論文 - 詳細
| RRC ID | 59664 |
|---|---|
| 著者 | Yamashita-Kashima Y, Yoshimura Y, Fujimura T, Shu S, Yanagisawa M, Yorozu K, Furugaki K, Higuchi R, Shoda J, Harada N. |
| タイトル | Molecular targeting of HER2-overexpressing biliary tract cancer cells with trastuzumab emtansine, an antibody-cytotoxic drug conjugate. |
| ジャーナル | Cancer Chemother Pharmacol |
| Abstract |
PURPOSE:Trastuzumab emtansine (T-DM1) provides clinical benefit in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2). However, its efficacy against biliary tract cancers (BTC) has not been evaluated. In this study, the effectiveness of T-DM1 in various BTC cell lines and xenograft models with different levels of HER2 expression was investigated. METHODS:HER2 expression status in xenografts and patient tissue microarrays was assessed by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). Cell-surface HER2 expression levels and cell growth inhibition in response to T-DM1 were examined in 17 BTC cell lines. The antitumor activity of T-DM1 was evaluated in four xenograft mouse models with different levels of HER2 expression. The effects of T-DM1 on HER2 signaling, antibody-dependent cell-mediated cytotoxicity (ADCC), cell cycle, and apoptosis were assessed in vitro. RESULTS:Cell-surface expression of HER2 was observed in both gallbladder carcinoma and cholangiocarcinoma tissues. The anti-proliferative activity of T-DM1 was higher in BTC cell lines and breast cancer cell lines with higher levels of HER2 expression. The HER2 status (IHC score|HER2-to-CEP17 ratio by FISH testing) of each BTC xenograft was 3 +|8.3 for KMCH-1, 2 +|4.7 for Mz-ChA-1, 1 +/0|1.4 for OCUG-1, and 0|1.1 for KKU-100, and T-DM1 showed antitumor activity in proportion to the HER2 status. T-DM1 inhibited HER2 signaling and induced ADCC, mitotic arrest, and apoptosis in KMCH-1 cells. CONCLUSIONS:T-DM1 exhibited preclinical activity in HER2-overexpressing BTC. Further evaluation in clinical studies is warranted. |
| 巻・号 | 83(4) |
| ページ | 659-671 |
| 公開日 | 2019-4-1 |
| DOI | 10.1007/s00280-019-03768-8 |
| PII | 10.1007/s00280-019-03768-8 |
| PMID | 30659304 |
| MeSH | Ado-Trastuzumab Emtansine / administration & dosage* Ado-Trastuzumab Emtansine / pharmacology Animals Antineoplastic Agents, Immunological / administration & dosage* Antineoplastic Agents, Immunological / pharmacology Apoptosis / drug effects Biliary Tract Neoplasms / drug therapy* Biliary Tract Neoplasms / genetics Biliary Tract Neoplasms / pathology Breast Neoplasms / drug therapy Cell Line, Tumor Cell Proliferation / drug effects Cholangiocarcinoma / drug therapy Female Humans In Situ Hybridization, Fluorescence Male Mice Mice, Inbred BALB C Mice, Nude Molecular Targeted Therapy* Receptor, ErbB-2 / genetics* Xenograft Model Antitumor Assays |
| IF | 3.008 |
| 引用数 | 5 |
| リソース情報 | |
| ヒト・動物細胞 | TGBC2TKB(RCB1130) TGBC14TKB(RCB1186) TGBC24TKB(RCB1196) TGBC18TKB(RCB1169) TGBC50TKB(RCB1280) TGBC51TKB(RCB1281) TGBC52TKB(RCB1282) |