基于TGF-β1/Smad通路的益气养阴填髓法在非小细胞肺癌化疗的减毒增效机制及“金水相生”理论探讨

Chemotherapy is the main treatment of advanced lung cancer. The dose-limiting toxicity of chemotherapy drugs is the bottleneck of its efficacy. Our preliminary studies built through clinical practice proved that Supplementing Qi, Nourishing Yin and Filling Marrow (SQNYFM) can reduce bone marrow suppression after chemotherapy, increase the stability of the rate of tumor, and improve pulmonary symptoms. The results of animal experiments and clinical observations coincide with traditional Chinese medicine theory of mutual promotion between lung and kidney.but,the mechanism of attenuation and synergic with SQNYFM is unclear and we need to study for the mechanism of this exists in the treatment of lung cancer from Nourishing kidney and Filing marrow(NKFM) to reinforcing lung and controlling tumor(RLCT).TGF-β1/Smad signaling pathway can affect the occurrence and development of lung cancer, the bone marrow hematopoietic stem cells and the immune response regulation. This study will be completed by vivo and vitro experiments from angle of TGF-β1/Smad signaling pathway in gene and protein expression. The purpose of this study was to clarify the molecular pharmacological mechanism of attenuation and synergic for non-small cell lung cancer after chemotherapy, to explore dual control effects of lung tissue and bone marrow hematopoietic tissue, to testify the hypothesis of NKFM and RLCT through the dose-effect relationship research and its dose-effect relationship curve model calculation，to reveal the mechanism of mutual promotion between lung and kidney in the treatment of lung cancer, to find a effective attenuation and synergic treatment method providing a scientific basis in non-small cell lung cancer after chemotherapy.

化疗是中晚期肺癌最主要的治疗手段，而化疗药物的剂量限制性毒性是其疗效的瓶颈。我们前期通过临床实践构建的益气养阴填髓法可减轻化疗后骨髓抑制，提高瘤体稳定率，同时可改善肺部症状，其动物实验和临床观察结果与中医“金水相生”理论吻合，但其中减毒增效机制还不清楚，对于肺癌治疗中存在的这种“滋肾填髓→补肺抑瘤”机理需要研究。TGF-β1/Smad信号通路可影响肺癌的发生、发展，同时对骨髓造血干细胞及机体免疫反应也有调控作用。课题拟通过体内外实验，从TGF-β1/Smad信号通路的基因和蛋白表达角度阐明其对非小细胞肺癌化疗减毒增效的分子药理机制，以及对肺癌组织、骨髓造血组织的双重调控作用机制，并通过对其剂量-效应关系进行研究，计算量效关系的曲线模型以验证“滋肾填髓→补肺抑瘤”的假说，揭示肺癌治疗中存在“金水相生”的机理，为找到针对非小细胞肺癌化疗具有减毒增效作用的治疗方法提供科学依据。

益气养阴填髓方是非小细胞肺癌化疗的有效方剂。TGF-β1/Smad、PI3K/AKT/mTOR通路可调控非小细胞肺癌的发生和发展，也参与骨髓造血功能的调节，而抑制该通路可提高肿瘤治疗效果，增加化疗敏感性。本研究拟探讨益气养阴填髓方联合顺铂对肺癌组织、骨髓组织中TGF-β1/Smad、PI3K/AKT/mTOR通路的干预作用，以明确肺癌治疗中存在“金水相生”的机理。首先建立气阴两虚型C57BL/6J小鼠Lewis肺癌模型，进而通过观察小鼠肿瘤体积、测定瘤重、抑瘤率及骨髓有核细胞计数，Western Blot检测各组移植瘤组织及骨髓组织中TGF-β1/Smad、PI3K/AKT/mTOR通路相关蛋白表达。结果显示益气养阴填髓方单独使用无明显抗肿瘤作用，该方与顺铂联用可以显著抑制肺癌荷瘤小鼠体积增长，提高抑瘤率，增强顺铂的抗肿瘤作用。益气养阴填髓方可以减轻肺癌荷瘤小鼠化疗后引起的骨髓抑制，对骨髓造血细胞及骨髓有核细胞有保护作用，减轻肺癌荷瘤小鼠顺铂化疗对骨髓的损伤。益气养阴填髓方与顺铂联用对肺癌荷瘤小鼠TGF-β/ Smad和PI3K/AKT/mTOR通路发挥双重调控作用，且存在浓度依赖关系，肺癌的治疗中存在“滋肾填髓→补肺抑瘤”的关系。综合上述结果，本研究为探讨益气养阴填髓方增强肺癌顺铂化疗药物敏感性的机制奠定了坚实的工作基础。.项目资助发表SCI论文1篇，发表中文核心论文2篇，已接收1篇，获得国家自然科学基金面上项目1项。项目投入经费23万元，支出17.145万元，各项支出基本与预算相符。剩余经费5.855万元，剩余经费计划用于本项目研究后续支出。