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.

开发前列腺的其他治疗方法非常重要 癌症可以单独应用或与当前的联合应用 方式。 基因治疗的多种策略可能提供治疗作用 对于这种重要的疾病有好处。 小鼠前列腺重建 (MPR)模型系统可作为基因治疗的临床前模型 前列腺癌。 前列腺癌体内模型的有效性是 完善且其独特的功能提供了测试的机会 特定基因治疗方案的重要参数包括：一般的 功效;适当的治疗时机；以及比较 各种输送系统的效率。 我们已经测试了复制- 携带单纯疱疹病毒的有缺陷的重组腺病毒 体内胸苷激酶 (HSV-tk) 基因和随后的更昔洛韦 (GCV) 基因 体内使用源自 ras + myc=诱导的小鼠前列腺的细胞系 癌以及人类前列腺癌。 接种后 我们将小鼠前列腺癌细胞系转化为具有免疫能力的男性宿主 发现接受治疗的动物（n = 5）的皮下肿瘤在 体积减少至未处理动物 (n-15) 的 18%。 关于组织学评估 经治疗的肿瘤表现出显着更高水平的细胞凋亡 和坏死程度高于对照肿瘤。 HSV-tk基因治疗的疗效为 使用C57BL/6 MPR致癌模型进一步证明。 基本的 病变部位注射 Ad/HSV-tk 病毒，病毒和小鼠 用GCV治疗6天。 在对照组（n = 5）中，4 MPR 产生低分化癌（wt= 939 + 875 mg）并且！曾是 增生性（重量=77毫克）。 在治疗组（n-5）中，尽管是恶性的 存在细胞，广泛坏死和生长抑制明显 在所有情况下（wt+19+3mg）。 这些结果证明了以下方法的功效 HSV-tk/GCV 基因治疗以及 MPR 模型系统的实用性 临床前模型。 使用p53基因敲除小鼠的转移性MPR模型 允许将这些研究扩展到临床相关的各个方面 疾病。 原发部位病变位于肾包膜下，适用于 注射基因治疗载体，就像我们用 Ad(HSV-tk 和 可以评估影响转移的全身因素。 这 我们将评估的参数包括主要的整体生长反应 肿瘤、转移的数量和位置、细胞凋亡反应，以及 通过评估肿瘤的激活来发展免疫反应 浸润淋巴细胞以及评估排斥能力 随后用肿瘤细胞进行攻击。 我们建议使用这些临床前 测试参与生长抑制的基因（例如 p53 和 p21）的模型 以及可能增强局部免疫反应的基因（例如，IL-2 和 GM-CSF）以及 HSV-tk/GCV 基因治疗方案。 这 基因治疗与抗雄激素治疗相结合的疗效或 放射热治疗也将受到评估。 I期临床试验将进行 根据以下结果为选定的患者组开发 临床前试验和媒介安全性确定后。