桔梗对乳腺癌肺转移小鼠阿霉素治疗的减毒作用研究

Adriamycin is a commonly used drug in the adjuvant chemotherapy of breast cancer, but there is a dose-dependent cardiac toxicity. When the dose is more than 550mg/m2, the cardiac toxicity is more obvious, and it is not reversible. Therefore, it is of great clinical significance to find a drug to reduce the cardiac toxicity of adriamycin. Doxorubicin induced cardiotoxicity is the results of interaction of multiple factors, such as reactive oxygen species formation, calcium overload, mitochondrial damage, cell apoptosis and autophagy, which oxidative stress in the toxic effect of adriamycin play an important role. The Shennong Bencao "records of Platycodon grandiflorum main in chest and hypochondrium pain such as knife, faint panic palpitation gas, has the functions of promoting blood circulation, Qi, phlegm role, pharmacological studies also found that better antioxidant effect of Platycodon grandiflorum. This study intends to in breast cancer with lung metastasis mouse model based on establish the adriamycin induced myocardial damage model, through in vivo experiments, the dynamic observation of adriamycin induced mice myocardial damage process, from the heart, cardiac pathology, top2 beta and ROS, SOD, MDA and oxidation factor angle for the research of Platycodon grandiflorum on adriamycin induced mouse myocardial damage of reducing toxicity and mechanism of, and research of Platycodon grandiflorum and adriamycin combination of lung metastases from breast cancer the curative effect.

阿霉素是乳腺癌辅助化疗常用药物，但存在剂量依赖性的心脏毒性，当剂量超过550mg/m2时尤为明显，且不可逆。因此，寻找减低阿霉素心脏毒作用的药物具有重要临床意义。阿霉素的心脏毒性是多因素共同作用的结果，如活性氧的生成、钙超载、线粒体损伤、细胞凋亡和自噬等，其中氧化应激在阿霉素的毒性效应中起重要的作用。《神农本草经》记载桔梗主胸胁痛如刀刺，幽幽惊恐悸气，具有活血、行气、化痰作用，药理研究也发现桔梗有较好的抗氧化损伤作用。本研究拟在乳腺癌肺转移小鼠模型基础上，建立阿霉素致心肌受损模型，通过体内实验，动态观察阿霉素致小鼠心肌受损的过程，从心超、心脏病理、拓扑异构酶2β（top2β）以及活性氧（ROS）、超氧化物歧化酶(SOD）、丙二醛（MDA）等氧化因子等角度研究桔梗对阿霉素致小鼠心肌受损的减毒作用及其机制，并研究桔梗与阿霉素合用对乳腺癌肺转移的疗效影响。

乳腺癌是中国女性发病率第一位的恶性肿瘤。阿霉素（Doxorubicin，Dox）作为乳腺癌化疗方案的首选药物之一，其带来的心脏毒副作用受到临床高度重视，如何有效降低阿霉素所致心脏毒性是目前临床医生急需解决的重要课题。.本项目在前期临床研究的基础上，开展桔梗对乳腺癌肺转移小鼠阿霉素治疗过程中减毒作用的基础实验研究。本研究先后完成了桔梗提取物的制备及质量控制；桔梗对乳腺癌肺转移小鼠阿霉素心脏毒性的治疗作用及协同阿霉素抗肿瘤肺转移的药理学机制研究；桔梗对乳腺癌肺转移小鼠阿霉素治疗减毒作用的药代动力学研究三部分内容。.研究表明，桔梗对乳腺癌肺转移小鼠阿霉素心脏毒性发挥治疗作用，增加阿霉素抗肿瘤转移能力；桔梗联合阿霉素用药后能显著抑制乳腺癌肺转移小鼠肿瘤的生长发展及肺转移情况，保护心脏功能，其机制可能与抑制心肌氧化应激和细胞凋亡有关；桔梗能够提升阿霉素在小鼠肺脏的聚集、降低其在心脏的分布，从而协同增效并降低心脏毒副反应，验证了桔梗作为肺经引经药的科学性。