TISSUE SPECIFIC GENE THERAPY FOR PULMONARY METASTASIS

肺转移的组织特异性基因治疗

• 批准号: 6261183
• 负责人: Chinghai Kao
• 金额: $ 28.33万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-04 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6261183
• 关键词: Adenoviridae; Alphaherpesvirinae; cis platinum compound; combination cancer therapy; combination chemotherapy; doxorubicin; gene therapy; ifosfamide; laboratory rat; lung neoplasms; metastasis; methotrexate; neoplasm /cancer therapy; nonhuman therapy evaluation; osteosarcoma; recombinant virus; thymidine kinase; transfection /expression vector

DESCRIPTION: (Applicant's Abstract) The major goal of this application is to develop a new treatment modality for pulmonary metastasis. Malignant cells usually gain access to the bloodstream through thin-walled venous tumor vessels and grow in solid cores from which fragments or tumor cells may break off to form tumor emboli. Such emboli tend to lodge in the first capillary beds they encounter. Therefore, the lung is a common metastatic side of many human tumors that spread via the hematogenous route. Effective therapy for patients with pulmonary metastases is lacking. To improve the treatment of these lethal sequelae of cancer, the applicant developed a novel tissue-specific gene therapy modality to treat pulmonary metastasis using osteosarcoma as an ideal model system. The objective of this application is to enhance the efficacy of the applicant's tissue-specific gene-therapy approach and develop a novel gene-delivery technique for the treatment of pulmonary metastases. They hypothesis to be tested is: pulmonary metastases can be treated by tissue/tumor-specific promoter-based toxic gene therapy with recombinant adenovirus as a gene delivery vehicle. Treatment efficacy can be enhanced by 1) combining with chemotherapeutic agents, and 2) improving localized delivery of therapeutic agents using an isolated-single-lung-perfusion technique. To test these hypotheses the applicant proposes the following studies. (I) To study the possible benefit of combining gene therapy with chemotherapy, the beneficial effect of four commonly used chemotherapeutic agents, methotrexate, ifosfamide, doxorubicin and cisplatin, on herpes simplex virus thymidine kinase mediated cell- and tumor-kill will be evaluated. The doses of adenovirus, prodrugs, and chemotherapeutic agents for optimal therapeutic efficacy and the sequence of treatment will be studied. (II) To investigate the interaction between toxic gene therapy and chemotherapy, he will study the effect of chemotherapeutic agents on adenovirus mediated transgene expression, the effect of adenoviral gene expression on chemotherapy, and the collaborative efficacy of TK/prodrug and chemotherapeutic agent mediated cell-kill. In particular, the applicant will investigate the potential interference of virus attachment to its receptor and transportation to the nuclei. (III) To increase the local virus concentration and virus-target cell contact time, he will establish an isolated-single-lung-perfusion technique for locoregional delivery of adenovirus and evaluate its therapeutic advantage. He will also evaluate gene transduction efficacy of adenovirus delivered by the isolated-single-lung-perfusion technique.

描述：（申请人的摘要）该申请的主要目标是 开发治疗肺转移的新方法。恶性细胞 通常通过薄壁静脉肿瘤血管进入血流 并在固体核心中生长，碎片或肿瘤细胞可能从其中脱落 形成瘤栓。这种栓子往往会滞留在最先出现的毛细血管床中。 遇到。因此，肺部是许多人类肿瘤常见的转移侧 通过血行途径传播。对患有以下疾病的患者进行有效治疗 缺乏肺转移。为了改善这些致命疾病的治疗 癌症后遗症，申请人开发了一种新型组织特异性基因 以骨肉瘤为理想治疗肺转移的治疗方式 模型系统。该应用程序的目的是提高 申请人的组织特异性基因治疗方法并开发出一种新的 用于治疗肺转移的基因递送技术。他们 待检验的假设是：肺转移可以通过以下方法治疗 基于组织/肿瘤特异性启动子的重组毒性基因治疗 腺病毒作为基因递送载体。治疗效果可通过以下方式增强：1) 与化疗药物相结合，2) 改善局部递送 使用隔离单肺灌注技术的治疗剂。测试 申请人根据这些假设提出以下研究。 （一）研究 基因治疗与化疗相结合可能带来的好处 甲氨蝶呤、异环磷酰胺四种常用化疗药物的疗效 阿霉素和顺铂，对单纯疱疹病毒胸苷激酶介导的影响 将评估细胞和肿瘤杀灭作用。腺病毒、前药和药物的剂量 最佳治疗效果的化疗药物和治疗顺序 将研究治疗方法。 （二）研究有毒物质之间的相互作用 基因治疗和化疗，他会研究化疗的效果 药物对腺病毒介导的转基因表达的影响 化疗中的基因表达以及 TK/前药的协同功效 和化疗剂介导的细胞杀伤。特别是，申请人 将研究病毒附着对其受体的潜在干扰 以及到原子核的运输。 （三）增加本地病毒 浓度和病毒与靶细胞接触时间，他将建立一个 用于局部区域递送的隔离单肺灌注技术 腺病毒并评估其治疗优势。他还将评估基因 腺病毒的转导效率 隔离单肺灌注技术。