Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia induced by human lung squamous-cell carcinoma in athymic mice

Autor: John Foley, Ryan M. Gonterman, Davina A. Lewis, R. Laughner, P. F. Koltz, Ramiro E. Toribio, Raymond L. Konger, Thomas J. Rosol, Kiran S. Nadella, Gwendolen Lorch, Jennifer L. Gilmore
Jazyk: angličtina
Rok vydání: 2007
Předmět:
ZD1839
Cancer Research
medicine.medical_specialty
EGF Family of Proteins
Lung Neoplasms
Receptor
ErbB-3
Receptor
ErbB-2
medicine.medical_treatment
PTHrP
gefitinib
Mice
Nude
Antineoplastic Agents
Biology
Amphiregulin
Mice
Gefitinib
Growth factor receptor
Internal medicine
Cell Line
Tumor
medicine
Animals
Humans
ERBB3
Epidermal growth factor receptor
RNA
Messenger
Autocrine signalling
anilinoquinazolines
Glycoproteins
Mitogen-Activated Protein Kinase Kinases
Parathyroid hormone-related protein
Growth factor
Parathyroid Hormone-Related Protein
hypercalcaemia
Xenograft Model Antitumor Assays
ErbB Receptors
Gene Expression Regulation
Neoplastic
lung cancer
Endocrinology
Oncology
Cancer research
biology.protein
Carcinoma
Squamous Cell
Hypercalcemia
Quinazolines
Intercellular Signaling Peptides and Proteins
Translational Therapeutics
medicine.drug
Signal Transduction
Zdroj: British Journal of Cancer
ISSN: 1532-1827
0007-0920
Popis: The purpose of this study was to evaluate the role of the epidermal growth factor receptor (EGFR) in parathyroid hormone-related protein (PTHrP) expression and humoral hypercalcaemia of malignancy (HHM), using two different human squamous-cell carcinoma (SCC) xenograft models. A randomised controlled study in which nude mice with RWGT2 and HARA xenografts received either placebo or gefitinib 200 mg kg(-1) for 3 days after developing HHM. Effectiveness of therapy was evaluated by measuring plasma calcium and PTHrP, urine cyclic AMP/creatinine ratios, and tumour volumes. The study end point was at 78 h. The lung SCC lines, RWGT2 and HARA, expressed high levels of PTHrP mRNA as well as abundant EGFR protein, but very little erbB2 or erbB3. Both lines expressed high transcript levels for the EGFR ligand, amphiregulin (AREG), as well as, substantially lower levels of transforming growth factor-alpha (TGF-alpha), and heparin binding-epidermal growth factor (HB-EGF) mRNA. Parathyroid hormone-related protein gene expression in both lines was reduced 40-80% after treatment with 1 muM of EGFR tyrosine kinase inhibitor PD153035 and precipitating antibodies to AREG. Gefitinib treatment of hypercalcaemic mice with RWGT2 and HARA xenografts resulted in a significant reduction of plasma total calcium concentrations by 78 h. Autocrine AREG stimulated the EGFR and increased PTHrP gene expression in the RWGT2 and HARA lung SCC lines. Inhibition of the EGFR pathway in two human SCC models of HHM by an anilinoquinazoline demonstrated that the EGFR tyrosine kinase is a potential target for antihypercalcaemic therapy.
Databáze: OpenAIRE
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