Document Detail


In vitro and in vivo effects of combination of Trastuzumab (Herceptin) and Tamoxifen in breast cancer.
MedLine Citation:
PMID:  16155796     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Extensive interactions between estrogen receptor alpha (ERalpha) and HER2 signaling pathways have been described. Using BT-474 human breast cancer cells, we have previously shown that the combination of tamoxifen (TAM) and Herceptin results in strong synergistic growth inhibition, enhancement of G(0)-G(1) cell cycle accumulation, inhibition of HER2 activity and a cytostatic effect without cell death. To further examine the underlying mechanism of synergy, we investigated the effect of this drug combination on ERalpha function and growth factor downstream signaling. TAM caused a small increase in ERalpha levels while Herceptin had no effect, and both drugs caused an increase in the level of Ser118-phosphorylated ERalpha. However, both TAM and Herceptin individually inhibited ERalpha transcriptional activity, although the combination did not have a greater effect than either single agent. Herceptin inhibited MAPK and Akt activity, while TAM had no effect on these either as a single agent or when added to Herceptin. Using a BALB/c athymic BT-474 in vivo xenograft model, the drug combination (Herceptin 0.3 mg/kg i.p. twice weekly, TAM 1.0 mg/mouse i.p. three times per week) showed a greater inhibition of tumor growth compared to either single agent. Tumor extracts and fixed sections were examined at the end of the treatment period for treatment-specific alterations: we noted a paradoxical proliferation-inducing effect of TAM that was reversed by the addition of Herceptin. Our results indicate that combined targeting of both peptide growth factor receptors and ERalpha represents a promising breast cancer treatment strategy.
Authors:
Chun-Xia Wang; Debbie C Koay; Andrea Edwards; Zhao Lu; Gil Mor; Idris T Ocal; Michael P Digiovanna
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Publication Detail:
Type:  Evaluation Studies; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Breast cancer research and treatment     Volume:  92     ISSN:  0167-6806     ISO Abbreviation:  Breast Cancer Res. Treat.     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-09-12     Completed Date:  2006-01-27     Revised Date:  2013-05-08    
Medline Journal Info:
Nlm Unique ID:  8111104     Medline TA:  Breast Cancer Res Treat     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  251-63     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine (Section of Medical Oncology), Yale University School of Medicine, 333 Cedar Street, Room NSB288, 06510, New Haven, CT 06510, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies, Monoclonal / administration & dosage,  pharmacology
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Breast Neoplasms / drug therapy*,  pathology
Cell Line, Tumor
Drug Synergism
Estrogen Receptor alpha / drug effects*
Female
Humans
Mice
Mice, Nude
Phosphorylation / drug effects
Receptor, erbB-2 / drug effects*
Signal Transduction / drug effects
Tamoxifen / administration & dosage,  pharmacology
Xenograft Model Antitumor Assays
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Estrogen Receptor alpha; 10540-29-1/Tamoxifen; EC 2.7.10.1/Receptor, erbB-2; P188ANX8CK/trastuzumab

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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