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Failure of annexin-based apoptosis imaging in the assessment of antiangiogenic therapy effects.doc

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Failure of annexin-based apoptosis imaging in the assessment of antiangiogenic therapy effects

Lederleetal.EJNMMIResearch2011,1:26 /content/1/1/26 ORIGINAL RESEARCH OpenAccess Failureofannexin-basedapoptosisimagingin theassessmentofantiangiogenictherapyeffects WiltrudLederle1*,SusanneArns1,AnneRix1,FelixGremse1,DennisDoleschel1,J?rnSchmaljohann2, FelixMMottaghy2,3,FabianKiessling1andMoritzPalmowski1,2,4 Abstract Background:Molecularapoptosisimagingisfrequentlydiscussedtobeusefulformonitoringcancertherapy.We demonstratethatthesoleassessmentoftherapyeffectsbyapoptosisimagingcanbemisleading,dependingon thetherapyeffectonthetumorvasculature. Methods:ApoptosiswasinvestigatedbydeterminingtheuptakeofAnnexinVivobyopticalimaging(studypartI) andof 99 mTc-6-hydrazinonicotinic[HYNIC]-radiolabeledAnnexinVbygammacounting(studypartII)in subcutaneousepidermoidcarcinomaxenografts(A431)innudemiceafterantiangiogenictreatment(SU11248). Opticalimagingwasperformedbyopticaltomography(3D)and2Dreflectanceimaging(control,n=7;therapy,n =6).Accumulationoftheradioactivetracerwasdeterminedexvivo(control,n=5;therapy,n=6).Tumor vascularizationwasinvestigatedwithanopticalbloodpoolmarker(studypartI)andcontrast-enhancedultrasound (bothstudies).Datawerevalidatedbyimmunohistology. Results:Asignificantlyhigherapoptosisratewasdetectedintreatedtumorsbyimmunohistologicalterminal deoxynucleotidyltransferase-mediateddUTPnickendlabelingstaining(areafraction:control,0.023±0.015%; therapy,0.387±0.105%;P0.001).However,both2DreflectanceimagingusingAnnexinVivo(control,13±15FI/ cm2;therapy,11±7FI/cm2)andgammacountingusing 99 mTc-HYNIC-AnnexinV(tumor-to-muscleratiocontrol, 5.66±1.46;therapy,6.09±1.40)failedinshowinghigheraccumulationintreatedtumors.Opticaltomography evenindicatedhigherprobeaccumulationincontrols(control,81.3±73.7pmol/cm3;therapy,27.5±34.7pmol/ cm3).Vascularizationwasstronglyreducedaftertherapy,demonstratedbycontrast-enhancedultrasound,optical imaging,andimmunohistology. Conclusions:Thefailureofannexin-basedapoptosisassessmentinvivocanbeexplainedbythesignificant breakdownofthevascul