AMC Liver Center, Academic Medical Center University of Amsterdam, Amsterdam, The Netherlands.
Int J Oncol. 2010 Jan;36(1):233-44.
Pancreatic cancer is an aggressive malignancy with a dismal prognosis. To improve treatment options new treatments, such as adenoviral (Ad) gene therapy are necessary. However, low expression of the coxsackie and adenovirus receptor (CAR) in pancreatic cancer cells (PC) limits the therapeutic efficacy of these vectors. The aim of this study was to improve transduction of PC by recombinant adenoviruses by inserting peptides into the HI loop that binds to receptors highly expressed on pancreatic cancer and were shown to target these carcinomas in vivo. We report the successful incorporation into the HI loop of peptide Tyr-Ser-Ala (YSA), a peptide ligand targeting the EphrinA2 (EphA2) receptor, and K237, a peptide targeting to the vascular endothelial growth factor receptor-II (VEGFRII). Subsequently, we showed that both peptides enhanced the transduction of a number of human PC lines that abundantly express the targeted receptor. Additional competition studies confirmed that the YSA peptide redirects Ad-YSA from CAR and specifically targets the EphA2 receptor. Due to this transduction efficiency of Ad-YSA is increased not only in human pancreatic cancer cell lines but more importantly also in pancreatic cancer resection specimens. Since the YSA peptide has been shown to specifically target pancreatic cancer in patients, it may be expected that Ad-YSA will also display increased tropism for this tumour.
胰腺癌是一种侵袭性恶性肿瘤，预后不良。为了改善治疗方案，需要新的治疗方法，如腺病毒（Ad）基因治疗。然而，胰腺癌细胞（PC）中细胞表面coxsackie-adenovirus 受体（CAR）的低表达限制了这些载体的治疗效果。本研究旨在通过插入与在胰腺癌细胞中高度表达的受体结合的肽来改善重组腺病毒对 PC 的转导，这些肽已被证明可在体内靶向这些肿瘤。我们报告了成功地将靶向 EphrinA2（EphA2）受体的肽 Tyr-Ser-Ala（YSA）和靶向血管内皮生长因子受体-II（VEGFRII）的肽 K237 插入 HI 环中。随后，我们表明，这两种肽均增强了大量表达靶向受体的多种人胰腺癌细胞系的转导。进一步的竞争研究证实，YSA 肽使 Ad-YSA 从 CAR 重新定向，并特异性靶向 EphA2 受体。由于 Ad-YSA 的这种转导效率不仅在人胰腺癌细胞系中增加，而且更重要的是在胰腺癌切除标本中增加。由于已经表明 YSA 肽可特异性靶向患者的胰腺癌，因此可以预期 Ad-YSA 也将对这种肿瘤显示出增加的趋向性。
