基于肺癌微环境的化疗药物投递效率及中药益气活血法干预效应研究

Yiqi-Huoxue therapy has been widely carried out and improves therapeutic effects of chemo-drugs for cancer patients, the detailed mechanisms, however, is unknown. Our research showed Huayu Wan, a classic representative of Yiqi-Huoxue therapy, could boost cytoxan effect and make hemodynamic parameters improved based on clinical and mouse model research. Therefore, we hypothesize that Huayu Wan could improve therapeutic effects via increasing chemo-drugs delivery in tumor microenvironment. Here, an established Lewis lung cancer mice model will be set up. The amount of fluorescence adriamycin delivery in tumor will be quantified after treating Huayu Wan, and then, the effects of Huayu Wan on tumor hemodynamics and tumor environment will be observed, including tumor blood supply, vascular morphology and biological behavior of tumor stromal cells. Futhermore, the expression level of TGFβ/Smad signal pathway moleculars will be analyzed in tumor tissues. Therefore, we try to testify the hypothesis and uncover the potential mechanisms of application of Yiqi-Huoxue drugs for patients when accepting chemotherapy. Meanwhile, the possible signal pathway related to this hypothesis will be clarified. Based on all above, a theoryetical background will be provided when Yiqi-Huoxue drugs are used for for patients when accepting chemotherapy.

益气活血中药广泛应用于中晚期肿瘤的治疗中，当其与化疗药联合应用时可显著的提高化疗的临床疗效，但机制尚不明。我们的前期实验研究发现益气活血代表方化瘀丸具有显著的化疗增效、改善血流动力学指标的作用。在此基础上，本课题提出假说“益气活血中药通过提高肿瘤组织中化疗药物的投递效率而发挥化疗增效作用”。为验证该假说，本课题继续选取化瘀丸为研究对象，以Lewis肺癌C57BL/6小鼠为动物模型，1)定量分析化瘀丸对肺癌组织内荧光阿霉素投递效率的影响；2）拟从血流动力学和肿瘤组织微环境（微血管结构、功能、肿瘤基质纤维化）两个角度探讨化瘀丸对肿瘤组织血供、肿瘤微循环的影响；3）拟从分子水平初步分析化瘀丸作用下肿瘤组织和细胞TGFβ/Smad信号通路的变化。通过本研究验证课题假说、阐明化瘀丸化疗增效机制、寻找可能的信号通路靶点，进而为今后益气活血中药在化疗病人中的应用提供新的理论基础。

活血中药在肿瘤治疗中存在广泛争议（抑瘤与促瘤），课题组临床实践发现益气活血中药（代表方化瘀丸）与化疗联合使用时，具有明显减毒增效作用，但是具体机制不清。本课题提出假说“益气活血中药通过提高肿瘤组织中化疗药物的投递效率而发挥化疗增效作用”。为此，课题从体内与体外两个方面进行了研究，体外化瘀丸含药血清对肺癌细胞化疗疗效的影响；定量分析化瘀丸对肺癌组织内荧光阿霉素投递效率的影响，从分子水平初步分析化瘀丸化疗增效的具体机制。研究结果显示：化瘀丸含药血清提高Lewis细胞内阿霉素药物浓度，具有化疗增效作用。体内Lewis肺癌小鼠模型研究发现，在小鼠肺癌增殖早期，化瘀丸抑瘤效果明显，抑瘤机制主要通过抑制血管内皮生长因子VEGF表达。伴随肿瘤体积的增大，化瘀丸抑瘤效果消失，改变了肿瘤组织血流动力学，提高了血液流速。化瘀丸能够提高化疗药物在肿瘤组织中的投递效率，机制可能在于提高肿瘤组织中血流供应，促进肿瘤组织中微血管生成，进而起到增加化疗药物疗效的作用，为进一步指导临床应用益气活血中药提供了实验及理论依据。