Towards establishment of gene therapy for human pancreatic and endometrial cancers

1.在常见的染色体畸变区域中，12 q、17 p和18 q三个染色体区域的丢失与人类胰腺癌的不良预后相关。腺病毒介导的SMAD4基因在具有SMAD4纯合缺失的胰腺癌细胞系中的递送未显示任何细胞生长抑制。我们以前报道过，18q缺失是胰腺癌发生的早期事件。SMAD 4基因突变可能是胰腺癌发生的起始步骤，也可能是决定预后的因素。然而，在18q上可能存在与SMAD4.2不同的未知抑癌基因。我们和其他人先前报道了子宫内膜癌中PTEN基因的频繁体细胞突变。我们尝试通过腺病毒介导将该基因导入具有该基因两次突变的子宫内膜癌细胞系中进行基因治疗的试验。该试验在体外是成功的，并且在引入正常拷贝的PTEN后在肿瘤细胞中诱导凋亡。然而，这种尝试在体内并不成功。结果提示，PTEN基因经过适当的改良后，可作为子宫内膜癌基因治疗的候选基因。

1.Among regions of frequent chromosomal aberrations, loss of three chromosomal regions, 12q, 17p, and 18q, associated with poor prognosis in human pancreatic cancer. Adenoviral mediated delivery of the SMAD4 gene in pancreatic cancer cell lines with homozygous deletion of SMAD4 did not show any suppression of cell growth. We previously reported that, loss of 18q is an early event in pancreatic carcinogenesis. There is a possibility that mutation of the SMAD4 gene is responsible for the initial step of pancreatic carcinogenesis as well as prognosis defining factor. However, there is a possibility of unknown tumor suppressor gene on 18q that is distinct from SMAD4.2.We and others previously reported frequent somatic mutation of the PTEN gene in endometrial cancer. We attempted a trial of gene therapy by adenovirus mediated introduction of this gene in endometrial cancer cell lines with two-hit mutation of this gene. The trial was successful in vitro, and apoptosis was induced in tumor cells after introduction of normal copy of PTEN. However, the attempt was not successful in vivo. These results suggested that the PTEN gene is a good candidate for gene therapy in human endometrial cancer after appropriate improvement.