TUMOR CELL RADIOSENSITIZATION BY ADENOVIRAL-MEDIATED P16

肿瘤抑制基因在某些癌症中被删除或突变的频率很高，包括胶质瘤、黑色素瘤、乳腺癌和肺癌。肿瘤抑制基因功能的丧失改变了肿瘤放射治疗后生长停滞和细胞凋亡的途径。本课题的目的是验证腺病毒介导的肿瘤抑制基因转移是否能通过诱导肿瘤细胞凋亡来克服肿瘤细胞的辐射抗性。肿瘤细胞的耐药性仍然是限制放射治疗癌症的关键因素，新的基因治疗策略值得研究。初步数据支持某种基因的有效性，但在该基因与放疗联合进行临床试验之前，必须进行额外的转化研究和进一步的产品开发。具体目标将通过检查临床前体外和体内肿瘤模型中的放射致敏性，描述放射致敏的分子机制，以及开始生产，质量控制测试和该肿瘤抑制基因临床开发和商业化所需的分析开发来提供这些信息。最终，这些努力的结果将允许在该策略的未来临床试验中评估该基因在治疗癌症方面的治疗益处。拟议的商业应用：根据美国癌症协会的数据，1998年美国估计有171,500例肺癌新病例。肺癌占所有癌症确诊病例的14%，却占所有癌症死亡病例的28%。尽管在手术、放疗和化疗方面取得了进展，但肺癌的总体5年生存率仅为14%，这就要求需要新的治疗形式。这种基因治疗的独特应用将通过增强放射治疗的有效性来扩大肺癌的抗癌基因治疗选择。

Tumor suppressor genes are deleted or mutated with a high frequency in certain cancers including gliomas, melanomas, and carcinomas of the breast and lung. Loss of tumor suppressor gene function modifies the pathways of growth arrest and apoptosis following cancer treatment with radiation. The goal of this project is to validate whether adenoviral- mediated tumor suppressor gene transfer will overcome radiation resistance in tumor cells by and induce apoptosis. Tumor cell resistance remains a key limitation to the use of radiation in cancer treatment and novel gene therapy strategies deserve examination. Preliminary data support the efficacy of a certain gene, however additional translational studies and further product development must be performed before this gene can be taken to clinical trials in combination with radiotherapy. The specific aims will provide this information through examination of radiosensitization in preclinical in vitro and in vivo tumor models, delineation of the molecular mechanisms of radiosensitization, and initiation of the manufacture, quality control testing and assay development required for clinical development and commercialization of this tumor suppressor gene. Ultimately, the results of these efforts will allow assessment of this gene for its therapeutic benefit in the treatment of cancer in future clinical trials of this strategy. PROPOSED COMMERCIAL APPLICATION: According to the American Cancer Society there were an estimated 171,500 new cases of lung cancer in the USA in 1998. While lung cancer accounts for 14% of all cancers diagnosed, it is responsible for 28% of all cancer deaths. Despite advances in surgery, radiation therapy and chemotherapy, the overall 5 year survival rate in lung cancer is only 14%, mandating the need for novel forms of therapy. This unique application of gene therapy would expand anti-cancer gene therapy options for lung cancer by enhancing the effectiveness of radiotherapy.