艾滋病是威脅人類健康的一大殺手,，讓其“棄暗投明”幫助科學家對抗癌癥，聽起來似乎是件完全不可能的事情,。據(jù)每日科學網(wǎng)8月29日報道,，法國國家科學研究院（CNRS）的科學家日前就獨辟蹊徑，讓其成為了現(xiàn)實,。
利用艾滋病病毒（HIV）的復制機制,，該機構(gòu)的研究人員已經(jīng)培育出了一種突變體蛋白。該物質(zhì)能極大提高抗癌藥物的功效,，在與抗癌藥物聯(lián)合使用時,，藥物劑量減至先前的1/300即可達到同樣的療效。相關(guān)論文發(fā)表在8月23日出版的《公共科學圖書館—遺傳學》上,。該發(fā)現(xiàn)有望在癌癥和其他疾病的治療中發(fā)揮重要作用,。
HIV通過大量復制病毒將自己的遺傳物質(zhì)插入宿主細胞的方式來進行繁殖。其顯著特征是,，HIV通過不斷發(fā)生變異并產(chǎn)生多種不同突變蛋白（突變體）來進行繁殖,，這種特性使其能夠在復雜多變的環(huán)境中生存。迄今為止,，還沒有任何一種藥物能夠?qū)⑵鋸氐讱纭?/p>
法國國家科學研究院的科學家反其道而行之,，提出了使用HIV的策略來治療其他疾病，尤其是癌癥的設想,。
為了驗證這一想法,，他們首先通過向HIV基因中插入一種人類基因?qū)ζ溥M行改造。這種基因能夠促成脫氧胞苷激酶(dCK)的產(chǎn)生,。脫氧胞苷激酶是催化抗病毒和抗腫瘤藥物在人體內(nèi)合成其單磷酸鹽的關(guān)鍵酶,，是激活抗腫瘤藥物的關(guān)鍵所在。不少病毒或癌細胞對藥物的抗藥性都與人體細胞內(nèi)脫氧胞苷激酶的失活相關(guān),。因此,，近幾年來全世界的科學家們一直試圖通過增加脫氧胞苷激酶的活性、提高其效率的方式實現(xiàn)對腫瘤的抑制,。
根據(jù)HIV的繁殖方式,，該研究團隊建立一個包括近80個艾滋病病毒突變的突變體庫,，并結(jié)合抗癌藥物對其進行實驗以確定其功效。結(jié)果發(fā)現(xiàn),，這些突變體在識別脫氧胞苷激酶方面比傳統(tǒng)的未變異蛋白更有效,。當抗癌藥物與這些突變體蛋白聯(lián)合使用時，在劑量上只需原先的1/300即可達到同樣的療效,。
這種方法不但能夠降低大劑量抗癌藥物在使用時所有可能產(chǎn)生的副作用,，還能極大地提高效率。下一步,，研究人員還將在動物實驗中對單獨的突變體蛋白進行測試,。研究人員稱,，除治療癌癥外,，類似的療法在抗病毒治療中也具有一定潛力,。（生物谷Bioon.com）
doi:10.1371/journal.pgen.1002904
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Retrovolution: HIV–Driven Evolution of Cellular Genes and Improvement of Anticancer Drug Activation
Paola Rossolillo, Flore Winter, Etienne Simon-Loriere, Sarah Gallois-Montbrun, Matteo Negroni
In evolution strategies aimed at isolating molecules with new functions, screening for the desired phenotype is generally performed in vitro or in bacteria. When the final goal of the strategy is the modification of the human cell, the mutants selected with these preliminary screenings may fail to confer the desired phenotype, due to the complex networks that regulate gene expression in higher eukaryotes. We developed a system where, by mimicking successive infection cycles with HIV-1 derived vectors containing the gene target of the evolution in their genome, libraries of gene mutants are generated in the human cell, where they can be directly screened. As a proof of concept we created a library of mutants of the human deoxycytidine kinase (dCK) gene, involved in the activation of nucleoside analogues used in cancer treatment, with the aim of isolating a variant sensitizing cancer cells to the chemotherapy compound Gemcitabine, to be used in gene therapy for anti-cancer approaches or as a poorly immunogenic negative selection marker for cell transplantation approaches. We describe the isolation of a dCK mutant, G12, inducing a 300-fold sensitization to Gemcitabine in cells originally resistant to the prodrug (Messa 10K), an effect 60 times stronger than the one induced by the wt enzyme. The phenotype is observed in different tumour cell lines irrespective of the insertion site of the transgene and is due to a change in specificity of the mutated kinase in favour of the nucleoside analogue. The mutations characterizing G12 are distant from the active site of the enzyme and are unpredictable on a rational basis, fully validating the pragmatic approach followed. Besides the potential interest of the G12 dCK variant for therapeutic purposes, the methodology developed is of interest for a large panel of applications in biotechnology and basic research.
