Shekre {jomohon A@IACUA CARCINOGENESI 0954) Ki-ras Mutations in 4 (Methylnitrosamino)-1-(3-pyridyl) 1-butanone-Initiated and Butylated Hydroxytoluene - Promoted Lung Tumors in A/J Mice Matzinger William Castonguay' Ming You Sede Gunnino Jnd Andn of Pathology (SAM, WTG, MY} Medral Calicge 0f Ohio, CemuntEi Etolgy Toredo Onio; Jnc Laboraton Cncer {Jvul Uniersity Queber City. Cirnoceienticn (ACSnoo Fla Quedrr Cunjca hydrorytoluene (BHT) cn lung effects promotionza nutelaied tumorigenesis induced Dy (methy nitrosaminok-1-(3-Pyridyll Ebutanone (NNK) was evaluated two-stage lung tumori- model genesis Mice were treated separate expcriments with 1.54 mmolkg the Amouse mgmouse NNK, #hich induced of 8,4 the experiments Animals fed diet that Jod Jverjqc Tumargmousc g/kg BHT atter experiments cantancd daminisuration otIhe carcinoaen Tnee demonsuraicc the tuma multiplicity by 63% and 43%0 . Multiplicity tumors was not effected by Inorease tarestomacr dificrences morphology Jung effect of tumoI LCn esuit Dramotino BHT Mutations the Ki-ras oncogene from induced by NNK (19 tumors) by NNK plus diet Tumots containing BFT (34 [um On charaderized nolymefase chui single-stranj Tct reaction coanmationa NNK-ind jced polymoronism and Gunect prcmoted with BHT ontaincd scquencino lumor Ki-fos genes with Valcc GC_AT Only 34 NNK-induced and cransuion: Inc sccono codan BHT promoted tumors '329} had These data suggest tha the NNK- (7ty (nufucicristic Ki-ras aiteration initiated mouse which specific mutation the Ki-ras iuno rumonidencsis pathxay involve promoted by BHT oncoqene alterec piedominanty non-ras Mechanism wher These Kuman Ine &iet 1934 Wiley Lu; gastric tumors; 0-methylguanine Key words: lobacco Clard cells, Type pncumocyil INTRODUCTION [12] Many locds in tre North Ameri- velopreni cancei coniain (r Jnuioxdan: butylated nydrorytolu- envitonmental Iaciors associaled Trmportont (BHT) Tnis anticxidanl preve nis oxygen-induced lpid sroking ceve opmen: numan canceis inclujelaraco deterioratn arid &iet |1/. Tobarco smoking Jaly cnain teiminatct Iree radi- cabkhed Ms Fherefore; BHT is used by the foxd proress: forlung cancer 2]as tobacco srroke toniains more Bacons Taclor rantidity inousn presenatie Dlevent than 40CD compcunds; which 43 have ceen snawn averace US wbcratory Lfmalled thai Cuem 4. The most Inauke a-imak Lontumes Wmtan 1-2 mg BxTJ [131, This compounc has brenknoxn carcinogenic agent conia ned nc'cot ciqareile goke 30 yr 414] Amethylnitrosamino)- | (3 pyridyl)-1 - Ce [CLIC Jabamian animaks Ihe nitrosamine Tn-F BHT has also bccn $rown t0 promate lung tumors in mice butancne (NNK}, which has iLMan-Jble >ecmiciy tcr 0 4-16]; hoxever laboratory animals mecnanksm acion UnnoY/n and has been Sug Iosues Tre study aumua presenics ncic "Js gested Imipotani elic _2icai lacior 106760 velod [wo-stage model TUUS lumorioenesu carcer /61. Smcae-icljici Jumjt Iciuinmy ald Using NNK, aruitonmanis imponani un caicing Knkh cul u-tndioxation an (esuils clfects NNK carcino of meinylated DNA acducts dumine tha 9ln; 7] Lung tumOrs FOMMainn investigate possible differences by NNK gFntix Nl Mice primarily have Ki-ras nauced Sdim transitions} onrocene ariialion mutations (GC_AT mousE Wmmors Incuced sccond lung NNK anc codon 12. althcugr SCEl Trom Indiced NNK Uclamnons Muanioos Aljo cled ound promotec codon 61 mth NYK (8, Tne specitic Ocse 1 12 have GC_ Ihe serond Dase Hantlcns codon Le the Jeen (enorie relult mcin qujnicg od- iormation [10}. addition inJutinu lumnois Wanentcgand Coccia(11] NNK vassrown Dy Ine Iund {orrcsponjing {ud891 JAnn + Laoutaton Cancer onoyce Tumoc In loreslornach Ine WJMCue Cimcoros76Or ~ahooloi Fnarmacy. LavalUruveTyiQuezec Cuy, Uurzer, Curwcy; Gik {P4 aose ievci mcurouse Jdminitered ntracasinica #Dorcvijtion; Bes des lobacco Jnd obacco smoke Dueianm pydidryiclyene some ccnonn Gnis [ne" nlrozm 101-142 Pnn l-:-Dulanait, PCR ponmcurhan ine numjn die: are established risk factors Iorthe 02. TcOio SSCP Mnac mcd contorm- Pohtnomhin IS4MyWcs
