C-CAM1 ADENOVIRUS IN HUMAN PROSTATE CANCER GENE THERAPY

描述：（申请人摘要）前列腺癌的自然史 对它的进展模式很感兴趣；然后原发部位到淋巴结 到骨头。 临床观察表明，骨骼可能提供独特的 复发性雄激素非依赖性（AI）生长的微环境 前列腺癌。 前列腺癌患者的死亡率是由于 AI 前列腺癌细胞从骨转移部位出现。 否 由于人工智能模型不多，因此已采用有效的治疗方法 可用于研究潜在机制。 最近， 申请人通过共接种人类建立了嵌合肿瘤模型 前列腺癌细胞系 (LNCaP) 和骨基质细胞 (MS) 转化为 无胸腺裸鼠，其中大多数肿瘤似乎是癌。 并且，前列腺特异性抗原 (PSA) 水平，一种组织特异性蛋白 仅由前列腺上皮分泌，从肿瘤中检测到 生育动物，与前列腺肿瘤的体积相关 在 AI 进展过程中进一步上调。 另外，申请人 证明骨基质细胞能够促进骨的出现 AI 前列腺癌。 总而言之，数据表明 LNCaP 肿瘤模型模拟前列腺癌的临床观察 进展。 众所周知，细胞粘附分子 (CAM) 发挥着 在细胞分化和发育中发挥重要作用。 此外，数据 分子遗传学研究表明 CAM 可能发挥抑制作用 在肿瘤发生中的作用。 最近申请人证明了C-CAM， 受雄激素调节的上皮特异性 CAM 充当肿瘤 前列腺癌进展的抑制剂。 根据这些结果，他 决定进一步检查表达 C-CAM 的重组体是否 腺病毒可能是前列腺癌基因治疗的潜在药物。 从体外表征中，他观察到大多数人类 前列腺癌细胞对 C-CAM 腺病毒非常敏感 感染且仍可检测到 C-CAM mRNA 和蛋白水平 感染后20天，表明C-的延长表达 病毒感染细胞中的 CAM 可能弥补缺点之一 半衰期短的重组腺病毒。 体内 将单剂量的 C-CAM 腺病毒注射到预先存在的细胞中 PC-3肿瘤，即AI肿瘤，能够抑制肿瘤的生长 超过3周。 相比之下，对照病毒未能具有 相同的效果。 另一方面，单剂量的 C-CAM 腺病毒 给药还可以预防盐野木的复发性人工智能肿瘤 模型。 基于这些结果，申请人认为 C-CAM 腺病毒可以成为前列腺癌治疗的潜在药物。 在 在这项研究中，申请人建议确定最佳剂量和 使用 C-CAM 腺病毒治疗前列腺癌的治疗方案 PC-3 和 Shionogi 型号。 他也想看看效果 C-CAM对上皮间质相互作用的干预作用 前列腺癌进展的 LNCaP 嵌合模型。 最后，他将 利用 PSA 启动子的组织特异性表达 设计前列腺癌治疗的新治疗策略。

DESCRIPTION: (Applicant's Abstract) Natural history of prostate cancer is intrigued by its progression pattern; primary site to lymph node then to bone. Clinical observations indicated that bone may provide a unique microenvironment for the growth of recurrent androgen independent (AI) prostate cancer. Mortality of prostate cancer patients is due to the emergence of AI prostate cancer cells from bony metastatic site. No effective treatment has been applied because not many AI models are available for studying the underlying mechanisms. Recently, the applicant established a chimeric tumor model by coinoculating human prostate cancer cell line (LNCaP) and bone stromal cells (MS) into athymic nude mouse where majority of tumors appeared to be carcinoma. And, prostate-specific antigen (PSA) levels, a tissue-specific protein secreted by a prostatic epithelium exclusively, detected from tumor bearing animals, correlated with the volume of prostate tumors and further upregulated during AI progression. Also, the applicant demonstrated that bone stromal cell is able to facilitate the emergence of AI prostate cancer. Taken together, data indicated that the LNCaP tumor model mimics clinical observations from prostate cancer progression. Cell adhesion molecules (CAMs) are known to play a critical role in cell differentiation and development. Moreover, data from molecular genetic studies suggest that CAMs may play a suppressive role in tumorigenesis. Recently the applicant demonstrated that C-CAM, an epithelial-specific CAM regulated by androgen acts as a tumor suppressor in prostate cancer progression. Based on these results, he decided to further examine whether C-CAM-expressing recombinant adenovirus could be a potential agent for prostate cancer gene therapy. From in vitro characterization, he observed that majority of human prostate cancer cells are very sensitive to the C-CAM adenoviral infection and that C-CAM mRNA and protein levels can still be detected 20 days after infection, suggesting that the prolonged expression of C- CAM in viral-infected cells may compensate for one of the disadvantages of the recombinant adenovirus with a short half-life. In vivo administration of a single dose of C-CAM adenovirus into the preexisting PC-3 tumors, the AI tumors, was able to suppress the growth of tumors for over 3 weeks. In contrast, the control virus failed to have the same effects. On the other hand, a single dose of C-CAM adenoviral administration could also prevent the recurrent AI tumors in the Shionogi model. Based on these results, the applicant believes that C-CAM adenovirus can be a potential agent for prostate cancer therapy. In this study, the applicant proposes to determine the optimal dose and treatment schedule of C- CAM adenovirus for prostate cancer using both the PC-3 and Shionogi models. He also would like to examine the effect of C-CAM on the intervention of epithelial-stromal interaction using the LNCaP chimeric model for prostate cancer progression. Finally, he will take advantage of the tissue-specific expression of PSA promoter to design a novel therapeutic strategy in prostate cancer therapy.