Radiation sensitivity/Apoptosis Induction in Cancer Cells--P53 Restoration

描述：（申请人描述）不可切除的原发性肺癌 仍然是肿瘤学中最棘手的问题之一。尽管使用 化疗和放射治疗的综合方式协议，局部 控制率不到20%。局部晚期 癌症（NSCLC）代表了一个极好的治疗靶点和模型系统， 涉及基因转移的临床方案大量的临床前 以及表达野生型的腺病毒载体的I期临床试验数据 p53（Ad-p53）支持启动临床试验，以测试 假设：（1）野生型p53在NSCLC细胞中过表达将 增强对外部束电离辐射的敏感性，以及（2） 联合治疗将改善局部控制和最终生存， 非小细胞肺癌。这项试验的设计将考虑到 与Ad-p53和放射组合相关的不良事件 单独使用Ad-p53可能会发生，并将首先使用小的 导入剂量递增研究。随后将进行II期临床试验 试验旨在实现以下具体目标。目标1：确定 Ad-p53与原发性放射联合病灶内给药 治疗增加了NSCLC患者的局部肿瘤控制， 随机临床试验，以确定诱导化疗，放疗 治疗和病灶内Ad-p53增加了局部肿瘤控制和生存 与仅诱导化疗和放疗相比。目标2： 确定定性和定量的毒性和可逆性 在病灶内施用Ad-p53与 NSCLC患者的放射治疗。目标3：开展实验室工作 实验以验证所提出的载体，Adv-p53和其他功能 为了使来自各种人类肿瘤的细胞对辐射敏感， 体外和体内。目的4：进行机制研究，以确定 基因治疗后细胞中激活的生化途径 恢复细胞凋亡倾向和放射增敏作用。

DESCRIPTION: (Applicant's Description) Unresectable primary lung cancer remains one of the most formidable problems in oncology. Despite the use of chemotherapy and radiation therapy in combined modality protocols, local control rates are less than 20 percent. Locally advanced non-small cell lung cancer (NSCLC) represents an excellent therapeutic target and model system for a clinical protocol involving gene transfer. A large volume of preclinical and the phase I clinical trial data for an adenoviral vector expressing wildtype p53 (Ad-p53) support the initiation of a clinical trial to test the hypothesis that: (1) over-expression of wild-type p53 in NSCLC cells will enhance sensitivity to external beam ionizing radiation, and (2) that the combination therapy will improve local control and ultimately survival in NSCLC. The design of this trial will take into consideration the possibility that adverse events related to the combination of Ad-p53 and radiation not seen with Ad-p53 alone could occur and will assess this first with a small run-in dose escalation study. This will be followed by a phase II clinical trial to address the following specific aims. Aim 1: To determine if the intralesional administration of Ad-p53 in conjunction with primary radiation therapy increases local tumor control in patients with NSCLC, and in follow-up randomized clinical trial, to determine if induction chemotherapy, radiation therapy, and intralesional Ad-p53 increased local tumor control and survival compared to induction chemotherapy and radiation therapy only. Aim 2: To determine the qualitative and quantitative toxicity and reversibility of toxicity following intralesional administration of Ad-p53 in conjunction with radiation therapy in patients with NSCLC. Aim 3: To conduct laboratory experiments to validate that the vectors proposed, Adv-p53 and others function to sensitize cells derived from various human tumors to radiation both in vitro and in vivo. Aim 4: To conduct mechanistic studies to determine the biochemical pathways activated in cells following gene therapy responsible for restoring apoptosis propensity and radiosensitization.