| Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER2/neu-overexpressing breast tumor xenografts. | |
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MedLine Citation:
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PMID: 21138857 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: We have shown that incomplete blockade of the human epidermal growth factor (HER) pathway is a mechanism of resistance to treatment with trastuzumab (T) in HER2-overexpressing tumor xenografts. We now investigate whether the addition of lapatinib (L), a dual HER1/2 kinase inhibitor, to T results in more potent inhibition of the pathway and therefore inhibition of tumor growth, and whether reduced dose and intermittent treatment with the combination is equally effective. EXPERIMENTAL DESIGN: Nude mice bearing HER2-overexpressing MCF7/HER2-18 or BT-474 xenograft tumors were treated with L and T, alone or in various combinations with other HER inhibitors. L + T for short duration (14 and 42 days), intermittent administration (14 days on/off), and reduced dosing (half dose) was also investigated. Inhibition of tumor growth, downstream signaling, proliferation, and induction of apoptosis were assessed. All statistical tests were two-sided. RESULTS: L + T was the most effective regimen in both MCF7/HER2-18 and BT-474 xenografts with complete regression (CR) of tumor observed in all mice. Intermittent and reduced dose treatment (½ dose) resulted in high rates of CR and low rates of tumor recurrence that were comparable to full dose continuous treatment. L + T resulted in significantly reduced downstream signaling and proliferation, and increased apoptosis. CONCLUSIONS: L + T is a potent and effective combination even when given in reduced dose or intermittent schedule potentially resulting in lower toxicity and reduced cost if translated to patients. These findings warrant timely clinical testing. |
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Authors:
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Mothaffar F Rimawi; Lisa S Wiechmann; Yen-Chao Wang; Catherine Huang; Ilenia Migliaccio; Meng-Fen Wu; Carolina Gutierrez; Susan G Hilsenbeck; Grazia Arpino; Suleiman Massarweh; Robin Ward; Robert Soliz; C Kent Osborne; Rachel Schiff |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-12-07 |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: 17 ISSN: 1078-0432 ISO Abbreviation: Clin. Cancer Res. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-03-17 Completed Date: 2011-07-22 Revised Date: 2013-05-08 |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 1351-61 Citation Subset: IM |
Copyright Information:
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©2011 AACR. |
Affiliation:
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Lester and Sue Smith Breast Center, Margaret M and Albert B Alkek Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. rimawi@bcm.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibodies, Monoclonal / pharmacology* Antibodies, Monoclonal, Humanized Antineoplastic Agents / pharmacology Apoptosis Breast Neoplasms / pathology* Cell Line, Tumor Gene Expression Regulation, Neoplastic Genes, erbB-2 / genetics Humans Mice Mice, Nude Neoplasm Transplantation Quinazolines / pharmacology* Receptor, erbB-2 / genetics*, metabolism Treatment Outcome |
| Grant Support | |
ID/Acronym/Agency:
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P01 CA030195/CA/NCI NIH HHS; P01 CA030195-23/CA/NCI NIH HHS; P01 CA30195/CA/NCI NIH HHS; P50 CA058183/CA/NCI NIH HHS; P50 CA058183-08/CA/NCI NIH HHS; P50CA58183/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Antineoplastic Agents; 0/Quinazolines; 0VUA21238F/lapatinib; EC 2.7.10.1/Receptor, erbB-2; P188ANX8CK/trastuzumab |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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