耐药性妇科肿瘤的治疗中光动力学疗法与多药耐药基因之间的相关性研究

Gynecologic cancer seriously effects on women's physical and mental health. During past 30 years, Photodynamic therapy (PDT) on gynecologic cancer treatment achieved noteworthy result. PDT has its advantages: high specificity to tumor; less toxicity and side effect and then no resistance. If the relationship between multidrug resistace (MDR) and PDT can be determined and change of biological functions can be clarified, PDT would have effective application in treatment of recurrent intractable gynecological cancer treatment. Development of modern medicine has made good achievements on the gynecology cancer treatment, however, it is difficult to cure recurrent intractable gynecological cancer because of MDR. There was extensive exploration and research on PDT, particularly on PDT induced apoptosis mechanism study. Previous research indicates that PDT dose not induce resistance to chemotherapy, PDT or radiotherapy. In order to apply the advantages of PDT on recurrent intractable gynecological cancer treatment, we must study about the relationship between MDR and PDT first. In this study will use the polymerase chain reaction(PCR), protein electrophoresis for detection of MDR1 and associated protein, observe the influence MDR1 on PDT effect and PDT to MDR1 expression. Furthermore, gene silencing technique and in vivo experiment will be performed for confirming results. The aim of this study is to investigate the relationship between MDR1 and PDT on resistance gynecological cancer, finally explore new therapeutic strategy on recurrent intractable gynecological cancer treatment.

近年来光动力疗法(PDT)在恶性妇科肿瘤的治疗中取得了令人瞩目的成就。除了选择特异性高、毒副作用少的优点以外PDT还具有不产生耐药性的优点。如能了解多药耐药性(MDR)与PDT的相关性，并能明确其生物学功能变化的机制，会将PDT所具有的独特优势能够有效地应用到耐药性妇科肿瘤的治疗当中。由于化疗后的复发性顽固性妇科肿瘤已经产生MDR，治疗比较困难，预后不佳。研究表明PDT不会对化疗，PDT及放疗 等 各种疗法产生耐性。前期工作显示妇科癌细胞迅速吸收光敏剂后，在光作用下诱导细胞凋亡，有效抑制肿瘤生长。本研究对比观察耐药性和非耐药性妇科肿瘤的PDT效果以外，利用聚合酶链反应、蛋白电泳来检测MDR1及其相关蛋白的表达变化，最后利用基因沉默和动物实验进一步明确其相关性。旨在探讨耐药性妇科肿瘤治疗中MDR1对PDT抗肿瘤效果的影响和PDT对MDR1表达的作用，针对耐药性妇科肿瘤开发PDT的新策略。

在本项目的研究中，我们首先观察到了Photodithazine，Photofrin，Photolonum 等二代光敏剂诱导的PDT对各种肿瘤细胞的生长抑制效果以及在对应的动物模型中抗肿瘤作用。其次，对多个宫颈癌细胞及卵巢癌细胞进行筛选形成耐药性后，观察其MDR1基因的表达。重点工作是通过对宫颈癌和卵巢癌的耐药性细胞的PDT治疗效果的比较来，探讨耐药性妇科肿瘤治疗中MDR1对PDT抗肿瘤效果的影响和PDT对MDR1表达的作用。发现Photofrin-PDT能够抑制宫颈癌及卵巢癌细胞生长，也能抑制耐药细胞的生长。虽然耐药细胞中的细胞毒性略差，在药物敏感细胞株和耐药细胞株中这种轻微的光细胞杀伤力不能以经典的Pgp-MDR体系来解释。然而在临床宫颈癌患者的研究中有了一些突破：发现FLNA在宫颈癌组织中有明显上调；FLNA的表达与淋巴结转移、宫旁浸润、对新辅助化疗的敏感性以及预后均有相关性。. 通过本研究发现PDT本身不产生或少产生耐药性和减轻已产生的对化疗药物的耐药性是有一定差距的；且光敏剂可能不仅仅通过Pgp-MDR的体系来克服其耐药性的，肿瘤的药耐药性需要从多角度和多种信号通道的分析来研究。而FLNA基因在宫颈癌对新辅助化疗的敏感性以及预后的相关性研究结果也可能成为其研究突破口。