CATIONIC LIPID/P53 GENE THERAPY IN LUNG CANCER PATIENTS

描述（改编自研究者摘要）：肺癌发生于 在慢性吸入的支气管上皮细胞中， 致癌物质的敏感宿主。p53基因在肿瘤的发生发展中起着重要的作用。 肺癌发生过程P53基因突变常与肿瘤的发生有关。 支气管化生进展为发育不良。恢复p53功能 通过基因转染技术， 吸入途径是一种合理和技术上可行的预防或 延缓癌前支气管上皮病变向肺部的进展 癌申请人已经开发了阳离子脂质/p53基因复合物（CLp 53）， 其通过区域递送在延迟支气管内肿瘤生长中有效 p53缺失或突变型人肺癌的小鼠模型。他们建议适应 该制剂用于气雾剂使用，并开始临床研究， 优化的雾化CLp 53制剂（aCLp 53）。被测试的假设 人支气管上皮中p53功能恢复可以 安全有效地通过吸入CLp 53基因来实现 配合物该建议的具体目标是： 气雾剂给药制剂;优化工作将集中在 粒度、喷雾器类型、pH值、增强组织渗透的添加剂 和CL/基因复合物保存，以及与支气管的潜在相互作用 粘液成分;通过肠道内给药研究CLp 53的临床前毒性 滴注和雾化在小鼠和兔子;这些研究是 对于IND申请至关重要;以及，通过以下方式进行CLp 53的I期临床研究： p53突变型非小细胞肺癌（NSCLC）患者的雾化。 I期临床研究的目的是： aCLp 53的耐受剂量、最佳方案和剂量限制性毒性; 产生关于aCLp 53恢复p53的能力的初步信息 在人支气管上皮中的功能;并且，研究沉积和 aCLp 53在肺中的分布。这项研究的结果将提供 关于这一新战略的潜在用途的初步但非常有价值的信息 治疗支气管癌前病变、原位癌， 支气管内肺肿瘤

DESCRIPTION (As Adapted From the Investigator's Abstract): Lung cancer arises in a bronchial epithelium diffusely damaged by the chronic inhalation of carcinogens in a susceptible host. The p53 gene plays an important role in the lung carcinogenesis process. P53 gene mutations are frequently involved in the progression of bronchial metaplasia to dysplasia. Restoration of p53 function in dysplastic bronchial epithelium by gene transfection technologies using the inhalation route is a logical and technically feasible strategy to prevent or delay the progression of premalignant bronchial epithelial lesions to lung cancer. The applicants have developed a cationic lipid/p53 gene complex (CLp53) that is effective by regional delivery in delaying endobronchial tumor growth in mouse models of p53-null or mutant human lung cancer. They propose to adapt this formulation for aerosol use and to initiate clinical studies with an optimized aerosolized CLp53 formulation (aCLp53). The hypothesis being tested is that restoration of p53 function in the human bronchial epithelium can be safely and effectively accomplished with the inhalation of CLp53 gene complexes. The specific aims of the proposal are: to develop a CLp53 formulation for administration as an aerosol; optimization efforts will focus on particle size, nebulizer type, pH, additives to enhance tissue penetration and CL/gene complex preservation, and potential interactions with bronchial mucus components; to study the preclinical toxicity of CLp53 by intratracheal instillation and aerosolization in mice and rabbits; these studies are essential for IND filing; and, to perform a Phase I clinical study of CLp53 by aerosolization in patients with p53 mutant non-small cell lung cancer (NSCLC). The objectives of the Phase I clinical study are: to determine the maximum tolerated dose, optimum schedule, and dose-limiting toxicity of aCLp53; to generate preliminary information on the ability of aCLp53 to restore p53 function in the human bronchial epithelium; and, to study the deposition and distribution of aCLp53 in the lungs. The results of this study will provide initial but very valuable information on the potential use of this new strategy in the treatment of bronchial premalignancy, carcinoma in situ, and endobronchial lung tumors.