【作者】 王雨轩；

【导师】 华子春；

【作者基本信息】 南京大学 ， 生物化学与分子生物学， 2013， 硕士

【摘要】 沙门氏菌作为目前最为成功的肿瘤治疗靶向细菌之一,在各种肿瘤实验动物模型的肿瘤治疗中得到了广泛应用并取得了良好的疗效。沙门氏菌作为一种厌氧菌,对缺氧环境具有趋化性,而肿瘤由于恶性增殖导致在其生长中心区出现一个低氧区。厌氧菌正是通过这个机制实现其靶向性效应。在进入体内后,沙门氏菌能通过诱导机体产生免疫反应等一系列机理促进机体对肿瘤的抵抗。后续的研究发现,沙门氏菌本身对肿瘤的治疗效果有限,它仅能在一定程度上抑制肿瘤的生长并促进机体的存活,但并不能有效地杀死肿瘤。于是人们开始利用其肿瘤靶向性向肿瘤部位运输抗肿瘤基因而对肿瘤进行联合治疗。这一策略大大提高了细菌治疗的疗效。也使得沙门氏菌成为了有效的肿瘤治疗靶向载体。IL-21是本世纪发现的y-Chain即γc家族细胞因子。近十年的研究揭示了IL-21在免疫系统中的重要功能。这种细胞因子能够有效地促进B,T细胞的增殖、发育及分化。除此以外,IL-21还能有效地激活CD8+T和NK细胞,促进这些细胞发挥其细胞毒效应。在揭示了其对免疫系统的强大作用后,IL-21被应用到肿瘤治疗中,在一系列成功的临床前数据支持下,IL-21目前已进入临床试验阶段。目前已经完成和正在进行的临床I期及II期数据有力支持了IL-21的肿瘤治疗效果,预示着其良好的药用前景。本论文中,作者首先利用分子生物学和细胞生物学方法,构建了IL-21的真核表达载体,并在细胞和动物水平上实现了表达。在本课题组沙门氏菌治疗黑色素瘤的前期基础上,作者首次将IL-21与沙门氏菌联合使用对黑色素瘤展开治疗。在引入IL-21之后,我们发现其与沙门氏菌产生了良好的协同效应。它们的联合使用有效地降低了黑色素瘤的生长速度,并大大延长了荷瘤鼠的存活时间。以上数据表明IL-21与沙门氏菌的联合治疗对黑色素瘤有着良好的抑制效果,这为细胞因子和细菌的肿瘤治疗提供了新的思路。更多还原

【Abstract】 As one of the most successful tumor-targeting bacterial, Salmonella has being administrated in pre-clinical experiments fighting against various tumors and facilitates treatment efficiently. Salmonella is prone to hpoxia area which is distributed in many tumors. Tumors were then targeted by salmonella via this area. Salmonella induced innate and adaptive immune in vivo to activate immunocytes to resist tumor. Subsequent research revealed limit effect of salmonella itself to treat cancer. Salmonella inhibits tumor growth and facilitate survival in limited ranges, instead of kill tumor efficiently. The advantage of tumor-targeting promotes salmonella to be a useful tool to treat cancer. Researchers applied it to be gene therapy vector to transport anti-tumor gene to tumor position. These strategies shed new light on therapeutic effectiveness of bacterial immensely.Interleukin-21(IL-21) was discovered in this century belongs to γ-Chain cytokine family and its critical regulatory roles in immune system was revealed in the past10years. IL-21promotes proliferation, development and differentiation of B and T immunocytes. Furthermore, it activates CD8+T and NK cells efficiently to augment their cytotoxic effects. IL-21was used to treat cancer immediately upon revealing its function. Based on its promising data from pre-clinical experiment, IL-21is assessed on clinical trial I and II stage now. The data from clinical trial Ⅰ and Ⅱ suggests A promising future of IL-21. In this paper, we cloned the mouse IL-21into pBLAST vector and verified its expression in cellular and tissular levels. We firstly combined IL-21with salmonella to treat murine melanoma. A great synergy was observed in treating murine melanoma with salmonella after combined with IL-21. The combination inhibits the growth of tumor and promotes survival efficiently. Further study exhibits IL-21induced CD4, CD8and NK cells infiltration may contribute to the synergy.Taken together, our data proved advanced therapeutic effectiveness of salmonella combined with IL-21, indicative of new light on the cancer treatment by cytokine and bacterial.更多还原