In:
Cancer Medicine, Wiley, Vol. 3, No. 5 ( 2014-10), p. 1256-1265
Abstract:
Amplification of c‐erbB2 has been reported in over 30% of uterine serous carcinoma ( USC ) and found to confer poor survival because of high proliferation and increased resistance to therapy. In this study, we evaluated for the first time Trastuzumab emtansine ( T‐DM1 ), a novel antibody–drug conjugate, against multiple epidermal growth factor receptor‐2 ( HER 2)‐positive USC cells in vitro followed by developing a supportive in vivo model. Fifteen primary USC cell lines were assessed by immunohistochemistry ( IHC ) and flow cytometry for HER 2 protein expression. C‐erbB2 gene amplification was evaluated using fluorescent in situ hybridization. Sensitivity to T‐ DM 1 and trastuzumab (T)‐induced antibody‐dependent cell‐mediated cytotoxicity was evaluated in 5‐h chromium release assays. T‐ DM 1 and T cytostatic and apoptotic activities were evaluated using flow‐cytometry‐based proliferation assays. In vivo activity of T‐ DM 1 versus T in USC xenografts in SCID mice was also evaluated. High levels of HER 2 protein overexpression and HER 2 gene amplification were detected in 33% of USC cell lines. T‐ DM 1 was considerably more effective than trastuzumab in inhibiting cell proliferation and in causing apoptosis ( P = 0.004) of USC showing HER 2 overexpression. Importantly, T‐ DM 1 was highly active at reducing tumor formation in vivo in USC xenografts overexpressing HER 2 ( P = 0.04) and mice treated with TDM ‐1 had significantly longer survival when compared to T‐treated mice and control mice ( P ≤ 0.0001). T‐ DM 1 shows promising antitumor effect in HER 2‐positive USC cell lines and USC xenografts and its activity is significantly higher when compared to T. T‐ DM 1 may represent a novel treatment option for HER 2‐positive USC patients with disease refractory to trastuzumab and traditional chemotherapy.
Type of Medium:
Online Resource
ISSN:
2045-7634
,
2045-7634
DOI:
10.1002/cam4.2014.3.issue-5
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
2659751-2