GENE THERAPY FOR PROSTATE CANCER

前列腺癌的基因治疗

• 批准号: 6217437
• 负责人: Timothy Charles Thompson
• 金额: $ 17.47万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217437
• 关键词: clinical research; clinical trial phase I; combination cancer therapy; gene targeting; gene therapy; genetically modified animals; human subject; human therapy evaluation; laboratory mouse; neoplasm /cancer genetics; neoplasm /cancer therapy; neoplastic cell; neoplastic growth; nonhuman therapy evaluation; oncogenes; prostate neoplasms; recombinant DNA; transfection /expression vector; tumor infiltrating lymphocyte; tumor suppressor genes

It is important to develop additional therapeutic approaches for prostate cancer which can be applied separately or in conjunction with current modalities. Various strategies for gene therapy may provide therapeutic benefits for this important disease. The mouse prostate reconstitution (MPR) model system can be used as a preclinical model for gene therapy in prostate cancer. The validity of thi in vivo model for prostate cancer is well established and its unique features provide an opportunity to test important parameters of specific gene therapy protocols including; general efficacy; appropriate timing o therapy; as well s the comparative efficiency of various delivery systems. We have tested a replication- defective recombinant adenovirus carrying the Herpes Simplex Virus thymidine kinase (HSV-tk) gene followed by grancicylovir (GCV) in vivo and in vivo using cell lines derived from a ras + myc=induced mouse prostate carcinoma as well as from human prostate-cancer. Following inoculation of the mouse prostate cancer line cell into immunocompetent male hosts, we found that subcutaneous tumors in treated animals (n=5) were reduced in volume to 18% that in untreated animals (n-15). On histologic evaluation athe treated tumors demonstrated significantly higher levels of apoptosis and necrosis than control tumors. The efficacy of HSV-tk gene therapy was further demonstrated using the C57BL/6 MPR carcinogenesis model. Primary site lesions were injected with Ad/HSV-tk virus and the virus and the mice were treated with GCV for 6 days. In the control group (n=5), 4 of the MPRs produced poorly differentiated carcinomas (wt= 939 + 875 mg) and ! was hyperplastic (wt=77 mg). In the treated group (n-5), although malignant cells were present, extensive necrosis and growth suppression was apparent in all cases (wt+19 + 3 mg). These results demonstrate the efficacy of HSV-tk/GCV gene therapy as well as the utility of the MPR model system as a preclinical model. The metastatic MPR model using p53 knock-out mice allows extension of these studies to all aspects of clinically relevant disease. The primary site lesion, under the renal capsule, is suitable for injection of gene therapy vectors as we have done with Ad(HSV-tk and systemic factors which influence metastasis can be evaluated. The parameters we will evaluate include overall growth response of the primary tumor, number and location of metastases, apoptotic response, and development of an immune response by evaluating activation of tumor infiltrating lymphocytes as well as by evaluating the ability to reject subsequent challenge with tumor cells. We propose to use these preclinical models to test genes involved in growth suppression (e.g.,p53 and p21) a well as genes which may enhance the localized immune response (e.g., IL-2 and GM-CSF) together with in HSV-tk/GCV gene therapy protocol. The efficacy of the combination of gene therapy with anti-androgen therapy or radiothermy will also be evaluated. Phase I clinical trials will be developed for a select groups of patient based on the results of preclinical trials and after vector safety has been established.

为前列腺开发其他治疗方法很重要 可以单独应用或与电流结合使用的癌症 方式。 各种基因疗法的策略可能会提供治疗性 这种重要疾病的好处。 鼠标前列腺重构 （MPR）模型系统可以用作基因治疗的临床前模型 前列腺癌。 体内模型对前列腺癌的有效性是 建立良好及其独特功能为测试提供了机会 特定基因治疗方案的重要参数，包括：一般的 功效;适当的时机o治疗；以及比较 各种输送系统的效率。 我们已经测试了复制 - 携带疱疹单纯疱疹病毒的重组腺病毒有缺陷 胸苷激酶（HSV-TK）基因，然后是grancicylovir（GCV）体内和 使用源自RAS + MYC =诱导的小鼠前列腺的细胞系的体内细胞系 癌以及人类前列腺癌。 接种后 小鼠前列腺癌系细胞进入免疫能力的雄性宿主，我们 发现治疗动物中的皮下肿瘤（n = 5）减少了 在未经治疗的动物中的体积为18％（N-15）。 关于组织学评估 A型肿瘤显示出明显更高的凋亡水平 和坏死比对照肿瘤。 HSV-TK基因疗法的功效是 使用C57BL/6 MPR癌变模型进一步证明。 基本的 将现场病变注射AD/HSV-TK病毒和病毒和小鼠 用GCV处理6天。 在对照组（n = 5）中，其中4个 MPRS产生的癌（WT = 939 + 875 mg）和！曾是 增生（WT = 77 mg）。 在治疗组（N-5）中，尽管恶性 存在细胞，广泛的坏死和生长抑制是明显的 在所有情况下（WT + 19 + 3 mg）。 这些结果证明了 HSV-TK/GCV基因疗法以及MPR模型系统的实用性 临床前模型。 使用p53敲除小鼠的转移MPR模型 允许将这些研究扩展到临床相关的各个方面 疾病。 肾囊下的主要部位病变适合 像我们对AD一样（HSV-TK和 可以评估影响转移的系统因素。 这 我们将评估的参数包括主要的总体增长响应 肿瘤，转移的数量和位置，凋亡反应和 通过评估肿瘤的激活来开发免疫反应 浸润淋巴细胞以及通过评估拒绝的能力 随后对肿瘤细胞的挑战。 我们建议使用这些临床前 测试涉及生长抑制的基因的模型（例如，p53和p21） 以及可能增强局部免疫反应的基因（例如，IL-2 和GM-CSF）与HSV-TK/GCV基因治疗方案一起。 这 基因治疗与抗雄激素治疗的功效或 也将评估Radiothermy。 第一阶段的临床试验将是 根据 建立了临床前试验和向量安全后。