Type

Journal Article

Authors

R O'Connor
M Clynes
L O'Driscoll
F O'Sullivan
A Devery
N O'Donovan
J Crown
D M Collins

Subjects

Pharmacology

Topics
kinase independent gefitinib drug interactions taxoids pharmacology agents dose response relationship drug antagonists inhibitors cell growth docetaxel cell proliferation tyrosine lung neoplasms lung cancer quinazolines erlotinib humans lapatinib metabolism receptor drug effects drug resistance multiple drug therapy cell line tumor protein kinase inhibitors p glycoproteins carcinoma non small cell lung receptor epidermal growth factor adenosine triphosphatases cancer cell lines antineoplastic combined chemotherapy protocols growth inhibitors pharmacokinetics administration dosage

Tyrosine kinase inhibitors potentiate the cytotoxicity of MDR-substrate anticancer agents independent of growth factor receptor status in lung cancer cell lines. (2009)

Abstract To investigate the interactions of Epidermal Growth Factor Receptor (EGFR)-inhibiting tyrosine kinase inhibitors (TKIs) on P-gp-mediated drug resistance, we tested three TKIs, lapatinib, gefitinib and erlotinib in direct ATPase assays and in Non-Small Cell Lung Cancer (NCSLC) cell lines with defined low levels of growth factor receptor expression. The three TKIs potentiated the action of known P-gp substrate cytotoxic drugs at therapeutically-relevant concentrations. However, more detailed analysis revealed that the interaction of lapatinib with P-gp was distinct from that of gefitinib and erlotinib, and was characterised by direct inhibition of the stimulated P-gp ATPase activity. Lapatinib proved the most potent P-gp modulator of the TKIs examined. Drug transport studies in the P-gp-over-expressing A549-Taxol cell line showed that lapatinib and erlotinib are capable of increasing docetaxel accumulation at clinically achievable concentrations. Combination studies with P-gp substrate chemotherapeutic agents, demonstrated that all three TKIs have significant potential to augment cytotoxic activity against P-gp-positive malignancies, however, interestingly, these agents also potentiated the toxicity of epirubicin in non-P-gp resistant parental cells. Our observations suggest that the combination of lapatinib with a taxane or anthracycline warrants clinical investigation in NSCLC to examine if beneficial or detrimental interactions may result.
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Full list of authors on original publication

R O'Connor, M Clynes, L O'Driscoll, F O'Sullivan, A Devery, N O'Donovan, J Crown, D M Collins

Experts in our system

1
Robert O'Connor
Dublin City University
Total Publications: 71
 
2
Martin Clynes
Dublin City University
Total Publications: 209
 
3
Lorraine O'Driscoll
Trinity College Dublin
Total Publications: 152
 
4
Finbarr O'Sullivan
Dublin City University
Total Publications: 21
 
5
Norma O'Donovan
Dublin City University
Total Publications: 52
 
6
John Crown
Dublin City University
 
7
D M Collins
Dublin City University
Total Publications: 16