瘤细胞的浸润和粘附 ↓肿瘤细胞的增殖 ↑肿瘤细胞的凋亡 ↑协同其他抗肿瘤药物 NBPs的间接抗肿瘤效果 ↓破骨细胞活性 ↓肿瘤血管生成 ↑ ?? T细胞抗肿瘤活性 肿瘤细胞浸润 肿瘤细 胞增值 激活破骨 细胞活性 骨转移 双膦酸盐作用于肿瘤转移的不同阶段 Adapted from Mundy GR, et al. Nature Reviews Cancer 2019;2:584-593. 间接抗肿瘤 直接抗肿瘤 血管内渗 血管形成 主要肿瘤 转移 粘附外渗 在远处血管 被捕捉 微量转移 抑制血管生成 刺激免疫监视 减少骨粘附 诱导肿瘤 细胞凋亡 减少对基质的浸润 协同使用 抗肿瘤药物 抑制骨吸收 体外及动物模型证实唑来膦酸和化疗序贯有协同作用 图1：多柔比星与唑来膦酸的序贯治疗协同增加体外MCF-7乳腺癌细胞的凋亡 图2：多柔比