TUMOR CELL RADIOSENSITIZATION BY ADENOVIRAL-MEDIATED P16

肿瘤抑制基因在包括胶质瘤、黑色素瘤、乳腺癌和肺癌在内的某些癌症中以高频率缺失或突变。肿瘤抑制基因功能的丧失改变了肿瘤放射治疗后的生长停滞和细胞凋亡的途径。本项目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细胞凋亡来克服肿瘤细胞的辐射抗性。肿瘤细胞耐药性仍然是辐射在癌症治疗中应用的一个关键限制，新的基因治疗策略值得研究。初步数据支持某种基因的疗效，但在将该基因与放射治疗结合起来进行临床试验之前，必须进行更多的翻译研究和进一步的产品开发。具体目标将通过检查临床前的体外和体内肿瘤模型的放射增敏作用，描绘放射增敏的分子机制，以及启动这种肿瘤抑制基因的临床开发和商业化所需的制造、质量控制测试和分析开发来提供这一信息。最终，这些努力的结果将使在这一策略的未来临床试验中评估该基因在癌症治疗中的治疗益处成为可能。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例新的肺癌病例。虽然肺癌占所有确诊癌症的14%，但它占所有癌症死亡人数的28%。尽管在手术、放射治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%，迫切需要新的治疗形式。这种独特的基因治疗应用将通过提高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.