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6 results on '"Stéphane Puyo"'

1. Cardiac Propagation Pattern Mapping With Vector Field for Helping Tachyarrhythmias Diagnosis With Clinical Tridimensional Electro-Anatomical Mapping Tools

Author

Takeshi Kitamura, Josselin Duchateau, Mélèze Hocini, Frederic Sacher, Michel Haïssaguerre, Rémi Dubois, Stéphane Puyo, Corentin Dallet, Ruairidh Martin, Gwladys Ravon, Nicolas Derval, Carole Dumas-Pomier, Caroline H. Roney, Edward J. Vigmond, Laura Bear, IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], CHU Bordeaux [Bordeaux], Institut de Mathématiques de Bordeaux (IMB), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Modélisation et calculs pour l'électrophysiologie cardiaque (CARMEN), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut de Mathématiques de Bordeaux (IMB), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-IHU-LIRYC, and Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-CHU Bordeaux [Bordeaux]

Subjects
Tachycardia, Computer science, medicine.medical_treatment, Conduction velocity, 0206 medical engineering, Biomedical Engineering, 02 engineering and technology, Electrocardiography, Clinical diagnostic tools, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Humans, Computer Simulation, cardiovascular diseases, Medical diagnosis, Tachyarrhythmias, business.industry, Body Surface Potential Mapping, Propagation pattern, Electro-anatomical mapping, Heart, Pattern recognition, Ablation, 020601 biomedical engineering, Cardiac mapping, 3. Good health, Cardiac Imaging Techniques, cardiovascular system, Vector field, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Artificial intelligence, medicine.symptom, business, Vector fields, Algorithms, Intracardiac Catheters
Abstract

International audience; Ventricular (VT) and atrial (AT) tachycardias are some of the most common clinical cardiac arrhythmias. For ablation of tachycardia substrates, two clinical diagnosis methods are used: invasive electroanatomical mapping for an accurate diagnosis using electrograms (EGMs) acquired with intracardiac catheters, and localized on the surface mesh of the studied cavities; and noninvasive electrocardiographic imaging (ECGi) for a global view of the arrhythmia, with EGMs mathematically reconstructed from body surface electrocardiograms using 3-D cardio-thoracic surface meshes obtained from CT-scans. In clinics, VT and AT are diagnosed by studying activation time maps that depict the propagation of the activation wavefront on the cardiac mesh. Nevertheless, slow conduction areas-a well-known proarrhythmic feature for tachycardias-and tachycardia specific propagation patterns are not easily identifiable with these maps. Therefore, local characterization of the activation wavefront propagation can be helpful for improving VT and AT diagnoses. The purpose of this study is to develop a method to locally characterize the activation wavefront propagation for clinical data. For this, a conduction velocity vector field is estimated and analyzed using divergence and curl mathematical operators. The workflow was first validated on a simulated database from computer models, and then applied to a clinical database obtained from ECGi to improve AT diagnosis. The results show the relevancy and the efficacy of the proposed method to guide ablation of tachyarrhythmias.

Published
2019

2. Localized Structural Alterations Underlying a Subset of Unexplained Sudden Cardiac Death

Author

Ruben Coronel, Stéphane Puyo, Michael J. Ackerman, Mélèze Hocini, Grégoire Massoullié, Pierre Jaïs, Louis Labrousse, Masateru Takigawa, Josselin Duchateau, Frederic Sacher, Olivier Piot, Sylvain Ploux, Jean-Jacques Schott, Xavier Pillois, Thomas Pambrun, Nicolas Derval, Estelle Gandjbakhch, Christophe Leclerc, Nicolas Klotz, Rémi Dubois, Edward J. Vigmond, Jean-Sylvain Hermida, Olivier Bernus, Philippe Ritter, Ruairidh Martin, David J. Tester, Arnaud Denis, Philippe Maury, Koonlawee Nademanee, Pierre Bordachar, David Benoist, Corentin Dallet, Michel Haïssaguerre, Richard D. Walton, Jean-Luc Pasquié, Ghassen Cheniti, Solena Le Scouarnec, Mark Potse, Hubert Cochet, IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Université de Bordeaux (UB), CHU Bordeaux [Bordeaux], Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Haut-Lévêque [CHU Bordeaux], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Mayo Clinic, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Toulouse [Toulouse], Bibliothèque interuniversitaire de santé (BIUS), Université Paris Descartes - Paris 5 (UPD5), Institut de Mathématiques de Bordeaux (IMB), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), Modélisation et calculs pour l'électrophysiologie cardiaque (CARMEN), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-CHU Bordeaux [Bordeaux], White Memorial Medical Center, Cardiology, ACS - Heart failure & arrhythmias, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Inria Bordeaux - Sud-Ouest, and MORNET, Dominique

