Molecular Resistance Fingerprint of Pemetrexed and Platinum in a Long-Term Survivor of Mesothelioma 英文参考文献.docVIP

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Molecular Resistance Fingerprint of Pemetrexed and Platinum in a Long-Term Survivor of Mesothelioma 英文参考文献.doc

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Molecular Resistance Fingerprint of Pemetrexed and Platinum in a Long-Term Survivor of Mesothelioma 英文参考文献

MolecularResistanceFingerprintofPemetrexedand PlatinuminaLong-TermSurvivorofMesothelioma OlufDimitriR?e1,2*,AdamSzulkin3,EndreAnderssen4,ArnarFlatberg1,HelmutSandeck5, ToreAmundsen6,7,StenEvenErlandsen1,KatalinDobra3,SteinHaraldSundstr?m2 1Department of Cancer Research and Molecular Medicine (IKM), Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, 2CancerClinic,LevangerHospital,Nord-Tr?ndelagHealthTrust,Levanger,Norway,3DivisionofPathology,DepartmentofLaboratoryMedicine,KarolinskaInstitutetand University Hospital Huddinge, Stockholm, Sweden, 4Laboratory of Molecular Medical Research, Institute of Clinical Medicine, University of Troms?, Troms?, Norway, 5Department ofPathology andMedicalGenetics,St.OlavsHospital,Trondheim, Norway, 6Department ofThoracicMedicine,St.OlavsHospital,Trondheim,Norway, 7DepartmentofCirculationandMedicalImaging,FacultyofMedicine,NorwegianUniversityofScienceandTechnology,Trondheim,Norway Abstract Background: Pemetrexed, a multi-folate inhibitor combined with a platinum compound is the first-line treatment of malignantmesothelioma,butmediansurvivalisstilloneyear.Intrinsicandacquiredresistancetopemetrexediscommon, but its biological basis is obscure. Here we report for the first time a genome-wide profile of acquired resistance in the tumour from an exceptional case with advanced pleural mesothelioma and almost six years survival after 39 cycles of second-linepemetrexed/carboplatintreatment. MethodologyandPrincipalFindings:Genome-wideanalysiswithIlluminaBeadChipKitof25,000geneswasperformedon mRNAfrompre-treatmentandpost-resistancebiopsiesfromthisindividualaswelloncaseandcontrolsamplesfromour previously published study (in total 17 samples). Cell specific expression of proteins encoded by selected genes were analysedbyimmunohistochemistry.SerialserumlevelsofCA125,CYFRA21-1andSMRPlevelswereexamined.TSprotein, themaintargetofpemetrexedwasoverexpressed.ProteinsandgenesrelatedtoDNAdamageresponse,elonga