美國科學家利用納米粒子成功地運送具有致命毒素的白喉基因，“以毒攻毒”徹底殺死了胰腺癌細胞,。該研究第一次展示了在胰腺癌細胞實驗上的這種獨特策略,，為未來臨床前動物研究,，甚至是全新的臨床方法提供了可能。該項研究成果刊登在最新一期《癌癥生物學與治療》（Cancer Biology and Therapy）期刊上,。
領(lǐng)導該項研究的美國托馬斯 杰弗遜大學杰弗遜醫(yī)學院外科系助理教授喬納森?布羅迪博士指出,，胰腺癌在美國是死亡率排名第四的癌癥，患者從診斷開始通常只能存活不到1年的時間,。除了少數(shù)患者可以實施外科手術(shù)外,，目前幾乎還沒有有效的、有針對性的胰腺癌治療方法,。研究人員急需將有關(guān)這種疾病的大量分子信息轉(zhuǎn)化成新穎的治療方法,。
科學家在多種癌細胞中發(fā)現(xiàn)了間皮素（mesothelin），并在進一步研究中得知,，間皮素的蛋白質(zhì)在促進胰腺癌成長過程中扮演著重要的角色,，當胰腺癌細胞中的間皮素升高時，癌細胞數(shù)量就會快速增加,，同時也加強了擴散速度,。
研究人員發(fā)現(xiàn)，當胰腺癌產(chǎn)生足夠的蛋白質(zhì)IDO（雙加氧酶）時,，癌細胞便會轉(zhuǎn)移到淋巴結(jié)內(nèi),，并且瓦解在免疫系統(tǒng)中扮演重要角色的淋巴細胞——T細胞，進而使得人體免疫系統(tǒng)無法抑制腫瘤的生長,。研究人員通過使用一種可分解生物的納米系統(tǒng),，發(fā)現(xiàn)白喉毒素是“間皮素表達”胰腺癌細胞的自殺基因,。將白喉毒素基因放入胰腺癌細胞內(nèi)，可抑制癌細胞的蛋白質(zhì)合成機制,。同時,，通過關(guān)閉胰腺癌細胞生產(chǎn)蛋白質(zhì)來有效地殺死癌細胞。研究結(jié)果表明,，白喉毒素基因的傳遞可抑制95%以上的胰腺腫瘤細胞,，在單次治療后6天就能造成胰腺癌細胞的大量死亡。而且,，這種治療方法的靶標只針對胰腺癌細胞,，而毒素不會被正常細胞吸收，從而提供了一個潛在的“治療之窗”,。
布羅迪表示,，該方法的靶標是一種可在超過3/4的胰腺癌患者身上發(fā)現(xiàn)的分子，這也意味著這項實驗如果充分實現(xiàn),，將給七成以上的胰腺癌患者提供康復的希望,。下一步，研究人員將盡快從動物實驗邁向臨床實驗,，從而確定胰腺癌細胞的自殺基因是否僅存于該癌細胞內(nèi),。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
