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Superior in vitro and in vivo activity of trastuzumab-emtansine (T-DM1) in comparison to trastuzumab, pertuzumab and their combination in epithelial ovarian carcinoma with high HER2/neu expression.
- Source :
-
Gynecologic oncology [Gynecol Oncol] 2017 Oct; Vol. 147 (1), pp. 145-152. Date of Electronic Publication: 2017 Jul 10. - Publication Year :
- 2017
-
Abstract
- Background: Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. The objective of this study was to compare the anti-tumor activity of HER2/neu-targeting monoclonal antibodies, trastuzumab (T), pertuzumab (P), combination of trastuzumab and pertuzumab (T+P) and trastuzumab-emtansine (T-DM1) in EOC with high HER2/neu expression.<br />Methods: Primary EOC cell lines were established and cell blocks were analyzed for HER2/neu expression. Cytostatic, apoptotic and antibody-dependent cell-mediated cytotoxicity (ADCC) activities of T, P, T+P and T-DM1 were evaluated in vitro. The in vivo antitumor activity was tested in xenograft models with 3+ HER2/neu expression.<br />Results: High (3+) HER2/neu expression was detected in 40% of the primary EOC cell lines. T, P, T+P, and T-DM1 were similarly effective in inducing strong ADCC against primary EOC cell lines expressing 3+ HER2/neu. The combination of T and P was more cytostatic when compared with that of T or P used alone (p<0.0001 and p<0.0001, respectively). T-DM1 induced significantly more apoptosis when compared with T+P (p<0.0001). Finally, T-DM1 was significantly more effective in tumor growth inhibition in vivo in EOC xenografts overexpressing HER2/neu when compared to T alone, P alone and T+P (p=0.04).<br />Conclusion: In vitro and in vivo experiments with 3+ HER2/neu expressing EOC revealed limited anti-tumor activity of T or P. T-DM1 showed superior anti-tumor activity to T and P as single agents and as a combination. Our preclinical data support the design of clinical studies with T-DM1 for the treatment of chemotherapy-resistant EOC overexpressing HER2/neu.<br /> (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Aged
Animals
Antibodies, Monoclonal, Humanized administration & dosage
Antineoplastic Combined Chemotherapy Protocols pharmacology
Carcinoma metabolism
Cell Line, Tumor
Cell Proliferation drug effects
Disease Models, Animal
Drug Combinations
Female
Humans
Maytansine administration & dosage
Maytansine analogs & derivatives
Mice
Mice, SCID
Middle Aged
Ovarian Neoplasms metabolism
Receptor, ErbB-2 metabolism
Trastuzumab administration & dosage
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Carcinoma drug therapy
Ovarian Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1095-6859
- Volume :
- 147
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Gynecologic oncology
- Publication Type :
- Academic Journal
- Accession number :
- 28705408
- Full Text :
- https://doi.org/10.1016/j.ygyno.2017.07.009