美国科学家利用纳米粒子成功地运送具有致命毒素的白喉基因，“以毒攻毒”彻底杀死了胰腺癌细胞。该研究第一次展示了在胰腺癌细胞实验上的这种独特策略，为未来临床前动物研究，甚至是全新的临床方法提供了可能。该项研究成果刊登在最新一期《癌症生物学与治疗》（Cancer Biology and Therapy）期刊上。
领导该项研究的美国托马斯 杰弗逊大学杰弗逊医学院外科系助理教授乔纳森?布罗迪博士指出，胰腺癌在美国是死亡率排名第四的癌症，患者从诊断开始通常只能存活不到1年的时间。除了少数患者可以实施外科手术外，目前几乎还没有有效的、有针对性的胰腺癌治疗方法。研究人员急需将有关这种疾病的大量分子信息转化成新颖的治疗方法。
科学家在多种癌细胞中发现了间皮素（mesothelin），并在进一步研究中得知，间皮素的蛋白质在促进胰腺癌成长过程中扮演着重要的角色，当胰腺癌细胞中的间皮素升高时，癌细胞数量就会快速增加，同时也加强了扩散速度。
研究人员发现，当胰腺癌产生足够的蛋白质IDO（双加氧酶）时，癌细胞便会转移到淋巴结内，并且瓦解在免疫系统中扮演重要角色的淋巴细胞——T细胞，进而使得人体免疫系统无法抑制肿瘤的生长。研究人员通过使用一种可分解生物的纳米系统，发现白喉毒素是“间皮素表达”胰腺癌细胞的自杀基因。将白喉毒素基因放入胰腺癌细胞内，可抑制癌细胞的蛋白质合成机制。同时，通过关闭胰腺癌细胞生产蛋白质来有效地杀死癌细胞。研究结果表明，白喉毒素基因的传递可抑制95%以上的胰腺肿瘤细胞，在单次治疗后6天就能造成胰腺癌细胞的大量死亡。而且，这种治疗方法的靶标只针对胰腺癌细胞，而毒素不会被正常细胞吸收，从而提供了一个潜在的“治疗之窗”。
布罗迪表示，该方法的靶标是一种可在超过3/4的胰腺癌患者身上发现的分子，这也意味着这项实验如果充分实现，将给七成以上的胰腺癌患者提供康复的希望。下一步，研究人员将尽快从动物实验迈向临床实验，从而确定胰腺癌细胞的自杀基因是否仅存于该癌细胞内。（生物谷Bioon.com）
生物谷推荐原始出处：
Cancer Biology and Therapy，Volume: 7，Issue: 10，Pages: 1584 - 1590，SL Showalter，JR Brody
Nanoparticulate delivery of diphtheria toxin DNA effectively kills mesothelin expressing pancreatic cancer cells
SL Showalter, Y-H Huang, A Witkiewicz, CL Costantino, CJ Yeo, JJ Green, R Langer, DG Anderson, JA Sawicki and JR Brody
Pancreatic cancer is the fourth leading cause of cancer-related deaths in this country, and there is currently no effective targeted treatment for this deadly disease. A dire need exists to rapidly translate our molecular understanding of this devastating disease into effective, novel therapeutic options. Mesothelin is a candidate target protein shown by a number of laboratories to be specifically overexpressed in pancreatic cancers and not in the adjacent normal tissue. Translational investigations have shown promising results using this molecule as a therapeutic target (e.g., vaccine strategies). In addition, the mesothelin promoter has been cloned and dissected and can therefore be used as a vehicle for regulating expression of DNA sequences. Using a novel, proven, biodegradable nanoparticulate system, we sought to target mesothelin-expressing pancreatic cancer cells with a potent suicide gene, diphtheria toxin-A (DT-A). We first confirmed reports that a majority of pancreatic cancer cell lines and resected pancreatic ductal adenocarcinoma specimens overexpressed mesothelin at the mRNA and protein levels. High mesothelin-expressing pancreatic cancer cell lines produced more luciferase than cell lines with undetectable mesothelin expression when transfected with a luciferase sequence under the regulation of the mesothelin promoter. We achieved dramatic inhibition of protein translation (>95%) in mesothelin-expressing pancreatic cancer cell lines when DT-A DNA, driven by the mesothelin promoter, was delivered to pancreatic cancer cells. We show that this inhibition effectively targets the death of pancreatic cancer cells that overexpress mesothelin. The work presented here provides evidence that this strategy will work in pre-clinical mouse pancreatic cancer models, and suggests that such a strategy will work in the clinical setting against the majority of pancreatic tumors, most of which overexpress mesothelin.