Subjects
Male, Time Factors, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Action Potentials, 030204 cardiovascular system & hematology, Sudden cardiac death, 0302 clinical medicine, Heart Rate, Risk Factors, Cause of Death, 030212 general & internal medicine, Epicardial mapping, Incidence, Cardiac Pacing, Artificial, Progression-Free Survival, 3. Good health, [SDV] Life Sciences [q-bio], ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Cardiology, Female, Catheter ablation, Electrophysiologic Techniques, Cardiac, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, Adolescent, Purkinje Fibers, Young Adult, 03 medical and health sciences, Predictive Value of Tests, Physiology (medical), Internal medicine, medicine, Humans, Ventricular fibrillation, Endocardium, business.industry, Original Articles, medicine.disease, Death, Sudden, Cardiac, business
Abstract

Supplemental Digital Content is available in the text., Background: Sudden cardiac death because of ventricular fibrillation (VF) is commonly unexplained in younger victims. Detailed electrophysiological mapping in such patients has not been reported. Methods: We evaluated 24 patients (29±13 years) who survived idiopathic VF. First, we used multielectrode body surface recordings to identify the drivers maintaining VF. Then, we analyzed electrograms in the driver regions using endocardial and epicardial catheter mapping during sinus rhythm. Established electrogram criteria were used to identify the presence of structural alterations. Results: VF occurred spontaneously in 3 patients and was induced in 16, whereas VF was noninducible in 5. VF mapping demonstrated reentrant and focal activities (87% versus 13%, respectively) in all. The activities were dominant in one ventricle in 9 patients, whereas they had biventricular distribution in others. During sinus rhythm areas of abnormal electrograms were identified in 15/24 patients (62.5%) revealing localized structural alterations: in the right ventricle in 11, the left ventricle in 1, and both in 3. They covered a limited surface (13±6 cm2) representing 5±3% of the total surface and were recorded predominantly on the epicardium. Seventy-six percent of these areas were colocated with VF drivers (P

Published
2018

3. From old alkylating agents to new minor groove binders

Author

Philippe Pourquier, Danièle Montaudon, Stéphane Puyo, Pourquier, Philippe, IHU-LIRYC, CHU Bordeaux [Bordeaux]-Université Bordeaux Segalen - Bordeaux 2, Signalisation et Mecanismes Moleculaires de l'Apoptose, and Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Genetics, Alkylating Agents, O6-methylguanine, Alkylation, business.industry, [SDV]Life Sciences [q-bio], Hematology, DNA, Bioinformatics, Tumor response, [SDV] Life Sciences [q-bio], Oncology, Drug Resistance, Neoplasm, Neoplasms, Medicine, Animals, Humans, business, Antineoplastic Agents, Alkylating, ComputingMilieux_MISCELLANEOUS, Minor groove, Signal Transduction
Abstract

Alkylating agents represent the oldest class of anticancer agents with the approval of mechloretamine by the FDA in 1949. Even though their clinical use is far beyond the use of new targeted therapies, they still occupy a major place in the treatment of specific malignancies, sometimes representing the unique option for the treatment of refractory tumors. Here, we are reviewing the major classes of alkylating agents, with a particular focus on the latest generations of compounds that specifically target the minor groove of the DNA. These naturally occurring derivatives have a unique mechanism of action that explains the recent regain of interest in developing new classes of alkylating agents that could be used in combination with other anticancer drugs to enhance tumor response in the clinic.

