Sensitivity of cancer cells to truncated diphtheria toxin.
Sensitivity of cancer cells to truncated diphtheria toxin.
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DOI：
10.1371/journal.pone.0010498
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发表时间：
2010-05-05
期刊：
影响因子：
3.7
通讯作者：
Waisman DM
中科院分区：
文献类型：
--
作者：
Zhang Y;Schulte W;Pink D;Phipps K;Zijlstra A;Lewis JD;Waisman DM
白喉毒素（DT）已被用作一种有前景的抗癌剂，用于靶向递送细胞毒治疗其他无法治疗的肿瘤。DT是一种非常有效的毒素，单个分子进入细胞就可以致命。通过删除细胞受体结合域，并将剩余的催化部分与选择性结合到癌细胞表面的靶向蛋白结合，DT靶向于癌细胞。人们一直认为，“无受体”DT不能与细胞结合并杀死细胞。在本研究中，我们报道了“无受体”重组DT385实际上对多种癌细胞系具有细胞毒性。通过细胞增殖、细胞染色和细胞凋亡检测DT385的体外细胞毒性。在体内研究中，采用鸡毛囊尿囊膜（CAM）系统评价DT385对血管生成的影响。采用CAM和小鼠模型系统分别评价DT385对HEp3和Lewis肺癌（LLC）肿瘤生长的影响。在18个人类癌细胞系中，15个被DT385影响，IC50范围为0.12-2.8µM。此外，高浓度的DT385不能影响生长受阻的细胞。DT385的细胞毒性是由于抑制蛋白合成和诱导细胞凋亡。在体内，DT385抑制CAM系统血管生成和肿瘤生长，抑制小鼠LLC肿瘤的皮下生长。DT385具有抗血管生成和抗肿瘤活性，具有潜在的治疗潜力。
Diphtheria toxin (DT) has been utilized as a prospective anti-cancer agent for the targeted delivery of cytotoxic therapy to otherwise untreatable neoplasia. DT is an extremely potent toxin for which the entry of a single molecule into a cell can be lethal. DT has been targeted to cancer cells by deleting the cell receptor-binding domain and combining the remaining catalytic portion with targeting proteins that selectively bind to the surface of cancer cells. It has been assumed that “receptorless” DT cannot bind to and kill cells. In the present study, we report that “receptorless” recombinant DT385 is in fact cytotoxic to a variety of cancer cell lines. In vitro cytotoxicity of DT385 was measured by cell proliferation, cell staining and apoptosis assays. For in vivo studies, the chick chorioallantoic membrane (CAM) system was used to evaluate the effect of DT385 on angiogenesis. The CAM and mouse model system was used to evaluate the effect of DT385 on HEp3 and Lewis lung carcinoma (LLC) tumor growth, respectively. Of 18 human cancer cell lines tested, 15 were affected by DT385 with IC50 ranging from 0.12–2.8 µM. Furthermore, high concentrations of DT385 failed to affect growth arrested cells. The cellular toxicity of DT385 was due to the inhibition of protein synthesis and induction of apoptosis. In vivo, DT385 diminished angiogenesis and decreased tumor growth in the CAM system, and inhibited the subcutaneous growth of LLC tumors in mice. DT385 possesses anti-angiogenic and anti-tumor activity and may have potential as a therapeutic agent.
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DOI：
10.1073/pnas.022649699
发表时间：
2002-01-22
影响因子：
11.1
作者：
Li, G;Nelsen, C;Hendrickson, EA
通讯作者：
Hendrickson, EA
影响因子：
--
作者：
COLLIER, RJ
通讯作者：
COLLIER, RJ
影响因子：
11.4
作者：
Black, JH;McCubrey, JA;Frankel, AE
通讯作者：
Frankel, AE
DOI：
10.1073/pnas.83.21.8258
发表时间：
1986-11-01
影响因子：
11.1
作者：
MURPHY, JR;BISHAI, W;NAGLE, S
通讯作者：
NAGLE, S
影响因子：
4.8
作者：
Cherepanov, P;Pluymers, W;Debyser, Z
通讯作者：
Debyser, Z