低剂量分次照射联合曲妥珠单抗对心脏损伤的功能和机制研究

Radiation therapy is an important part of multidisciplinary treatment of thoracic malignant tumors. Cardiac toxicity has been proved to be the major toxicity that impacts survival from radiotherapy. Patients with early breast cancer are the population with great focus on radiation-induced cardiac toxicity because of good prognosis and diversity in multidisciplinary approaches. The degree of radiation-induced cardiac toxicity relates directly to the dose-volume of heart irradiated, which is defined as type I injury. The dose distribution to the heart in the era of intensity-modulated radiotherapy displays the pattern of low dose with large volume, which is fundamentally different to the old pattern of small volume with high dose. However, there is still no guideline of dose limitation of heart in usage of intensity-modulated radiotherapy. The cardiac toxicity induced by trastuzumab is type II injury. In patients with HER2 over-expression, cardiac safety of combined therapy of radiation with trastuzumab is a common clinical question. In the previous studies from our team, low dose volume of heart irradiated was found to be correlated with early abnormalities in systolic as well as diastolic function. Current project purposes first, using animal model of rats exposed to fractionated low dose irradiation with trastuzumab, as to explore the correlation of pathophysiology of injured heart with functional cardiac images. Second, to explore the impact of trastuzumab on fractionated low dose irradiation-induced damage and the potential molecular mechanism on primary myocardial cell. The proposed study will provide scientific evidence and technical strategy to the cardiac safety under modern radiotherapeutic model.

放射治疗是胸部恶性肿瘤综合治疗的重要组成部分，放射性心脏损伤显著影响放疗生存获益。早期乳腺癌因为预后好、治疗手段丰富等特点，成为放射性心脏损伤重点关注对象。放射性心脏损伤为I型损伤，和心脏受照剂量-体积直接相关。调强放疗时代乳腺癌患者的心脏剂量分布呈现大体积低剂量特点，和既往小体积高剂量模式明显不同，但心脏剂量限制标准存在指南空白。曲妥珠单抗的心脏毒性为II型损伤，HER2阳性乳腺癌放疗和曲妥珠单抗联合的心脏安全性是临床关注焦点。本课题组既往研究发现心脏低剂量体积增加和早期心脏功能异常明确相关。本研究拟采用大鼠模型，基于小动物心脏功能检测平台，探索低剂量分次照射联合曲妥珠单抗处理后，心脏组织病理学改变和功能影像变化的关系；运用原代心肌细胞模型，探索曲妥珠单抗对低剂量分次照射后的心肌细胞损伤的影响及潜在分子机制。为乳腺癌调强放疗的心脏安全性提供数据，填补指南空白。

放射治疗是胸部恶性肿瘤综合治疗重要组成部分，心脏毒性是影响生存的主要损伤。早期乳腺癌因为预后良好，综合治疗手段丰富，成为放射性心脏损伤重点关注对象。 放射性心脏损伤和心脏受照剂量-体积直接相关，为I型损伤。调强放疗时代乳腺癌的心脏剂量分布呈现大体积，低剂量特点，和既往小体积高剂量模式有重大差别。HER2过表达乳腺癌放射治疗和曲妥珠单抗联合应用的心脏安全是常见临床问题。曲妥珠单抗的心脏毒性为II型损伤。本课题组既往研究已经发现低剂量体积的增加和早期心脏收缩及舒张功能异常有明确相关性。本研究采用小鼠模型和心肌细胞系，通过辐照联合或不联合曲妥珠单抗处理，并在在小动物心超平台和小动物PET/CT平台，探索辐照联合曲妥珠单抗对心脏损伤的功能和潜在机制。研究结果发现：1.辐照对离体心肌细胞的放射性损伤呈剂量依赖性；同期应用曲妥珠单抗加重辐照对心肌细胞的损伤效应。曲妥珠单抗显著抑制NRF2及其下游分子的表达，抑制HER2下游信号Akt分子的磷酸化，促进 ROS 在细胞内的过度累积和促进胞内 DNA损伤等方式加重心肌的放射性损伤；2.辐照联合曲妥珠单抗可引起小鼠早期的心脏舒张功能障碍，但对早期心脏收缩功能及血清中 cTn-I 无显著影响。曲妥珠单抗可能通过促进小鼠心肌细胞的凋亡、DNA 损伤，促进心肌间微血管损伤等途径，加重辐照对小鼠心脏的早期放射性损伤作用；3.在晚期辐射诱发心脏损伤的小鼠模型中，同期应用曲妥珠单抗会加重辐照诱发的心脏损伤，主要表现在加重心肌缺血，促进心肌的纤维化和细胞凋亡。本研究明确了早期放射性损伤的组织学和功能学改变及其可能机制，及曲妥珠单抗加重心脏放射性损伤的潜在机制。