【作者】 马超；

【导师】 周庚寅；

【作者基本信息】 山东大学 ， 病理学与病理生理学， 2006， 博士

【摘要】 研究背景：肿瘤多药耐药(multidrug resistance，MDR)的产生是肿瘤化疗中经常遇到的现象，也是导致其化疗失败，肿瘤复发、转移的一个主要原因。原发性乳腺癌对化疗比较敏感，大多数初治患者应用结构和机制不同的各类细胞毒性药物获得缓解，但往往缓解率高，缓解期短，并且绝大多数产生了MDR。MDR的发生机制复杂，其中mdr1基因及其表达产物P-糖蛋白的过表达是最主要的原因。现已证实具有外排功能的P-gp在多种耐药的细胞系中高表达。现在关于P-gp在肿瘤细胞中高表达的机制并不十分清楚，因此MDR的产生机制和逆转方法的研究成为肿瘤研究的重点。除mdr1基因过表达这一主要因素外，肿瘤细胞微环境的改变与肿瘤多药耐药的关系成为MDR机制和逆转研究的新热点。肿瘤细胞微环境改变中最重要的是细胞的缺血缺氧，由于缺氧诱导因子-1(Hypoxia inducible factor 1，HIF-1)在细胞缺氧改变中占有重要中心地位，因此HIF-1与肿瘤细胞多药耐药的关系备受关注。 恶性肿瘤组织的一个显著特点就是快速增殖性。在肿瘤生长过程中，由于肿瘤细胞增生迅速，造成肿瘤微环境始终处于相对缺氧状态。实验表明，几乎所有的实体瘤中均有缺氧细胞存在，其数量与肿瘤的组织学类型及增长速度有关，通常其比例随肿瘤体积增加而增加。缺氧可触发肿瘤产生一系列应激性保护反应，使得肿瘤细胞在缺氧状态下免受损伤或死亡。有研究表明肿瘤细胞中存在的缺氧诱导因子—1在肿瘤缺氧环境中起着中枢纽带作用。HIF-1是一个由HIF-1α和HIF-1β亚单位构成的异二聚体，其中HIF-1中亚单位HIF-1α对氧的依赖性较强，当周围环境的氧浓度下降时，HIF-1α表达增加，并且其表达增加表现在多个水平上，包括转录和蛋白等水平，但主要是蛋白水平明显增多。亚单位HIF-1β对氧的依赖性较弱，但在HIF-1中也必不可少，因为只有在两个亚单位聚合并且发生适形性变化后，与其要调节的下游因子或酶的低氧反应性元件(hypoxic responsive element，HRE)结合，才能发挥调节作用。HIF-1α在人类多种肿瘤组织中高表达，甚至在癌前病变和某些增生性疾病中出现，同时有研究表明实体肿更多还原

【Abstract】 Background: The multidurg resistance (MDR) of the tumor is the most important obstacle in clinical therapy. And it is also the main reason that leads to the clinical chemotherapy failure and results in relapse or distant metastasis of breast cancer. Primary breast cancer is much sensitive to chemotherapy and most of them can alleviate by using difference structural cytoxious drugs, but most of them come into being multidurg resistance soon which lead to high relapse rate and poor prognosis of breast cancer. The mechanism of MDR is much complex. One of the mechanisms underlying MDR has been assigned to enhanced removal of drugs due to over-expression of mdr1 gene which encode efflux transporter protein, such as P-glycoprotein (P-gp). Overexpression of P-gp has been shown to correlate with multidrug resistance in numerous multidrug resistant cell lines. At present, it is not fully understood how P-gp over-expression was mediated in cancer, so more attentions were put on the mechanisms of drug resistance and reversal stategies. Besides the mdrl gene and its protein P-gp, the relationship between the changes of cell microenvironment and MDR becomes a new hotspot. The most important change of cell microenvironment was the ischemia and hypoxia. Since hypoxia-inducible factor-1(HIF-1) plays an important role in cell microenvironment changes, it is very interesting to investigate the relationship between MDR and HIF-1.The microenvironment of rapidly growing tumors is associated with increased energy demand and diminished vascular supply, resulting in focal areas of prominent hypoxia. Hypoxia is an acknowledged feature of most solid tumors .The ability of tumors to adapt to a hypoxic microenvironment was increasingly recognized as an更多还原