Shekre {jomohon A@IACUA CARCINOGENESI 0954) Ki-ras Mutations in 4 (Methylnitrosamino)-1-(3-pyridyl) 1-butanone-Initiated and Butylated Hydroxytoluene - Promoted Lung Tumors in A/J Mice Sede Matzinger William Gunnino Ming You Jnd Andn Castonguay' CemuntEi of Pathology (SAM, WTG, MY} Medral Calicge 0f Ohio, Toredo Onio; Jnc Laboraton Cncer Etolgy Cirnoceienticn (ACSnoo Fla {Jvul Uniersity Queber City. Quedrr Cunjca promotionza effects nutelaied hydrorytoluene (BHT) cn lung tumorigenesis induced Dy (methy nitrosaminok-1-(3-Pyridyll Ebutanone (NNK) was evaluated two-stage model lung tumori- genesis the Amouse Mice were treated separate expcriments with 1.54 mmolkg mgmouse NNK, #hich induced Jverjqc of 8,4 Jod Tumargmousc the experiments Animals fed diet that cantancd g/kg BHT atter daminisuration otIhe carcinoaen Tnee experiments demonsuraicc Inorease the tuma multiplicity by 63% and 43%0 . Multiplicity tarestomacr tumors was not effected by dificrences Jung tumoI morphology LCn esuit Dramotino effect of BHT Mutations the Ki-ras oncogene from Tumots induced by NNK (19 tumors) by NNK plus diet containing BFT (34 [um On Tct charaderized nolymefase chui reaction single-stranj coanmationa polymoronism and Gunect scquencino NNK-ind jced lumor prcmoted with BHT ontaincd Valcc Ki-fos genes with GC_AT cransuion: Inc sccono codan Only 34 NNK-induced and BHT promoted tumors '329} had (7ty (nufucicristic Ki-ras aiteration These data suggest tha the NNK- initiated mouse iuno rumonidencsis pathxay which involve specific mutation the Ki-ras oncoqene alterec piedominanty non-ras Mechanism wher These Kuman promoted by BHT Ine &iet 1934 Wiley Lu; Key words: lobacco gastric tumors; 0-methylguanine Clard cells, Type pncumocyil INTRODUCTION velopreni cancei [12] Many locds in tre North Ameri- coniain (r Jnuioxdan: butylated nydrorytolu- (BHT) Tnis anticxidanl preve nis oxygen-induced lpid deterioratn Jaly cnain teiminatct Iree radi- Bacons Fherefore; BHT is used by the foxd proress: inousn presenatie Dlevent rantidity Lfmalled thai averace US Cuem Lontumes 1-2 mg BxTJ [131, This compounc has brenknoxn Ce [CLIC Jabamian animaks Tn-F 30 yr 414] BHT has also bccn $rown t0 promate lung tumors in mice 0 4-16]; hoxever mecnanksm acion UnnoY/n aumua Tre study presenics ncic "Js velod [wo-stage model TUUS lumorioenesu Using NNK, aruitonmanis imponani un caicing 9ln; dumine tha clfects NNK carcino gFntix investigate possible differences onrocene ariialion mousE Wmmors Incuced SCEl NNK anc Trom lung Uclamnons Indiced NNK promotec 1 {orrcsponjing JAnn + Laoutaton Cancer {ud891 Cimcoros76Or ~ahooloi Fnarmacy. LavalUruveTyiQuezec Cuy, Uurzer, Curwcy; Gik {P4 #Dorcvijtion; Dueianm pydidryiclyene [ne" nlrozm 101-142 Pnn l-:-Dulanait, PCR ponmcurhan TcOio SSCP Mnac mcd contorm- Pohtnomhin Trmportont envitonmental Iaciors associaled ceve opmen: numan canceis inclujelaraco sroking arid &iet |1/. Tobarco smoking cabkhed Ms Taclor forlung cancer 2]as tobacco srroke toniains more than 40CD compcunds; which 43 have ceen snawn Inauke Wmtan wbcratory a-imak 4. The most nc'cot carcinogenic agent conia ned ciqareile goke Ihe nitrosamine Amethylnitrosamino)- | (3 pyridyl)-1 - butancne (NNK}, which has iLMan-Jble >ecmiciy tcr Iosues laboratory animals and has been Sug gested Imipotani elic _2icai lacior 106760 Smcae-icljici Jumjt carcer /61. Iciuinmy ald Knkh cul u-tndioxation an (esuils FOMMainn of meinylated DNA acducts 7] Lung tumOrs nauced by NNK Sdim Nl Mice primarily have Ki-ras mutations (GC_AT transitions} sccond codon 12. althcugr Muanioos Aljo cled ound codon 61 mth Ocse NYK (8, Tne specitic GC_ Hantlcns Ihe serond Dase codon 12 have Jeen (enorie Le the relult mcin qujnicg od- iormation [10}. addition inJutinu lumnois Ine Iund NNK vassrown Dy Wanentcgand Coccia(11] onoyce Tumoc In loreslornach Ine WJMCue aose ievci mcurouse Jdminitered ntracasinica Bes des lobacco Jnd obacco smoke some ccnonn Gnis ine numjn die: are established risk factors Iorthe 02. IS4MyWcs