Kuhlmann K F D, van Geer M A, Bakker C T, Dekker J E M, Havenga M J E, Elferink R P J Oude, Gouma D J, Bosma P J, Wesseling J G
Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Cancer Gene Ther. 2009 Jul;16(7):585-97. doi: 10.1038/cgt.2009.4. Epub 2009 Jan 30.
Survival of patients with pancreatic cancer is poor. Adenoviral (Ad) gene therapy employing the commonly used serotype 5 reveals limited transduction efficiency due to the low amount of coxsackie-adenovirus receptor on pancreatic cancer cells. To identify fiber-chimeric adenoviruses with improved gene transfer, a library of Ad vectors based on Ad5 and carrying fiber molecules consisting of 16 other serotypes were transduced to human pancreatic carcinoma cell lines. Adenoviruses containing fibers from serotype 16 and 50 showed increased gene transfer and were further analyzed. In a gene-directed prodrug activation system using cytosine deaminase, these adenoviruses proved to be effective in eradicating primary pancreatic tumor cells. Fiber-chimeric Ad5 containing fiber 16 and wild-type Ad5 were also transduced ex vivo to slices of normal human pancreatic tissue and pancreatic carcinoma tissue obtained during surgery. It was shown that fiber-chimeric Ad5 with fiber 16 revealed an improved gene delivery to primary pancreatic tumor tissue compared to Ad5. In conclusion, fiber-chimeric adenoviruses carrying fiber 16 and 50 reveal a significantly enhanced gene transfer and an increased specificity to human pancreatic adenocarcinoma compared to Ad5, whereas transduction to normal pancreatic tissue was decreased. These findings expand the therapeutic window of Ad gene therapy for pancreatic cancer.
胰腺癌患者的生存率很低。由于胰腺癌细胞上柯萨奇病毒 - 腺病毒受体数量较少，采用常用血清型5的腺病毒（Ad）基因疗法显示出有限的转导效率。为了鉴定具有改善基因转移能力的纤维嵌合腺病毒，将基于Ad5并携带由其他16种血清型组成的纤维分子的Ad载体文库转导至人胰腺癌细胞系。含有血清型16和50纤维的腺病毒显示出基因转移增加，并进行了进一步分析。在使用胞嘧啶脱氨酶的基因导向前药激活系统中，这些腺病毒被证明可有效根除原发性胰腺肿瘤细胞。含有纤维16的纤维嵌合Ad5和野生型Ad5也在体外转导至手术中获得的正常人类胰腺组织和胰腺癌组织切片。结果表明，与Ad5相比，含有纤维16的纤维嵌合Ad5对原发性胰腺肿瘤组织的基因传递有所改善。总之，与Ad5相比，携带纤维16和50的纤维嵌合腺病毒显示出显著增强的基因转移以及对人胰腺腺癌的特异性增加，而对正常胰腺组织的转导则降低。这些发现拓宽了Ad基因疗法治疗胰腺癌的治疗窗口。
