Towards establishment of gene therapy for human pancreatic and endometrial cancers

1.在染色体异常多发区域中，12q、17p和18q三个染色体区域的缺失与胰腺癌的预后不良有关。腺病毒介导的Smad4基因在Smad4纯合子缺失的胰腺癌细胞株中的表达没有显示出任何对细胞生长的抑制。我们先前报道，18q缺失是胰腺癌发生的早期事件。Smad4基因突变可能是胰腺癌发生的始动步骤和预后决定因素。然而，在18q上可能存在与SMAD4.2不同的未知抑癌基因。2.我们等人曾报道过子宫内膜癌中PTEN基因频繁的体细胞突变。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尝试。体外实验获得成功，导入正常拷贝的PTEN基因可诱导肿瘤细胞发生凋亡。然而，这一尝试在体内并不成功。这些结果表明，经过适当的改进，PTEN基因是一个很好的候选基因治疗人子宫内膜癌。

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.