Gene Therapy for Esophageal Cancer

尽管晚期食管癌的手术治疗水平有所提高，多种治疗方法的应用，但对于无法切除的肿瘤患者，预后极差。基于食管癌的遗传背景，我们开发了多种针对人类食管癌的基因治疗策略。本文就食管癌的分子事件及p53基因治疗方法进行综述。首先，我们分析了食管癌中p53基因的改变和血管生成。其次，我们测试了p53重组腺病毒载体（Ad5CMV-p53）。Ad5CMV-p53感染人食管癌细胞系后，观察到明显的生长抑制。这一观察结果提示Ad5CMV-p53可能是局部晚期食管癌的潜在有效治疗剂。有希望的研究途径包括双重基因治疗和基因治疗与放射治疗的辅助使用。第三，基于近年来p53基因治疗肺癌和头颈部癌的临床试验报道，我们制定了p53基因治疗不可切除的晚期食管癌的临床方案。本临床试验旨在评估媒介的耐受性和疗效。截至2004年3月1日，共有9名患者入组I/II期临床试验。到目前为止，这些患者未发生与Ad5CMV-p53相关的严重不良事件，试验已安全进行。

Despite improvement of surgical treatment and application of multi-modality therapies to advanced esophageal cancer, the prognosis is extremely poor in patients with unresectable tumors. Based on the genetic background of esophageal cancer, we have developed various gene therapy strategies against human esophageal cancer. In this article, we reviewed molecular events of esophageal cancer and p53 gene therapy approaches for its treatment. First, we analyzed p53 genetic alterations and angiogenesis in esophageal cancer. Second, we tested a p53 recombinant adenoviral vector (Ad5CMV-p53). Significant growth suppression was observed following infection with Ad5CMV-p53 in human esophageal cancer cell lines. This observation suggests that Ad5CMV-p53 may be a potentially effective therapeutic agent for locally advanced esophageal cancer. Promising avenues for investigation include double gene therapy and adjuvant use of gene therapy with radiation therapy. Third, based on recent reports of clinical trials of p53 gene therapy for lung cancer and head and neck cancer, we developed a clinical protocol for p53 gene therapy for unresectable advanced esophageal cancer. This clinical trial was planned to evaluate vector tolerability and efficacy. Up to March 1, 2004, 9 patients were enrolled into this phase I/II trial. No serious adverse events related to Ad5CMV-p53 have occurred so far in these patients, and the trial has been safely conducted.