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

不能切除的原发肺癌仍然是肿瘤学中最棘手的问题之一。尽管在联合治疗方案中使用了化疗和放射治疗，但局部控制率不到20%。局部基因进展型非小细胞肺癌为基因转移的临床方案提供了一个很好的治疗靶点和模型系统。大量表达野生型p53的腺病毒载体(Ad-p53)的临床前和I期临床试验数据支持启动临床试验，以检验以下假设：1)野生型p53在非小细胞肺癌(NSCLC)细胞中的过表达将增强对外部射线电离辐射的敏感性，2)联合治疗将改善局部控制，并最终提高NSCLC的生存率。这项试验的设计将考虑到与Ad-P53和单独使用Ad-P53未见的放射相关的不良事件可能发生的可能性，并将首先通过小磨合剂量递增研究来评估这一点。随后将进行II期临床试验，以解决以下具体目标：目标1：确定与单纯诱导化疗和放疗相比，非小细胞肺癌患者局灶内给予Ad-p53联合放疗是否能增加局部肿瘤控制，并在后续的随机临床试验中，确定诱导化疗、放疗及病灶内Ad-p53是否可提高局部肿瘤控制及生存率。目的2：研究非小细胞肺癌患者瘤内注射Ad-P53联合放射治疗的定性和定量毒性及可逆性。目的3：进行实验室实验，以验证所提出的载体，如ADV-P53和其他载体，在体外和体内都能增强各种人类肿瘤细胞对辐射的敏感性。目的4：进行机制研究，以确定基因治疗后在细胞中激活的负责恢复细胞凋亡倾向和放射增敏的生化途径。

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 that 20 percent. Locally gene advanced 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 adenoviral vector expressing wildtype p53 (Ad-p53) support the initiation of a clinical trial to test the hypothesis that: 1) over-expression of wildtype p53 in non-small cell lung cancer (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 number 1: To determine if the intralesional administration of Ad-p53 in conjunction with primary radiation therapy increases local tumor control in patients with non-small cell lung cancer, and in follow-up randomized clinical trial, to determine if induction chemotherapy, radiation therapy, and intralesional Ad-p53 increases local tumor control and survival compared to induction chemotherapy and radiation therapy only. Aim number 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 non-small cell lung cancer. Aim number 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 number 4: To conduct mechanistic studies to determine the biochemical pathways activated in cells following gene therapy responsible for restoring apoptosis propensity and radiosensitization.