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

描述：(申请人？S描述)不能切除的原发性肺癌 仍然是肿瘤学中最可怕的问题之一。尽管使用了 联合治疗方案的化疗和放射治疗，当地 控制率不到20%。局部晚期非小细胞肺癌 癌症(NSCLC)代表着一种极好的治疗靶点和模型系统 一项涉及基因转移的临床方案。大量的临床前研究 表达野生型腺病毒载体的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 增强对外部束流电离辐射的敏感性，以及(2) 联合治疗将改善局部控制和最终存活率 非小细胞肺癌。这项试验的设计将考虑到这种可能性 与联合应用Ad-P53和放射治疗相关的不良反应 单独使用Ad-P53可能会发生这种情况，并将首先使用小的 磨合剂量递增研究。随后将进行二期临床试验。 试验旨在解决以下具体目标。目标1：确定 瘤内注射Ad-P53联合原发放射治疗 治疗增加非小细胞肺癌患者的局部肿瘤控制，并在随访中进行 随机临床试验，以确定诱导化疗、放射治疗 治疗和瘤内Ad-P53增加局部肿瘤控制和生存期 与单纯的诱导化疗和放射治疗相比。目标2：实现 测定其定性和定量毒性及可逆性 联合应用Ad-P53瘤内给药的毒性 非小细胞肺癌患者的放射治疗。目标3：开展实验室 实验验证所提出的载体、Adv-P53和其他载体的功能 为了使来自各种人类肿瘤的细胞对辐射敏感， 体外和体内。目标4：进行机械学研究以确定 基因治疗后细胞中激活的生化途径与 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.