Anti-Cancer Vectors that Express TRAIL

表达 TRAIL 的抗癌载体

• 批准号: 6788362
• 负责人: DREW L. LICHTENSTEIN
• 金额: $ 24.76万
• 依托单位: VIRRX, INC
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-12 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6788362
• 关键词: Adenoviridae; CD95 molecule; adenosine diphosphate; antineoplastics; apoptosis; athymic mouse; biotechnology; cytotoxicity; female; gene expression; gene therapy; histopathology; immunofluorescence technique; liver cells; liver neoplasms; lung; lung neoplasms; neoplasm /cancer remission /regression; neoplasm /cancer therapy; neoplastic cell; tissue /cell culture; transfection /expression vector; tumor necrosis factor alpha; virus replication; xenotransplantation

DESCRIPTION (provided by applicant): We have developed replication-competent oncolytic adenovirus (Ad) vectors for cancer gene therapy that are designed to spread rapidly from cell to cell by virtue of the fact that they express ADP, an Ad protein that is expressed predominantly late in infection and that is required for efficient virus release at the culmination of the replication cycle. The vectors fall into one of two basic groups, those that express mutant E1A proteins, which restricts vector replication to dividing cells, or those that express wild-type E1A proteins. The vectors KD3 and VRX-007 are the prototypes of the former and latter group, respectively. With aim of improving our vectors to more effectively destroy cells within the tumor mass as well as kill tumor cells that have metastasized, we constructed four different oncolytic vectors in the KD3 or VRX-007 genetic background that express the cancer therapeutic protein TRAIL. We have demonstrated that our vectors kill cells directly by lysis of infected cells and by TRAIL-induced apoptosis of uninfected cells. In this grant application, we will further characterize the oncolytic properties of the TRAIL-expressing vectors in different tumor cell lines and in normal cells. We will evaluate the TRAIL vectors for their ability to suppress the growth of human tumors growing in nude mice. Mice treated with the vectors will be examined with respect to tumor growth, virus replication, expression of TRAIL, and pathology of the tumors and normal tissues. As critical test, we will inject the vectors into a tumor on one flank of a nude mouse and determine the vector's effect on a tumor located on the contralateral flank.

描述（由申请人提供）： 我们已经开发了癌症基因疗法的溶瘤腺病毒（AD）载体（AD）向量，旨在凭借表达ADP（一种ADP，一种ADP，这是一种在感染中表达的ADP，并且是在复制周期中释放时释放出来所必需的，从而迅速扩散到细胞到细胞。矢量属于两个基本组之一，即表达突变E1a蛋白的基本组之一，该蛋白将矢量复制限制为分裂细胞或表达野生型E1A蛋白的细胞。向量KD3和VRX-007分别是前组和后组的原型。为了改善媒介以更有效地破坏肿瘤质量内的细胞，并杀死已经转移的肿瘤细胞，我们在KD3或VRX-007遗传背景中构建了四个不同的溶瘤载体，以表达癌症治疗蛋白的踪迹。我们已经证明，我们的载体通过裂解感染细胞和踪迹诱导的未感染细胞凋亡直接杀死细胞。在此赠款应用中，我们将进一步表征在不同肿瘤细胞系和正常细胞中表达轨道向量的溶瘤特性。我们将评估步道向量的能力，以抑制裸鼠生长的人类肿瘤的生长。用矢量处理的小鼠将在肿瘤生长，病毒复制，踪迹表达以及肿瘤和正常组织的病理学方面进行检查。作为关键测试，我们将向向量注入裸鼠的一个侧面，并确定载体对位于对侧侧面的肿瘤的影响。