美國科學(xué)家對(duì)痘苗病毒進(jìn)行了基因改良,，以此作為治療的手段,，取得了良好的治療癌癥效果。這一研究發(fā)表在近期出版的美國《臨床研究雜志》上,。
這項(xiàng)研究由賓夕法尼亞匹茲堡大學(xué)病毒學(xué)家斯蒂芬·索恩尼領(lǐng)導(dǎo),。研究人員首先從痘苗病毒中剔除了兩個(gè)基因，這兩個(gè)基因?qū)τ诓《驹谡＜?xì)胞中的生長(zhǎng)是必要的,；然后移接了一段基因,，使痘苗病毒能制造粒細(xì)胞-巨噬細(xì)胞集落刺激因子，刺激機(jī)體的免疫系統(tǒng),，識(shí)別并攻擊被病毒感染了的腫瘤,。
研究人員利用肝臟癌瘤已經(jīng)傳播到肺部的兔子進(jìn)行試驗(yàn)，將上述改造好的工程病毒注入野兔體內(nèi),，發(fā)現(xiàn)肝臟和肺部的腫瘤都變小了,，而沒有接受注射的兔子，肝臟腫瘤擴(kuò)大了4倍，肺部腫瘤也變得明顯,。索恩尼表示,，如果加大注射劑量，或用病毒療法再輔以其它醫(yī)療方法,，我們很可能會(huì)攻克癌癥,。
索恩尼表示，他們正在和美國食品藥品監(jiān)督管理局磋商,，計(jì)劃明年初將這種病毒療法在患固體腫瘤的癌癥病人身上進(jìn)行人體試驗(yàn),。他認(rèn)為，人體組織研究顯示,，病毒不會(huì)感染正常細(xì)胞,，但在治療中，仍需要一些安全措施,，如注射疫苗免疫球蛋白,，以預(yù)防及少見的對(duì)疫苗的不良反應(yīng)。
10多年來,，科學(xué)家一直在改造病毒,，使它們能有選擇地感染、破壞癌細(xì)胞,，但收效甚微,。至今最先進(jìn)的腫瘤增殖腺病毒ONYX-015是一種改造的腺病毒，中國已于2005年用它治療頭頸癌,。賓夕法尼亞費(fèi)城?？怂?蔡斯癌癥中心的醫(yī)療腫瘤學(xué)家路易斯·維納說，痘苗病毒可能比ONYX-015更加先進(jìn),，它的抗腫瘤效果更強(qiáng)，但我們?nèi)孕柚?jǐn)慎對(duì)待,，因?yàn)檫@些只經(jīng)過了動(dòng)物試驗(yàn),，用在人體上效果可能不太理想。（生物谷Bioon.com）
生物谷推薦原始出處：
Clinical Cancer Research 15, 1730, March 1, 2009.doi: 10.1158/1078-0432.CCR-08-2008
Oncolytic Adenoviral Mutants with E1B19K Gene Deletions Enhance Gemcitabine-induced Apoptosis in Pancreatic Carcinoma Cells and Anti-Tumor Efficacy In vivo
Stephan Leitner1, Katrina Sweeney1, Daniel ?berg1, Derek Davies2, Enrique Miranda1, Nick R. Lemoine1 and Gunnel Halldén1
Authors' Affiliations: 1 Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, and 2 FACS Laboratory, London Research Institute, Cancer Research UK, Lincolns Inn Fields, London, United Kingdom
Requests for reprints: Gunnel Halldén, Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
Purpose: Pancreatic adenocarcinoma is a rapidly progressive malignancy that is highly resistant to current chemotherapeutic modalities and almost uniformly fatal. We show that a novel targeting strategy combining oncolytic adenoviral mutants with the standard cytotoxic treatment, gemcitabine, can markedly improve the anticancer potency.
Experimental Design: Adenoviral mutants with the E1B19K gene deleted with and without E3B gene expression (AdE1B19K and dl337 mutants, respectively) were assessed for synergistic interactions in combination with gemcitabine. Cell viability, mechanism of cell death, and antitumor efficacy in vivo were determined in the pancreatic carcinoma cells PT45 and Suit2, normal human bronchial epithelial cells, and in PT45 xenografts.
Results: The E1B19K-deleted mutants synergized with gemcitabine to selectively kill cultured pancreatic cancer cells and xenografts in vivo with no effect in normal cells. The corresponding wild-type virus (Ad5) stimulated drug-induced cell killing to a lesser degree. Gemcitabine blocked replication of all viruses despite the enhanced cell killing activity due to gemcitabine-induced delay in G1/S-cell cycle progression, with repression of cyclin E and cdc25A, which was not abrogated by viral E1A-expression. Synergistic cell death occurred through enhancement of gemcitabine-induced apoptosis in the presence of both AdE1B19K and dl337 mutants, shown by increased cell membrane fragmentation, caspase-3 activation, and mitochondrial dysfunction.
Conclusions: Our data suggest that oncolytic mutants lacking the antiapoptotic E1B19K gene can improve efficacy of DNA-damaging drugs such as gemcitabine through convergence on cellular apoptosis pathways. These findings imply that less toxic doses than currently practiced in the clinic could efficiently target pancreatic adenocarcinomas when combined with adenoviral mutants.
