Abstract
Chemotherapy drug resistance is a major obstacle in the treatment of cancer. It can result from an increase in levels of cellular drug efflux pumps, such as P-glycoprotein (P-gp). Lapatinib, a growth factor receptor tyrosine kinase inhibitor, is currently in clinical trials for treatment of breast cancer. We examined the impact of co-incubation of chemotherapy drugs in combination with lapatinib in P-gp over-expressing drug resistant cells. Unexpectedly, lapatinib treatment, at clinically relevant concentrations, increased levels of the P-gp drug transporter in a dose- and time-responsive manner. Conversely, exposure to the epidermal growth factor (EGF), an endogenous growth factor receptor ligand, resulted in a decrease in P-gp expression. Despite the lapatinib-induced alteration in P-gp expression, use of accumulation, efflux and toxicity assays demonstrated that the induced alteration in P-gp expression by lapatinib had little direct impact on drug resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
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Adenocarcinoma / drug therapy
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Adenocarcinoma / pathology
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Adenocarcinoma of Lung
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Carcinoma, Squamous Cell / drug therapy
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Carcinoma, Squamous Cell / pathology
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / drug effects
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Epidermal Growth Factor / metabolism
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Lapatinib
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Lung Neoplasms / drug therapy
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Lung Neoplasms / pathology
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Male
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Middle Aged
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / pharmacology*
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Quinazolines / administration & dosage
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Quinazolines / pharmacology*
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Time Factors
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Protein Kinase Inhibitors
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Quinazolines
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Lapatinib
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Epidermal Growth Factor