C-CAM1 ADENOVIRUS IN HUMAN PROSTATE CANCER GENE THERAPY

描述：(申请人摘要)前列腺癌的自然病史 对它的进展模式很感兴趣；然后从原发部位到淋巴结 到骨子里。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。不是 已经应用了有效的治疗方法，因为没有多少人工智能模型 可用于研究潜在的机制。最近， 申请者通过联合接种人建立了嵌合肿瘤模型 前列腺癌细胞系(LNCaP)和骨基质细胞(MS) 裸鼠裸鼠，肿瘤多为癌。 还有，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，与前列腺肿瘤体积和 在人工智能进展过程中进一步上调。此外，申请人 说明骨基质细胞能够促进骨肉瘤的出现 人工智能前列腺癌。综上所述，数据表明LNCaP 肿瘤模型模拟前列腺癌的临床观察 进步。细胞黏附分子(CAM)被认为是一种 在细胞分化和发育中起关键作用。此外，数据 来自分子遗传学的研究表明，CAMs可能起到抑制作用 在肿瘤发生中的作用。最近，申请人证明了C-CAM， 雄激素调节的上皮细胞特异性细胞间黏附分子可作为肿瘤 前列腺癌进展中的抑制因子。基于这些结果，他 决定进一步研究表达C-CAM的重组 腺病毒有可能成为前列腺癌基因治疗的潜在靶点。 从体外特征来看，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，提示C-蛋白的持续表达 病毒感染细胞中的CaM可能会弥补其中一个缺点 半衰期短的重组腺病毒。活体内 将单剂C-CAM腺病毒注射到已有的 PC-3肿瘤，AI肿瘤，能够抑制肿瘤的生长 已经超过3周了。相比之下，对照病毒未能获得 同样的效果。另一方面，单剂C-CAM腺病毒 给药还可以预防Shionogi复发的AI肿瘤 模特。根据这些结果，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……里面 在这项研究中，申请人建议确定最佳剂量和 C-CAM腺病毒联合应用治疗前列腺癌的方案 PC-3和Shionogi型号。他还想研究一下这种影响 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，他会 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.