GENE THERAPY FOR PROSTATE CANCER

前列腺癌的基因治疗

• 批准号: 6316543
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6316543
• 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.

开发前列腺癌的其他治疗方法很重要。 可单独应用或与电流联合应用的癌症 医疗模式。基因治疗的各种策略可能会提供治疗 对这一重要疾病的好处。小鼠前列腺重建术 (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 完善的功能和独特的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：总则 疗效；恰当的治疗时机；以及S的对照 各种输送系统的效率。我们已经测试了一种复制- 携带单纯疱疹病毒的缺陷性重组腺病毒 胸苷激酶(HSV-tk)基因和格兰昔洛韦(GCV)在体内和 使用ras+myc=诱导的小鼠前列腺来源的细胞系进行体内实验 癌症和人类前列腺癌也是如此。在接种了 将小鼠前列腺癌细胞系转入免疫活性雄性宿主，我们 发现经治疗的动物(n=5)的皮下肿瘤在 体积降至未经处理动物(n-15)的18%。浅谈组织学评价 治疗后的肿瘤细胞的凋亡率显著升高。 与对照肿瘤相比，有更强的抗肿瘤活性。HSV-tk基因治疗的疗效为 进一步用C57BL/6 MPR致癌模型进行了论证。主要 局部皮损注射Ad/HSV-tk病毒，病毒和小鼠 用环丙沙星治疗6d。对照组(n=5)，4例。 MPR产生低分化癌(wt=939+875 mg)和！曾经是 增生性(wt=77 mg)。在治疗组(n-5)，虽然恶性 细胞存在，广泛坏死，生长抑制明显。 所有病例(wt+19+3 mg)。这些结果证明了 HSV-tk/GCV基因治疗及MPR模型系统的应用 临床前模型。利用p53基因敲除小鼠建立转移性MPR模型 允许将这些研究扩展到临床相关的所有方面 疾病。原发部位病变位于肾被膜下，适合于 注射基因治疗载体，就像我们对Ad(HSV-tk和 影响转移的系统因素可以评估。这个 我们将评估的参数包括主树的总体生长响应 肿瘤、转移的数量和位置、细胞凋亡反应以及 评价肿瘤活动性的免疫反应研究进展 浸润性淋巴细胞以及通过评估排斥的能力 随后对肿瘤细胞的挑战。我们建议使用这些临床前研究 测试与生长抑制有关的基因的模型(例如，p53和p21)a 以及可增强局部免疫反应的基因(如IL-2 和GM-CSF)联合应用于HSV-tk/GCV基因治疗方案。这个 基因治疗与抗雄激素联合治疗卵巢癌的疗效 还将对辐射热能进行评估。第一阶段临床试验将是 根据结果为选定的一组患者开发的 临床前试验和病媒安全性已确定之后。