生物谷報(bào)道：大多數(shù)人都不會認(rèn)為炭疽熱毒素是什么好東西，但美國科學(xué)家的一項(xiàng)最新研究證實(shí),，類似的細(xì)菌毒素有望在將來成為有效的癌癥治療方法,。相關(guān)論文發(fā)表在2008年1月的《生物化學(xué)雜志》（Journal of Biological Chemistry）上。
雖然在一般人看來,，與炭疽熱有關(guān)的毒性風(fēng)險(xiǎn)幾乎“葬送”了該細(xì)菌毒素在臨床應(yīng)用的可能性,，但事實(shí)上的情況卻并非如此，該毒素對黑色素瘤細(xì)胞具有相當(dāng)?shù)倪x擇性,。為了開發(fā)出一種潛在的安全治療方法，在最新的研究中,，美國國立衛(wèi)生研究院過敏與傳染病研究所（NIAID）的Stephen Leppla和同事創(chuàng)造出了變異的炭疽熱毒素,，它們只有在基質(zhì)金屬蛋白酶（MMP）存在的條件下才能開啟。而值得一提的是,，通常只有癌細(xì)胞中才會過量表達(dá)MMP蛋白,。
研究人員隨后利用小鼠檢測了該改造細(xì)菌毒素，結(jié)果發(fā)現(xiàn),，所有實(shí)驗(yàn)小鼠都承受住了相當(dāng)?shù)亩舅貏┝?，而如果是等量的天然毒素，絕對是致命的,。研究人員還注意到,，改造毒素能夠比天然毒素更有效地殺滅黑色素瘤，這是由于它具有高度的特異性,，同時(shí)在血液中的濃度半衰期也較長,。
此外，進(jìn)一步的研究還證實(shí),，得益于對血管發(fā)生（angiogenesis）的抑制,，改造炭疽熱毒素的抗癌能力不只限于黑色素瘤，也能夠抗擊其他類型的癌癥,，比如結(jié)腸癌和肺癌,。
新的研究成果意味著，細(xì)菌毒素用于抗癌是可行的,，未來有望開發(fā)出基于“以毒攻癌”的臨床治療方法,。（科學(xué)網(wǎng) 任霄鵬/編譯）
生物谷推薦英文原文：
J. Biol. Chem., Vol. 283, Issue 1, 529-540, January 4, 2008
Matrix Metalloproteinase-activated Anthrax Lethal Toxin Demonstrates High Potency in Targeting Tumor Vasculature*
Shihui Liu, Hailun Wang, Brooke M. Currie, Alfredo Molinolo, Howard J. Leung, Mahtab Moayeri, John R. Basile, Randall W. Alfano¶, J. Silvio Gutkind, Arthur E. Frankel¶, Thomas H. Bugge1, and Stephen H. Leppla2
From the Laboratory of Bacterial Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892, Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, and ¶Cancer Research Institute of Scott & White Memorial Hospital, Temple, Texas 76502
Anthrax lethal toxin (LT), a virulence factor secreted by Bacillus anthracis, is selectively toxic to human melanomas with the BRAF V600E activating mutation because of its proteolytic activities toward the mitogen-activated protein kinase kinases (MEKs). To develop LT variants with lower in vivo toxicity and high tumor specificity, and therefore greater potential for clinical use, we generated a mutated LT that requires activation by matrix metalloproteinases (MMPs). This engineered toxin was less toxic than wild-type LT to mice because of the limited expression of MMPs by normal cells. Moreover, the systemically administered toxin produced greater anti-tumor effects than wild-type LT toward human xenografted tumors. This was shown to result from its greater bioavailability, a consequence of the limited uptake and clearance of the modified toxin by normal cells. Furthermore, the MMP-activated LT had very potent anti-tumor activity not only to human melanomas containing the BRAF mutation but also to other tumor types, including lung and colon carcinomas regardless of their BRAF status. Tumor histology and in vivo angiogenesis assays showed that this anti-tumor activity is due largely to the indirect targeting of tumor vasculature and angiogenic processes. Thus, even tumors genetically deficient in anthrax toxin receptors were still susceptible to the toxin therapy in vivo. Moreover, the modified toxin also displayed lower immunogenicity compared with the wild-type toxin. All these properties suggest that this MMP-activated anti-tumor toxin has potential for use in cancer therapy.
* This work was supported by the intramural research programs of the NIAID and the NIDCR, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
