GENETIC RADIOIMMUNOTHERAPY OF PANCREATIC CANCER

描述（申请人的摘要）：胰腺癌具有90%的死亡率 由于局部/区域研究中心疾病进展的发生率， 远处转移。 申请人建议开发新的 结合了基因治疗和放射性配体的优点的治疗 技术. 目前人类放射免疫治疗的局限性反映了 低肿瘤抗原表达和抗体的肿瘤穿透受限 分子。 申请人提出开发基因治疗载体以诱导 肿瘤细胞以高亲和力表达高水平的膜受体 用于肽配体，其可以被构建为携带放射性同位素。 这些 配体是低分子量的，以增强肿瘤穿透， 利用同位素将辐射传递到几个肿瘤细胞直径 （距离），以弥补低于通用肿瘤细胞转染 rates. 申请方将使用小鼠模型研究局部肿瘤部位 使用瘤内和全身载体策略研究人类胰腺癌。 放射性标记肽在转移部位的定位研究将 利用鼠肝转移模型和全身施用 嗜性修饰的腺病毒或在 肿瘤特异性启动子。 设计和测试适当的 放射性标记的配体将同时开发以优化剂量， 时间表、生物分布、治疗和毒性问题。 这些研究将 开发这种独特的基因治疗/放射治疗模式， 也为其他癌症的治疗提供了有价值的信息。

DESCRIPTION (Applicant's Abstract): Pancreatic cancer has a 90% mortality rate due to progression of disease at both the local/regional site and metastases to distant sites. The applicant proposes to develop a new treatment which combines the benefits of gene therapy and radioligand technology. The current limitations of radioimmunotherapy in man reflect low tumor antigen expression and restricted tumor penetration of antibody molecules. The applicant proposes to develop gene therapy vectors to induce tumor cells to express high levels of membrane receptors with high affinity for peptide ligands which can be constructed to carry radioisotopes. These ligands are low molecular weight to enhance tumor penetration and will utilize isotopes which deliver radiation to several tumor cell diameters (distance) to compensate for less than universal tumor cell transfection rates. The applicant will address the local tumor site using murine models of human pancreatic cancer using intratumor and systemic vector strategies. Studies of localization of radiolabeled peptides in metastatic sites will utilize a murine hepatic metastases model and systemic administration of tropism-modified adenoviruses or adenoviruses under the control of tumor-specific promoters. The design and testing of appropriate radiolabeled ligands will be developed concurrently to optimize dose, schedule, biodistribution, therapy, and toxicity issues. These studies will develop this unique paradigm of gene therapy/radiation therapy which will provide information valuable to therapy of other cancers as well.