Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Anticancer Drugs. 2012 Jun;23(5):525-33. doi: 10.1097/CAD.0b013e32834ea5b3.
High expression of vascular endothelial growth factor (VEGF) in patients with breast cancer has been associated with a poor prognosis, indicating that VEGF could be linked to the efficacy of chemotherapy and radiotherapy. It has also been suggested that radiation resistance is partly due to tumour cell production of angiogenic cytokines, particularly VEGF receptor (VEGFR). This evidence indicates that inhibition of VEGFR might enhance the radiation response. Sorafenib tosylate (Bay 54-9085) is an oral, small-molecule multikinase inhibitor of several targets including RAF/MEK/ERK MAP kinase signalling, VEGFR-2, VEGFR-3 and platelet-derived growth factor receptor-beta. Sorafenib has shown clinical efficacy in treating solid tumours such as renal cell and hepatocellular carcinomas. However, strategies are yet to be identified to prolong and maximize the anticancer effect of this multikinase inhibitor. The objective of this study was to determine whether a combination of Sorafenib and radiation will enhance the treatment response in vitro and in vivo. Radio-modulating effect of Sorafenib was assessed by performing clonogenic assays. In addition, cell cycle analyses as well as annexin-V apoptosis assays were performed 24 and 48 h after treatment, respectively. To confirm our in-vitro results, tumour growth delay assays were performed. Our results showed a strong and supra-additive antitumour effect of radiation combined with Sorafenib in vitro (dose enhancement factor of 1.76). The combined therapy demonstrated a strong and significant G2/M cell cycle arrest (combined treatment vs. irradiated alone: P<0.0008). Moreover, annexin-V staining showed a significant increase in the level of apoptosis (combined treatment vs. irradiated alone: P<0.0004). Study of the syngeneic model demonstrated the superior potency of the Sorafenib combined with radiotherapy. Our results demonstrate that higher antitumour activity can be achieved when radiation and Sorafenib are combined.
高表达血管内皮生长因子（VEGF）的乳腺癌患者预后不良，表明 VEGF 可能与化疗和放疗的疗效有关。也有研究表明，辐射抗性部分是由于肿瘤细胞产生血管生成细胞因子，特别是 VEGF 受体（VEGFR）。这些证据表明，抑制 VEGFR 可能增强辐射反应。索拉非尼甲磺酸盐（Bay 54-9085）是一种口服的小分子多激酶抑制剂，可抑制多个靶点，包括 RAF/MEK/ERK MAP 激酶信号通路、VEGFR-2、VEGFR-3 和血小板衍生生长因子受体-β。索拉非尼已显示出在治疗肾细胞癌和肝细胞癌等实体瘤方面的临床疗效。然而，目前还没有确定延长和最大限度发挥这种多激酶抑制剂抗癌作用的策略。本研究旨在确定索拉非尼联合放疗是否能增强体外和体内的治疗反应。通过集落形成实验评估索拉非尼的放射调节作用。此外，分别在治疗后 24 和 48 小时进行细胞周期分析和 Annexin-V 凋亡分析。为了证实我们的体外结果，还进行了肿瘤生长延迟实验。我们的结果表明，索拉非尼联合放疗在体外具有很强的、超相加的抗肿瘤作用（剂量增强因子为 1.76）。联合治疗表现出强烈的、显著的 G2/M 细胞周期阻滞（联合治疗与单独放疗相比：P<0.0008）。此外，Annexin-V 染色显示凋亡水平显著增加（联合治疗与单独放疗相比：P<0.0004）。同种异体模型的研究表明，索拉非尼联合放疗具有更强的效力。我们的结果表明，当放疗和索拉非尼联合使用时，可以实现更高的抗肿瘤活性。
