生物谷报道：大多数人都不会认为炭疽热毒素是什么好东西，但美国科学家的一项最新研究证实，类似的细菌毒素有望在将来成为有效的癌症治疗方法。相关论文发表在2008年1月的《生物化学杂志》（Journal of Biological Chemistry）上。
虽然在一般人看来，与炭疽热有关的毒性风险几乎“葬送”了该细菌毒素在临床应用的可能性，但事实上的情况却并非如此，该毒素对黑色素瘤细胞具有相当的选择性。为了开发出一种潜在的安全治疗方法，在最新的研究中，美国国立卫生研究院过敏与传染病研究所（NIAID）的Stephen Leppla和同事创造出了变异的炭疽热毒素，它们只有在基质金属蛋白酶（MMP）存在的条件下才能开启。而值得一提的是，通常只有癌细胞中才会过量表达MMP蛋白。
研究人员随后利用小鼠检测了该改造细菌毒素，结果发现，所有实验小鼠都承受住了相当的毒素剂量，而如果是等量的天然毒素，绝对是致命的。研究人员还注意到，改造毒素能够比天然毒素更有效地杀灭黑色素瘤，这是由于它具有高度的特异性，同时在血液中的浓度半衰期也较长。
此外，进一步的研究还证实，得益于对血管发生（angiogenesis）的抑制，改造炭疽热毒素的抗癌能力不只限于黑色素瘤，也能够抗击其他类型的癌症，比如结肠癌和肺癌。
新的研究成果意味着，细菌毒素用于抗癌是可行的，未来有望开发出基于“以毒攻癌”的临床治疗方法。（科学网 任霄鹏/编译）
生物谷推荐英文原文：
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.