Published
2014

4. Gene Expression Signature Predicting High-Grade Prostate Cancer Responses to Oxaliplatin

Author

Stéphane Puyo, Philippe Pourquier, Audrey Kauffmann, Nadine Houede, Pierre Richaud, Jacques Robert, IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Bioénergie et Microalgues (EBM), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Aimé Cotton (LAC), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-École normale supérieure - Cachan (ENS Cachan), Signalisation et Mecanismes Moleculaires de l'Apoptose, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Environnement, Bioénergie, Microalgues et Plantes (EBMP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), and Pourquier, Philippe

Subjects
Male, Organoplatinum Compounds, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Bioinformatics, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, DU145, Prostate, Cell Line, Tumor, LNCaP, medicine, Humans, Gene silencing, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, Cisplatin, 0303 health sciences, business.industry, Prostatic Neoplasms, Cancer, medicine.disease, 3. Good health, Oxaliplatin, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, Neoplasm Grading, Transcriptome, business, medicine.drug
Abstract

Prostate cancer is one of the leading causes of cancer-related deaths among men. Several prognostic factors allow differentiation of low-grade tumors from high-grade tumors with high metastatic potential. High-grade tumors are currently treated with hormone therapy, to which taxanes are added when the tumors become resistant to castration. Clinical trials with other anticancer agents did not take into account the genetic backgrounds of the tumors, and most trials demonstrated low response rates. Here we used an in silico approach to screen for drug candidates that might be used as alternatives to taxanes, on the basis of a published expression signature involving 86 genes that could distinguish high-grade and low-grade tumors (Proc Natl Acad Sci USA 103:10991-10996, 2006). We explored the National Cancer Institute databases, which include data on the gene expression profiles of 60 human tumor cell lines and the in vitro sensitivities of the cell lines to anticancer drugs, and we identified several genes in the signature for which expression levels were correlated with chemosensitivity. As an example of the validation of this in silico approach, we identified a set of six genes for which expression levels could predict cell sensitivity to oxaliplatin but not cisplatin. This signature was validated in vitro through silencing of the genes in DU145, LNCaP, and C4-2B prostate cancer cells, which was accompanied by changes in oxaliplatin but not cisplatin cytotoxicity. These results demonstrate the relevance of our approach for the identification of both alternative treatments for high-grade prostate cancers and new biomarkers to predict clinical tumor responses.

Published
2012

5. The Polyphenolic Ellagitannin Vescalagin Acts As a Preferential Catalytic Inhibitor of the α Isoform of Human DNA Topoisomerase II

Author

Rémi Jacquet, Céline Auzanneau, Danièle Montaudon, Francesca De Giorgi, Denis Deffieux, Philippe Pourquier, Stéphane Puyo, Laurent Pouységu, Assia Elkaoukabi-Chaibi, Stéphane Quideau, François Ichas, Pourquier, Philippe, Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1 (UB)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Plateforme de génétique moléculaire des cancers d'Aquitaine, UNICANCER-UNICANCER, Signalisation et Mecanismes Moleculaires de l'Apoptose, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC)

Subjects
Gene isoform, [SDV]Life Sciences [q-bio], Down-Regulation, Antineoplastic Agents, Biology, 01 natural sciences, Catalysis, 03 medical and health sciences, chemistry.chemical_compound, Epipodophyllotoxin, Antigens, Neoplasm, medicine, Tumor Cells, Cultured, Humans, Protein Isoforms, Doxorubicin, DNA Breaks, Double-Stranded, Cytotoxicity, Poly-ADP-Ribose Binding Proteins, Etoposide, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, Pharmacology, chemistry.chemical_classification, 0303 health sciences, 010405 organic chemistry, Topoisomerase, DNA, Kinetoplast, Hydrolyzable Tannins, 3. Good health, 0104 chemical sciences, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], Enzyme, DNA Topoisomerases, Type II, chemistry, Biochemistry, biology.protein, Molecular Medicine, Oxidation-Reduction, DNA, medicine.drug
Abstract

