Subject(s)
Endometrial Neoplasms , Microsatellite Instability , Antibodies, Monoclonal, Humanized , DNA Mismatch Repair/genetics , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/genetics , Female , Humans , Microsatellite Repeats , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/geneticsABSTRACT
BACKGROUND: Uterine serous carcinomas (USCs) are an aggressive form of uterine cancer that may rely on HER2/neu amplification as a driver of proliferation. The objective of this paper is to assess the sensitivity of USC cell lines with and without HER2/neu gene amplification to afatinib, an irreversible ErbB tyrosine kinase inhibitor, and to test the efficacy of afatinib in the treatment of HER2-amplified USC xenografts. METHODS: Eight of fifteen primary USC cell lines (four with HER2 amplification and four without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signalling and cell cycle distribution were determined by flow cytometry assays. Mice harbouring xenografts of HER2/neu-amplified USC were treated with afatinib by gavage to determine the effect on tumour growth and overall survival. RESULTS: Primary chemotherapy-resistant USC cell lines harbouring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean ± s.e.m. IC50=0.0056 ± 0.0006 µM) and significantly more sensitive than HER2/neu-non-amplified USC cell lines (mean ± s.e.m. IC50=0.563 ± 0.092 µM, P<0.0001). Afatinib exposure resulted in abrogation of cell survival, inhibition of HER2/neu autophosphorylation and S6 transcription factor phosphorylation in HER2/neu overexpressing USC and inhibited the growth of HER2-amplified tumour xenografts improving overall survival (P=0.0017). CONCLUSIONS: Afatinib may be highly effective against HER2/neu-amplified chemotherapy-resistant USC. The investigation of afatinib in patients harbouring HER2/neu-amplified USC is warranted.
Subject(s)
Cystadenocarcinoma, Serous/drug therapy , Endometrial Neoplasms/drug therapy , Quinazolines/pharmacology , Receptor, ErbB-2/metabolism , Uterine Neoplasms/drug therapy , Adult , Afatinib , Aged , Aged, 80 and over , Animals , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cystadenocarcinoma, Serous/metabolism , Cystadenocarcinoma, Serous/pathology , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Female , Humans , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , In Vitro Techniques , Mice , Mice, SCID , Middle Aged , Phosphorylation/drug effects , Receptor, ErbB-2/genetics , Signal Transduction/drug effects , Tumor Cells, Cultured , Uterine Neoplasms/metabolism , Uterine Neoplasms/pathology , Xenograft Model Antitumor AssaysABSTRACT
The peptide (D-Pro4)-beta-casomorphin1-5 is a potent and long acting analgesic. Furthermore it is able to antagonize apomorphine-induced behavioral patterns, which are preferentially used as screening methods to detect dopaminolytic or neuroleptic properties. Because all of these tests do not exclude interaction of drugs with transmission systems other than the dopaminergic, biochemical studies were undertaken to estimate possible influences of the opioid peptide on processes of dopaminergic, serotonergic, and cholinergic transmission systems. In lower concentrations (D-Pro4)-beta-casomorphin1-5 enhances the potassium-stimulated release of acetylcholine from hippocampal slices and the basal overflow of dopamine from striatal slices. In high concentrations an augmentation of the potassium evoked release of dopamine and a reduction of the binding of [3H]spiperone on dopaminergic and serotonergic striatal receptors could be observed. These biochemical findings are discussed with regard to the behavioral patterns induced by this opioid peptide.
