CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers.
CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers.
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DOI：
10.1038/sj.bjc.6604437
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发表时间：
2008-07-08
影响因子：
8.8
通讯作者：
Carter, P. J.
中科院分区：
文献类型：
--
作者：
Smith, L. M.;Nesterova, A.;Ryan, M. C.;Duniho, S.;Jonas, M.;Anderson, M.;Zabinski, R. F.;Sutherland, M. K.;Gerber, H-P;Van Orden, K. L.;Moore, P. A.;Ruben, S. M.;Carter, P. J.
CD 133/CD 133蛋白-1是一种五跨膜糖蛋白，在包括结直肠和胶质母细胞瘤在内的各种实体瘤中过表达。CD 133在胰腺癌、胃癌和肝内胆管癌中高表达，占50%。定量流式细胞术分析显示，一组已建立的肝细胞癌、胰腺癌和胃癌细胞系表达的CD 133水平高于正常上皮细胞或骨髓祖细胞。鼠抗人CD 133抗体（AC 133）与强效细胞毒性药物单甲基澳瑞他汀F（MMAF）结合，在体外有效抑制Hep 3B肝细胞和KATO III胃癌细胞的生长，IC 50值为2-7 ng ml−1。通过半胱天冬酶活化测定，MMAF诱导癌细胞凋亡。抗CD 133-药物偶联物（AC 133-vcMMAF）显示在敏感细胞系中与溶酶体标志物CD 107 a内化和共定位。相反，在耐药细胞系Su.86.86中，缀合物内化并与小窝标记Cav-1共定位。添加氯化铵（一种溶酶体运输和加工的抑制剂）可抑制AC 133-vcMMAF在Hep 3B和KATO III中的细胞毒性作用。抗CD 133-药物缀合物治疗导致SCID小鼠中Hep 3B肿瘤生长的显著延迟。抗CD 133抗体-药物偶联物作为根除CD 133+肿瘤的治疗策略值得进一步评价。
CD133/prominin-1 is a pentaspan transmembrane glycoprotein overexpressed in various solid tumours including colorectal and glioblastomas. CD133 was found here to be highly expressed in ⩾50% of pancreatic, gastric and intrahepatic cholangiocarcinomas. Quantitative flow cytometric analysis showed that a panel of established hepatocellular, pancreatic and gastric cancer cell lines expressed CD133 at levels higher than normal epithelial cells or bone marrow progenitor cells. A murine anti-human CD133 antibody (AC133) conjugated to a potent cytotoxic drug, monomethyl auristatin F (MMAF), effectively inhibited the growth of Hep3B hepatocellular and KATO III gastric cancer cells in vitro with IC50 values of 2–7 ng ml−1. MMAF induced apoptosis in the cancer cells as measured by caspase activation. The anti-CD133-drug conjugate (AC133-vcMMAF) was shown to internalise and colocalised with the lysosomal marker CD107a in the sensitive cell lines. In contrast, in the resistant cell line Su.86.86, the conjugate internalised and colocalised with the caveolae marker, Cav-1. Addition of ammonium chloride, an inhibitor of lysosomal trafficking and processing, suppressed the cytotoxic effect of AC133-vcMMAF in both Hep3B and KATO III. Anti-CD133-drug conjugate treatment resulted in significant delay of Hep3B tumour growth in SCID mice. Anti-CD133 antibody-drug conjugates warrant further evaluation as a therapeutic strategy to eradicate CD133+ tumours.
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影响因子：
4.7
作者：
Doronina, SO;Mendelsohn, BA;Senter, PD
通讯作者：
Senter, PD
影响因子：
4.7
作者：
Dubowchik, GM;Firestone, RA;Trail, PA
通讯作者：
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影响因子：
5.7
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
11.2
作者：
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通讯作者：
Maitland, NJ