Polyphenolic ellagitannins are natural compounds that are often associated with the therapeutic activity of plant extracts used in traditional medicine. They display cancer-preventing activity in animal models by a mechanism that remains unclear. Potential targets have been proposed, including DNA topoisomerases II (Top2). Top2α and Top2β, the two isoforms of the human Top2, play a crucial role in the regulation of replication, transcription, and chromosome segregation. They are the target of anticancer agents used in the clinic such as anthracyclines (e.g., doxorubicin) or the epipodophyllotoxin etoposide. It was recently shown that the antitumor activity of etoposide was due primarily to the inhibition of Top2α, whereas inhibition of Top2β was responsible for the development of secondary malignancies, pointing to the need for more selective Top2α inhibitors. Here, we show that the polyphenolic ellagitannin vescalagin preferentially inhibits the decatenation activity of Top2α in vitro, by a redox-independent mechanism. In CEM cells, we also show that transient small interfering RNA-mediated down-regulation of Top2α but not of Top2β conferred a resistance to vescalagin, indicating that the α isoform is a preferential target. We further confirmed that Top2α inhibition was due to a catalytic inhibition of the enzyme because it did not induce DNA double-strand breaks in CEM-treated cells but prevented the formation of Top2α- rather than Top2β-DNA covalent complexes induced by etoposide. To our knowledge, vescalagin is the first example of a catalytic inhibitor for which cytotoxicity is due, at least in part, to the preferential inhibition of Top2α.

Published
2012

6. Impact of EGFR gene polymorphisms on anticancer drug cytotoxicity in vitro

Author

Stéphane Puyo, Jacques Robert, and Valérie Le Morvan

Subjects
Pharmacology, Cell Survival, Single-nucleotide polymorphism, Antineoplastic Agents, General Medicine, Biology, In Vitro Techniques, medicine.disease_cause, Molecular biology, Polymorphism, Single Nucleotide, ErbB Receptors, Exon, Drug Resistance, Neoplasm, Cell Line, Tumor, Genetics, biology.protein, medicine, Molecular Medicine, Humans, Epidermal growth factor receptor, Allele, Carcinogenesis, Tyrosine kinase, Allele frequency, Gene
Abstract

Background and objective: The epidermal growth factor receptor (EGFR) plays a major role in cell proliferation of epithelial tissues, and its alterations frequently contribute to oncogenesis. Several common polymorphisms of the EGFR gene have been described, at the level of both coding and regulatory sequences. Some of these polymorphisms are associated with alterations of EGFR expression and/or activity and may have an impact on the activity of anticancer agents. This study aims to analyze the relationships between specific EGFR functional polymorphisms and anticancer drug activity. Method: We investigated, in the panel of 60 human tumor cell lines established by the National Cancer Institute (NCI-60), whether the EGFR polymorphisms −216G>T, −191C>A, Arg521Lys (R521K), Val592Ala (V592A), and Cys624Phe (C624F), and the intron 1 (CA)n repeat were associated with EGFR gene expression and the in vitro cytotoxicity of anticancer agents using data extracted from the NCI database. We also looked for mutations of exons 18–21, known to enhance the activity of tyrosine kinase inhibitors, and the deletion of exons 2–7, associated to the oncogenesis of glioblastomas. Results: In the NCI-60 cell lines, only two mutations were observed, both in exon 19, in a leukemia and melanoma cell line. These mutations have not been described previously in clinical samples and their functional role is uncertain. The allele frequencies of the −216G>T, −191C>A, and R521K single nucleotide polymorphisms (SNPs) in the NCI-60 panel were 33%, 8.5%, and 27%, respectively; the V592A and C624F SNPs were not found in any NCI-60 cell line. The intron 1 CA repeat was highly variable in the cell lines; 32 cell lines having a total number of repeats below 35, and 27 having a total number of repeats above 35. The heterozygous and variant homozygous cell lines for the -216G>T SNP presented a significantly higher expression of the EGFR gene than the homozygous wild-type lines. In contrast, there was no association between the −191C>A or R521K SNPs and EGFR gene expression. No association could be detected between the number of CA repeats in intron 1 and the expression of EGFR. The cell lines having at least one variant T allele at the −216G>T SNP were more sensitive to erlotinib and less sensitive to geldanamycin, topoisomerase I and II inhibitors, and alkylating agents than those without a variant allele. No relationship was detected between anticancer drug sensitivity and the −191C>A SNP. The R521K SNP was associated to lower sensitivity to alkylating agents. The number of CA repeats was associated with significant differences in anticancer drug activity: a high total number of CA repeats (>35 per diploid genome) was associated to increased sensitivity to alkylating agents and topoisomerase I and II inhibitors. Discussion: We provide evidence in this work that EGFR polymorphisms are associated with significant differences in the in vitro cytotoxicity of several types of DNA-interfering agents. Studies attempting a clinical validation of these clues are warranted.

Published
2008

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