联合氧化苦参碱与小剂量干扰素抑制肝癌术后复发的机制研究

The residual liver is the major target for HCC recurrence after curative resection. In our early study, we evaluated the relationship of HCC recurrence to the inflammatory related cells/ genes of the residual liver and the level of GGT and ALT. We verified that the inflammatory status of the residual liver is an important indicator for HCC recurrence. Therefore, therapies which target at the inflammatory status can theoretically reduce HCC recurrence. Arrcording to the theory of "seed and soil", we should select therapies which could both regulate the hepatic inflammatory reaction and inhibit tumor cells. In our earlier in vivo and in vitro studies, we found that low-dose IFN-αin combination with oxymatrine could significantly inhibit the growth of planted tumors, reduce the occurrence of lung metastases and reduce the mortality. Such effect is not only related to the antitumor ability of IFN-αand oxymatrine, but also to the ability of regulating the hepatic inflammtory reaction of the combination of IFN-αand oxymatrine. However, the mechanism behind these phenomenon is far from clear although we had found the down-reguliton of COX-2 expression might be involved. Hence, in the present investigation, we are try to identify the safety and anti-tumor mechanism of the combination of IFN-αand oxymatrine.Moreover, we will investigate the impact on hepatic stellate cells of oxymatrine in vitro an in vivo.

残余肝脏是肝癌根切后转移复发主要靶器官。在前期研究中，我们综合分析了肝脏局部炎症相关细胞/基因与外周血肝酶[γ-谷氨酰转移酶和丙氨酸转氨酶]，证实了术后肝脏炎症状态是一个重要的复发预测指标。干扰素α和氧化苦参碱都是临床常用的治疗病毒性肝炎的常用药物，而且被证实对肝癌等恶性肿瘤有一定的抑制作用。通过体外细胞和体内动物实验，我们发现小剂量干扰素α虽然不良反应明显减少，但不能有效的改善肝脏炎症状态，其抗复发效果有限；而联合氧化苦参碱后，能显著抑制移植瘤生长，降低肺转移率，延长生存期，这不仅与两药合用后所产生显著的抑制肿瘤细胞侵袭转移能力有关，更与联合用药后能有效的调节肝脏炎症反应相关。本课题的目的不仅在于阐明两药联合安全性，更要进一步阐明相关机制：1、研究氧化苦参碱对炎症微环境的调节作用（以肝星状细胞为代表）2、验证与小剂量IFN-α联合氧化苦参碱抑制肝癌复发转移的密切相关的COX-2相关基因

IFN-α和氧化苦参碱都是临床常用的治疗病毒性肝炎的常用药物，而且被证实对肝癌等恶性肿瘤有一定的抑制作用。通过体外细胞和体内动物实验，我们发现小剂量IFN-α虽然不良反应明显减少，但不能有效的改善肝脏炎症状态，其抗复发效果有限；而联合氧化苦参碱后，能显著抑制移植瘤生长，降低肺转移率，延长生存期，这不仅与两药合用后所产生显著的抑制肿瘤细胞侵袭转移能力有关，更与联合用药后能有效的调节肝脏炎症反应相关。COX-2 表达受抑制是小剂量IFN-α 联合氧化苦参碱具有显著的协同疗效的关键。本研究证实了两药联合的安全性，并阐明了氧化苦参碱对炎症微环境的调节作用，验证了小剂量IFN-α联合氧化苦参碱抑制肝癌复发转移与COX-2相关基因密切关系。