In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma

Autor: Pei Hui, Emiliano Cocco, Peter E. Schwartz, Marilisa Cargnelutti, Sergio Pecorelli, Marta Bellone, K. ElSahwi, Maysa M. Abu-Khalaf, Francesca Casagrande, Masoud Azodi, Dan-Arin Silasi, Natalia Buza, Alessandro D. Santin, Thomas J. Rutherford, Fattaneh A. Tavassoli, Stefania Bellone
Rok vydání: 2009
Předmět:
Cytotoxicity
Immunologic
Cancer Research
Receptor
ErbB-2
0302 clinical medicine
Trastuzumab
Epidermal growth factor
Medicine
Lymphocytes
skin and connective tissue diseases
Antibody-dependent cell-mediated cytotoxicity
0303 health sciences
medicine.diagnostic_test
Antibodies
Monoclonal
Drug Synergism
uterine serous papillary cancer
Middle Aged
3. Good health
Killer Cells
Natural
Adenocarcinoma
Papillary
Oncology
030220 oncology & carcinogenesis
Uterine Neoplasms
Monoclonal
Adenocarcinoma
Immunohistochemistry
Female
Pertuzumab
Dimerization
Signal Transduction
medicine.drug
endometrial carcinoma
In Vitro Techniques
Antibodies
Monoclonal
Humanized
Flow cytometry
03 medical and health sciences
pertuzumab
Cell Line
Tumor
Humans
neoplasms
Aged
030304 developmental biology
business.industry
Antibody-Dependent Cell Cytotoxicity
Complement System Proteins
medicine.disease
Immunoglobulin G
Immunology
Cancer research
Interleukin-2
Drug Screening Assays
Antitumor
Translational Therapeutics
business
Zdroj: British Journal of Cancer
ISSN: 1532-1827
0007-0920
Popis: Background: Uterine serous papillary adenocarcinoma (USPC) is a rare but highly aggressive variant of endometrial cancer. Pertuzumab is a new humanised monoclonal antibody (mAb) targeting the epidermal growth factor type II receptor (HER2/neu). We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu. Methods: Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time PCR for HER2/neu expression. c-erbB2 gene amplification was evaluated using fluorescent in situ hybridisation (FISH). Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays. Pertuzumab cytostatic activity was evaluated using proliferation-based assays. Results: Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH. The remaining FISH-negative USPCs expressed HER2/neu at 0/1+ levels. In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC. The addition of complement-containing plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs. In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC. Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (P=0.02). Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression. Conclusion: Pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines. Pertuzumab significantly increases tratuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic agent in patients harbouring advanced/recurrent and/or refractory USPC.
Databáze: OpenAIRE
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