GENE THERAPY FOR PROSTATE CANCER

重要的是要开发额外的治疗方法，前列腺 可以单独或与电流联合应用的癌症 方式。 基因治疗的各种策略可以提供治疗性的 对这一重大疾病的好处。 小鼠前列腺重建 (MPR)模型系统可用作基因治疗的临床前模型， 前列腺癌 该前列腺癌体内模型的有效性是 其独特的功能提供了一个测试的机会， 特定基因治疗方案的重要参数，包括： 疗效;适当的治疗时机;以及比较 各种输送系统的效率。 我们测试了一个复制品- 携带单纯疱疹病毒的缺陷型重组腺病毒 胸苷激酶（HSV-tk）基因，然后是体内的格兰昔洛韦（GCV）， 体内使用来源于ras + myc=诱导的小鼠前列腺的细胞系 癌以及人前列腺癌。 接种后， 小鼠前列腺癌细胞系细胞进入免疫活性的雄性宿主，我们 发现治疗动物（n=5）的皮下肿瘤减少， 体积为未处理动物的18%（n = 15）。 组织学评价 经顺铂治疗的肿瘤细胞凋亡水平显著升高， 和坏死。 HSV-tk基因治疗的疗效是 使用C57 BL/6 MPR致癌模型进一步证实。 初级 用Ad/HSV-tk病毒注射病变部位， 用GCV治疗6天。 在对照组（n=5）中， MPR产生低分化癌（wt= 939 ± 875 mg）和！是 增生（wt=77 mg）。 在治疗组（n-5），虽然恶性 细胞存在，广泛坏死和生长抑制明显 在所有情况下（wt+19 + 3 mg）。 这些结果证明了 HSV-tk/GCV基因治疗以及MPR模型系统作为 临床前模型 应用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包膜下，适合于 注射基因治疗载体，如我们用Ad（HSV-tk和 可以评估影响转移的全身因素。 的 我们将评估的参数包括主要生长反应， 肿瘤，转移的数量和位置，凋亡反应，和 通过评估肿瘤的活化来发展免疫应答 浸润淋巴细胞以及通过评估排斥的能力， 随后用肿瘤细胞攻击。 我们建议使用这些临床前 测试参与生长抑制的基因的模型（例如，p53和p21）a 以及可以增强局部免疫应答的基因（例如，IL-2 和GM-CSF）与HSV-tk/GCV基因治疗方案一起。 的 基因治疗与抗雄激素治疗联合的疗效，或 还将评估放射治疗。 I期临床试验将在 根据以下结果为选定的患者组开发 临床前试验和载体安全性确立后。

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.