BIOLOGIC AND CT ASSESSMENT OF COLON CANCER GENE THERAPY

结肠癌基因治疗的生物学和 CT 评估

• 批准号: 2377319
• 负责人: RONALD G CRYSTAL
• 金额: $ 12.17万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 1998-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2377319
• 关键词: Adenoviridae; aminohydrolases; clinical research; colon neoplasms; combination cancer therapy; cytosine; enzyme activity; enzyme induction /repression; flucytosine; gene therapy; human genetic material tag; human subject; human therapy evaluation; liver neoplasms; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; tomography; transfection /expression vector

DESCRIPTION: (Applicant's Abstract) In vivo gene therapy has the potential to aid in the local control of malignancy by creating high concentrations of transgene products within target tissues. One approach is to deliver genes coding for enzymes which can convert systemically administered prodrugs to toxic metabolites, theoretically achieving high local concentrations of the chemotherapeutic agent. This clinical study is focused on quantifying, in a controlled, blinded design, the local biologic and computed tomographic (CT) changes in hepatic metastases of colon carcinoma following direct administration of an adenovirus vector coding for the E. coli cytosine deaminase (CD) enzyme to one hepatic metastasis of biopsy-proven colorectal carcinoma, together with systemic administration of the prodrug 5-fluorocytosine (5FU). The rationale is, that by transferring the CD gene to the metastatic lesion, the cells will express the CD enzyme which will convert the prodrug 5FC to the toxic therapeutic agent 5-fluorouracil, thus suppressing tumor growth in the local milieu. A total of 18 individuals will be evaluated, with the possibility for up to 30 additional patients if required. Part A will include individuals who will undergo laparotomy 2 wk after vector administration to remove the treated and a control metastasis to evaluate biologic parameters in the treated and control tumor. Part B will include individuals treated in an identical fashion, but no surgery is scheduled, and the treated and control tumors can be evaluated with sequential, quantitative CT scans. This application is focused on supporting the laboratory analyses of the tumors removed at surgery, and the computerized analysis of the CT scans. In this context, the application has two specific aims: (1) To evaluate the hypothesis that the AdCD/5FC therapy will generate changes in the treated tumor relevant to "biologic efficacy", including expression of the CD gene and functional CD protein, accumulation of oligoclonal T-cells and antigen-specific cytotoxic T-cells in the tumor, and induction of apoptosis of tumor cells; and (2) to evaluate the hypothesis that this therapy will reduce the size of the treated tumor and/or the rate of growth of the treated tumor as assessed by computer-based quantitative volumetric and other growth parameters in sequential CT images over time.

描述：（申请人的摘要）体内基因治疗具有潜在的 通过产生高浓度的 靶组织内的转基因产物。 一种方法是将基因 编码能够将全身给药的前药转化为 有毒代谢物，理论上达到高的局部浓度， 化疗剂。 这项临床研究的重点是量化，在一个 对照、设盲设计、局部生物学和计算机断层扫描（CT） 结肠癌肝转移灶直接化疗后的变化 施用编码E.杆菌胞嘧啶 脱氨酶（CD）酶对活检证实的结直肠癌肝转移的影响 与全身施用前药一起治疗癌症 5-氟胞嘧啶（5 FU）。 其原理是，通过转移CD基因， 对于转移病灶，细胞将表达CD酶， 将前药5 FC转化为毒性治疗剂5-氟尿嘧啶， 抑制肿瘤在局部环境中的生长。 共18人 将进行评估，如果符合以下条件，则可能增加多达30名患者 必需的. A部分将包括将接受剖腹手术2周的个体 在给予载体以除去治疗的和对照转移瘤后 以评价治疗和对照肿瘤中的生物学参数。 B部分 将包括以相同方式治疗的个人，但没有手术， 计划，并且治疗和对照肿瘤可以用 连续定量CT扫描 该应用程序的重点是 支持手术切除肿瘤的实验室分析， 计算机化的CT扫描分析 在此背景下，该应用程序 两个具体的目的：（1）评估AdCD/5 FC治疗 将在治疗的肿瘤中产生与“生物功效”相关的变化， 包括CD基因和功能性CD蛋白的表达、积累 寡克隆T细胞和抗原特异性细胞毒性T细胞， 和诱导肿瘤细胞凋亡;和（2）评估 假设这种疗法将减少治疗肿瘤的大小 和/或通过基于计算机的免疫组织化学方法评估的治疗肿瘤的生长速率 连续CT图像中的定量体积和其他生长参数 随着时间