Gene therapy for the liver metastasis of the pancreatic cancer using p53 adenovirus vector

胰腺癌即使可以切除，但由于局部复发或肝转移，预后极差。虽然扩大的胰腺切除和术中放疗对控制局部复发是有效的，但化疗或其他常规治疗对肝转移无效。本研究的目的是评价门脉注射P53腺病毒载体治疗胰腺癌肝转移的有效性。结果表明，门脉注射P53腺病毒载体对携带P53基因突变的小鼠肝转移模型具有一定的抗肿瘤作用。反复应用P53重组腺病毒载体可增强小鼠肝转移模型的抗肿瘤作用。另一方面，利用无P53突变的肿瘤细胞株，我们不能确定门脉内注射P53腺病毒载体在小鼠肝转移模型中的抗肿瘤作用。此外，在我们的小鼠实验中，没有观察到门脉内注射P53腺病毒载体的任何副作用。为了将肿瘤基因治疗应用于肝转移的临床应用，我们还研究了门脉内注射IL-12转导的成纤维细胞。用类似的海洋肝转移模型证实了其对肝转移的抗肿瘤作用和抗肿瘤免疫的诱导。肿瘤基因治疗的临床应用有望改善肝转移患者的预后，提高患者的生活质量。

Prognosis of the pancreatic cancer, even if it is resectable, is extremely poor because of the local recurrence or the liver metastasis. Although extended pancreatectomy and intraoperative radiotherapy are effective to the control of the local recurrence, chemotherapy or other conventional therapies are not effective to the liver metastasis. A new therapy including a gene therapy is expected for the treatment of the pancreatic cancer.The purpose of this study is to evaluate the usefulness of intraportal administration of p53 adenovirus vector for the liver metastases of the pancreatic cancer.As a result, intraportal administration of p53 adenovirus vector showed antitumor effect to the murine liver metastasis models using tumor cell lines with p53 mutation. Repeated administration of p53 adenovirus vector could enhance the antitumor effect in murine liver metastasis models. On the other hand, using tumor cell lines without p53 mutation, we could not confirm the antitumor effect of intraportal administration of p53 adenovirus vector in the murine liver metastasis models. In additions, any side effect of intraportal administration of p53 adenovirus vector has not been observed in our murine experiments.With the aim of clinical application of cancer gene therapy to the liver metastasis, we have also examined the intraportal administration of IL-12 transduced fibroblast cells. The antitumor effect to the liver metastasis and the induction of antitumor immunity were confirmed using similar marine liver metastasis models. It is expected that the clinical application of cancer gene therapy would improve the prognosis of the liver metastasis and the quality of life in cancer patients.