vegf启动子驱动双自杀基因靶向治疗大肠癌的实验研究

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1、ABSTRACTtotumorcellsbyvectorsandexpressedselectivityinthetulllorcells；oncesufficientlevelsofenzymearepresentinthetransducedcells，aprodrugisadministered，thisisthesecondstep，theenzymeconvexnon—cytotoxicprodrugstocytotoxicdrugsSOastokillcancercells．Thusakeycomponentofsuici

2、degenetherapyisthatthesuicidegeneneedstobeexpressedselectivityandefficientlyintumorcellsinordertosparenormaltissuefromdamage．AlthoughpreviousattemptstotargetsuicidegenetherapytoCRCusingthecarcinoembryonicantigen(CEA)promoterhavedemons仃atedspecificity,thishasbeenachieved

3、atthecostof10··to300·-foldlossinactivitycompared谢mstrongbutnonspecificroussarcomavirus(RSV)orcytomegalovirus(CMV)promoters；What’SmoregenetherapyofCRCusingsuicidegenedrivenbyCEApromoterisnotadaptedtotumorswitlllowexpressionlevelofCEA．Recentyearstherapiesthattargettumorbl

4、oodvesselsattractmoreandmorepeople’Sattention．ManystudieshavefoundthatVEGFoverexpressinmanysolidtumorcells，butexpresslittleornotatallinnormalcells．AtthesametimetheexpressionofVEGFislinkedwitllthetumor’smalignance．SoweconstructtheadenoviruscontainingCDglyTKfusiongenedriv

5、enbyVEGFpromoter(AdVEGF-CDglyTK)anditWastransfectedintoCRCcelllineLovo．Agenetherapyvectorhastomeetseveralconditions：1．safety,whichCanbebetterachieved、析tllanonintegrativeveetogasitavoidstheriskforinsertionalmutagenesis；2．abilitytobeeasilyandinexpensivelyproducedatalarge-

6、scaleinthelaboratory；3．stabilityintargetcells，whichisfavoredwithlow-immunogenicvectors；4．highcapacityallowingthepossibilityofintroducingfull—lengthDNAsequencesformostgenes，longfull—lengthcDNAs，endogenouspromotersoradditionalregulatorysequencessuchasenhancersorinsulators

7、，whichcarlprovideatightlyregulatedexpressionofthetherapeuticgene，similartophysiologicconditions．Adenovirusesseemtoaccomplishmostoftheseconditionsastheyarenotintegrative，theyhaveacapacityof36kb，theyCanbe硕士学位论文easilyproducedathightitersinthelaboratoryandCanbedeliveredtoal

8、argemassofcells．That’Swhyweselecttheadenovirusasthevectorsforsuicidegenetherapy．Ourpreviousstudiesfoundthatthe