Frankel Arthur E, Powell Bayard L, Duesbery Nick S, Vande Woude George F, Leppla Stephen H
Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Curr Protein Pept Sci. 2002 Aug;3(4):399-407. doi: 10.2174/1389203023380567.
Most patients with cancer are treated with chemotherapy but die from progressive disease or toxicities of therapy. Current chemotherapy regimens primarily use cytotoxic drugs which damage cell DNA or impair cell proliferation in both malignant and normal tissues. After several treatment courses, the patients' tumor cells often overexpress multi-drug resistance genes which prevent further tumor cytoreduction. Novel agents which can kill such resistant tumor cells are needed. One such class of agents are targeted peptide toxins. Targeted peptide toxins consist of peptide toxins covalently linked to tumor selective peptide ligands. These molecules bind tumor cell surface receptors, internalize, and facilitate transfer of the toxin catalytic domains to the cytosol. Once in the cytosol, the enzyme activity leads to cell death. A number of plant, bacterial and fungal toxins have been used, and clinical trials with several of these have produced complete remissions in chemoresistant neoplasms. Nevertheless, there is a continuing need for novel targeted toxins. Many patients have pre-existing antibodies against the currently clinically used toxins and many toxins are inactive when used for myeloid malignancies where internalized proteins are rapidly routed and degraded in lysosomes. Anthrax toxins are the cytotoxic components of Bacillus anthracis. While the bacteria has been the source of serious illness, deaths and global anxieties related to past or future bioterrorism, the isolated toxins do not pose public health hazards. In fact, toxin treated patients will likely develop protective antibodies. Anthrax toxin is an excellent choice for tumor cell surface targeting. Other than U.S. military personnel immunized during the Gulf War, most people lack pre-existing antibodies. This may change in the future due to threats of additional terrorist acts, but for the present few patients will have antibodies to anthrax proteins. The separate subunits for binding, translocation and cell killing facilitate genetic engineering to yield tumor-specific cell killing. The toxins are more potent than most of the other peptide toxins and may yield highly efficacious targeted molecules. This essay will review anthrax toxin structure-function, preliminary experiments with re-targeted anthrax toxin and potential designs for new ligand-anthrax therapeutics.
大多数癌症患者接受化疗，但死于疾病进展或治疗毒性。当前的化疗方案主要使用细胞毒性药物，这些药物会损害恶性组织和正常组织中的细胞DNA或损害细胞增殖。经过几个疗程的治疗后，患者的肿瘤细胞通常会过度表达多药耐药基因，从而阻止进一步的肿瘤细胞减灭。因此需要能够杀死此类耐药肿瘤细胞的新型药物。一类这样的药物是靶向肽毒素。靶向肽毒素由与肿瘤选择性肽配体共价连接的肽毒素组成。这些分子结合肿瘤细胞表面受体，内化，并促进毒素催化结构域转移到细胞质中。一旦进入细胞质，酶活性就会导致细胞死亡。已经使用了多种植物、细菌和真菌毒素，其中几种的临床试验已使化疗耐药性肿瘤完全缓解。然而，仍然需要新型靶向毒素。许多患者预先存在针对当前临床使用毒素的抗体，并且许多毒素在用于髓系恶性肿瘤时无活性，因为内化的蛋白质在溶酶体中会迅速被转运和降解。炭疽毒素是炭疽杆菌的细胞毒性成分。虽然这种细菌一直是过去或未来生物恐怖主义相关严重疾病、死亡和全球焦虑的源头，但分离出的毒素不会构成公共卫生危害。事实上，接受毒素治疗的患者可能会产生保护性抗体。炭疽毒素是肿瘤细胞表面靶向的极佳选择。除了海湾战争期间接种疫苗的美国军事人员外，大多数人缺乏预先存在的抗体。由于未来可能发生更多恐怖袭击，这种情况可能会改变，但目前很少有患者会有针对炭疽蛋白的抗体。用于结合、转运和细胞杀伤作用的单独亚基便于进行基因工程，以实现肿瘤特异性细胞杀伤。这些毒素比大多数其他肽毒素更有效，可能会产生高效的靶向分子。本文将综述炭疽毒素的结构功能、重新靶向炭疽毒素的初步实验以及新型配体 - 炭疽治疗药物的潜在设计。
