different responses of human pancreatic adenocarcinomacell lines to oncolytic newcastle disease virus infection .pdf

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1、CancerGeneTherapy(2014)21,24–30&2014NatureAmerica,Inc.Allrightsreserved0929-1903/14www.nature.com/cgtORIGINALARTICLEDifferentresponsesofhumanpancreaticadenocarcinomacelllinestooncolyticNewcastlediseasevirusinfection11233PRABuijs,CHJvanEijck,LJHofland,RAMFouchierandBGvandenHoogenNewcastlediseasevirus

2、(NDV)isanaturallyoccurringoncolyticviruswithclinicallyprovenefficacyagainstseveralhumantumortypes.SelectivereplicationinandkillingoftumorcellsbyNDVisthoughttooccurbecauseofdifferencesininnateimmuneresponsesbetweennormalandtumorcells.InourefforttodeveloponcolyticvirotherapywithNDVforpatientswithpancr

3、eaticcancer,weevaluatedtheresponsestoNDVinfectionandinterferon(IFN)treatmentof11differentestablishedhumanpancreaticadenocarcinomacelllines(HPACs).HereweshowthatallHPACsweresusceptibletoNDV.However,thisNDVinfectionresultedindifferentreplicationkineticsandcytotoxiceffects.Betterreplicationresultedinm

4、orecytotoxicity.NocorrelationwasobservedbetweendefectsintheIFNpathwaysandNDVreplicationorNDV-inducedcytotoxicity.IFNproductionbyHPACsafterNDVinfectiondifferedsubstantially.PretreatmentofHPACswithIFNresultedindiminishedNDVreplicationanddecreasedthecytotoxiceffectsinmostHPACs.Thesefindingssuggestthatn

5、otallHPACshavefunctionaldefectsintheinnateimmunepathways,possiblyresultinginresistancetooncolyticvirustreatment.ThesedatasupporttherationalefordesigningrecombinantoncolyticNDVswithoptimizedvirulencethatshouldlikelycontainanantagonistoftheIFNpathways.CancerGeneTherapy(2014)21,24–30;doi:10.1038/cgt.2

6、013.78;publishedonline3January2014Keywords:pancreaticadenocarcinoma;oncolyticvirotherapy;Newcastlediseasevirus;innateimmunityINTRODUCTIONsurroundingthetumorcellsuponNDVinfection,besideshavingAnestimated277000newcasesofpancreaticadenocarcinomaantiviraleffects,mightexertanantiproliferativeeffectagain

7、st1humanpancreaticadenocarcinomacelllines(HPACs).14ariseworldwideyearly,and266000patientsdieofthisdisease.RadicalsurgeryistheonlypotentialcurativetreatmentoptiontoSeveralnaturallyoccurringNDVstrainshaveshow