Gene Therapy for Esophageal Cancer

尽管晚期食道癌的手术治疗有所改进，多种治疗手段的应用，但不能切除的肿瘤患者的预后极差。基于食道癌的遗传背景，我们开发了多种针对人类食道癌的基因治疗策略。本文就食道癌的分子事件及P53基因治疗方法作一综述。首先，我们分析了食道癌中P53基因的改变和血管生成。其次，我们检测了P53重组腺病毒载体(Ad5CMV-P53)。Ad5CMV-P53对人食道癌细胞株的生长有明显的抑制作用。这一观察结果表明，Ad5CMV-P53可能是一种潜在的治疗局部晚期食道癌的有效药物。有希望的研究途径包括双基因治疗和基因治疗与放射治疗的辅助使用。第三，根据近期报道的肺癌和头颈癌p53基因治疗的临床试验，我们制定了不能手术切除的晚期食道癌的p53基因治疗的临床方案。这项临床试验计划评估媒介的耐受性和有效性。截至2004年3月1日，有9名患者参加了这项I/II期试验。到目前为止，这些患者中还没有发生与Ad5CMV-P53相关的严重不良事件，试验已经安全进行。

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.