C-CAM1 ADENOVIRUS IN HUMAN PROSTATE CANCER GENE THERAPY

描述：（申请人的摘要）前列腺癌的自然史 对它的进展模式很感兴趣;原发部位转移到淋巴结， 去骨。 临床观察表明，骨可以提供独特的 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。 没有 有效的治疗方法已经应用，因为没有太多的人工智能模型， 可用于研究潜在机制。 近日 申请人建立了一种嵌合肿瘤模型， 前列腺癌细胞系（LNCaP）和骨基质细胞（MS）， 无胸腺裸鼠，其中大多数肿瘤似乎是癌。 前列腺特异性抗原（PSA）水平，一种组织特异性蛋白质 仅由前列腺上皮分泌，从肿瘤中检测到 与前列腺肿瘤体积相关， 在AI进展期间进一步上调。 此外，申请人 证明了骨基质细胞能够促进 人工智能前列腺癌 总之，数据表明，LNCaP 肿瘤模型模拟前列腺癌的临床观察 进展 细胞粘附分子（CAM）是已知的发挥， 在细胞分化和发育中起重要作用。 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， 由雄激素调节的上皮特异性CAM作为肿瘤 前列腺癌进展的抑制因子。 根据这些结果，他 决定进一步研究表达C-CAM的重组体 腺病毒有可能成为前列腺癌基因治疗的一种潜在药物。 从体外表征中，他观察到大多数人 前列腺癌细胞对C-CAM腺病毒非常敏感， 仍然可以检测到C-CAM mRNA和蛋白水平 感染后20天，表明C- 病毒感染细胞中的CAM可以弥补其中一个缺点 重组腺病毒的半衰期很短。 体内 将单剂量的C-CAM腺病毒施用到预先存在的 PC-3肿瘤，AI肿瘤，能够抑制肿瘤的生长 超过3周。 相比之下，对照病毒没有 同样的效果。 另一方面，单剂量的C-CAM腺病毒 给药也可以预防Shionogi中AI肿瘤的复发， 模型 基于这些结果，申请人认为C-CAM 腺病毒可能是治疗前列腺癌的潜在药物。 在 在本研究中，申请人建议确定最佳剂量， C-CAM腺病毒治疗前列腺癌的方案， PC-3和盐野木型号。 他还想检验 C-CAM对上皮-基质相互作用的干预， 前列腺癌进展的LNCaP嵌合模型。 最后，他会 利用PSA启动子的组织特异性表达， 设计一种新的前列腺癌治疗策略。

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.