BIOLOGIC AND CT ASSESSMENT OF COLON CANCER GENE THERAPY

（申请人摘要）体内基因治疗具有潜力

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.