Selective Killing of Tumors Deficient in Methylthioadenosine Phosphorylase A Novel Strategy 英文参考文献.docVIP

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Selective Killing of Tumors Deficient in Methylthioadenosine Phosphorylase A Novel Strategy 英文参考文献.doc

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SelectiveKillingofTumorsDeficientin MethylthioadenosinePhosphorylase:ANovelStrategy MartinLubin1*,AdamLubin2 1DartmouthMedicalSchool,Hanover,NewHampshire,UnitedStatesofAmerica,2Amtek,Hanover,NewHampshire,UnitedStatesofAmerica Abstract Background: The gene for methylthioadenosine phosphorylase (MTAP) lies on 9p21, close to the gene CDKN2A that encodes the tumor suppressor proteins p16 and p14ARF. MTAP and CDKN2A are homozygously co-deleted, with a frequencyof35to70%,inlungandpancreaticcancer,glioblastoma,osteosarcoma,soft-tissuesarcoma,mesothelioma,and T-cell acute lymphoblastic leukemia. In normal cells, but not in tumor cells lacking MTAP, MTAP cleaves the natural substrate, 59-deoxy-59-methylthioadenosine (MTA), to adenine and 5-methylthioribose-1-phosphate (MTR-1-P), which are thenconvertedtoadeninenucleotidesandmethionine.ThisdistinctdifferencebetweennormalMTAP-positivecellsand tumorMTAP-negativecellsledtoseveralproposalsfortherapy.WeofferanovelstrategyinwhichbothMTAandatoxic adenineanalog,suchas2,6-diaminopurine (DAP),6-methylpurine(MeP),or2-fluoroadenine(F-Ade),areadministered.In MTAP-positivecells,abundantadenine,generatedfromsuppliedMTA,competitivelyblockstheconversionofananalog,by adeninephosphoribosyltransferase(APRT),toitsactivenucleotideform.InMTAP-negativetumorcells,thesuppliedMTA cannotgenerateadenine;henceconversionoftheanalogisnotblocked. PrincipalFindings:Weshowthatthiscombinationtreatment–adenineanalogplusMTA–killsMTAP-negativeA549lung tumorcells,whileMTAP-positivehumanfibroblasts(HF)areprotected.Inco-culturesofthebreasttumorcellline,MCF-7, andHFcells,MCF-7isinhibitedorkilled,whileHFcellsproliferaterobustly.5-fluorouracil(5-FU)and6-thioguanine(6-TG) mayalsobeusedwithourstrategy.ThoughneitheranalogisactivatedbyAPRT,inMTAP-positivecells,adenineproduced fromsuppliedMTAblocksconversionof5-FUand6-TGtotheirtoxicnucleotideformsbycompetingfor5-phosphoribosyl- 1-pyrophosphate (PRPP). The combination of MTA with 5-FU or 6-TG, in the treatment of MTAP-neg