TNF-related apoptosis-inducing ligan (TRAIL) gene therapy for prostate cancer

描述(申请人提供)：前列腺癌的最终治疗仅限于根治性手术或局部或区域性疾病的放射治疗。基因转移技术为前列腺癌新疗法的开发提供了潜力。拟议的项目将使用独特的凋亡剂，肿瘤坏死因子相关的凋亡诱导配体(TRAIL)和以胶原为基础的基质，以增强基因输送系统，以增强免疫激活。目标/假设：该项目的长期目标是开发一种有效的前列腺癌治疗方法。具体地说，治疗包括病毒介导的细胞毒蛋白TRAIL基因进入前列腺，导致前列腺肿瘤细胞凋亡死亡和系统抗肿瘤免疫激活。具体目的：(1)确定前列腺腔内注射明胶海绵载体Ad5-TRAIL的局部和全身毒性。(2)检测经会阴给药后Ad5-TRAIL在人前列腺癌组织中的分布，确定经会阴给药对前列腺癌的治疗作用。研究设计：这项建议的主要焦点是在临床局限性前列腺癌患者中使用前列腺内注射Ad5-TRAIL进行I期临床试验。注射将在胶原基质(明胶海绵)中进行，我们预计这将加强输送和分布。还将确定与前列腺内注射Ad5-TRAIL相关的局部和全身毒性。TRAIL是一种有效的细胞毒剂，只影响前列腺癌细胞。这些研究将有助于开发最大化基因传递的方法，并确定局部基因转移治疗的毒性和有效性，这可能为未来的研究提供基础，从而为前列腺癌的新治疗方法奠定基础。

DESCRIPTION (provided by applicant): Definitive treatment of prostate cancer is limited to radical surgery or radiation therapy for localized or regional disease. Gene transfer technology offers the potential for the development of new therapies for prostate cancer. The proposed project will employ the unique apoptotic agent, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and a collagen-based matrix that enhances gene delivery system to augment immune activation. Objective/hypothesis: The long-term objective of the project is to develop an effective treatment for prostate cancer. Specifically, treatment involves the viral-mediated transfer of the gene for the cytotoxic protein TRAIL into the prostate, resulting in prostate tumor cell apoptotic death and activation of systemic antitumor immunity. Specific Aims: (1) Determine the local and systemic toxicity associated with intraprostatic injection of Ad5-TRAIL delivered in Gelfoam. (2) Examine the distribution of Ad5-TRAIL within the human prostate after transperineal injection and determine the effect of transperineal injection of Ad5-TRAIL on existent prostate cancer. Study Design: The primary focus of this proposal is to conduct a phase I clinical trial using intra-prostatic injection of Ad5-TRAIL in patients with clinically localized prostate cancer. The injections will be administered in a collagen matrix (Gelfoam) which we expect will enhance delivery and distribution. The local and systemic toxicity associated with intraprostatic injection of Ad5-TRAIL will also be determined. TRAIL is an effective cytotoxic agent which affects only prostate cancer cells. The proposed studies will help develop methods to maximize gene delivery and determine the toxicity and effectiveness of localized gene transfer therapy which could provide the basis for future studies leading to a new therapeutic approach for prostate cancer.