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rsrArf srprynr Nahonat (-anrrr tnstoule I rum the Oana-1 a.lrr (anter Inst.lule, New 1 ngland tXaaunets Ilosp.tal, R..gham and Nonmen's llotpujl, and 1lasvard Mrdnal Sth.N.l, U..ston IN(Kf AS11/ R11(/1sAMINf. 1:) tIp1AKC UY CARCINOMA ('t I I.S Ike to1a1 celtular content of Ihe flumescenl tnho(hondriJl-specifrc Jye, rhudammr 121 (KA 121). wai yuamd.td by bulanol ealraclion as a funt/nM u( Irmr of fyM.Wrt and dotr fur a va..ety of ce111.nes Ihese retulls were enmlureJ wrtA ehur.alwrns ma.k by /luorescence maros.npy on dye localnal.un and mNoeMrndrial morphn/•.gy Ihert appeaseJ tu be two categories of cell lypes based on RA 121 upla\e /M.se wh.ch p.n(Irturvr/y pcamula/t the dye, swA as I AAKh ascilel lumur cells, carcmoma Jer.vtd Lnrt MCF 7, ra( a•2, 17, lltl a, and normal Lbwbhsl line (('1. 61, anJ those whn.h aplrar to e0u.l.h.ate w.lA the eelqcellular dye wnA.n I h of i/stubalw.n in Rh 121 (1 yg/wJl with a mm.mal kvel of uplake, swA as the normal tlsilhelial•derived Lnes CV I and MIXK and the Iransformrd frbroblas/ line 64F). WqAie tht f.rsl caleRury. the ahtulute value of uptake per cell torretateJ with the concen/ralwn of Rh 121 In the medium and with IAe period of e.poturt In the dye up /o a point of appafen/ cellular aarutalw.n iht knRth of linse reouned lor apparent saluolwn depended on the cell Ispe In the seconJ casegnry, eQud.b.ation was very early, and IAt total uplaie was a lunoinn of 1he etuaceRalar euncenl.atn.n (of Rh-12) Ihit prul.ably does not repreunl a sasuratn.n tevel of dye canlrM in the non accumulalrng, /ow uplaLe cell lines Iluortscence m.c.nscopy revraled that RA 121 A.raliaation wsf initially m.h.thnndna/ speci/.c fqr all the cell Lnes euminrd. Over Irmt, atteralams in m.hschond..al mnrph.dnay and cyhy+lasmfc lluwnntence was obxrveJ in /he high uptake cell Lnrs hul not in the minimal upule cell lines Incubatan of the high uptahe llel a cell line with the mdochossdual membrane pru.nlial inMfnlor, p Irifluoromelho.yphenylhydraaone, substantially decreased RA1:1 uplatt. lhete ahservahunt may inJrcate a Ilan\/e/mNn.nrtlalfJ characleUslic of earcinoma cell euto.hnnJria It may be possible lo etpluit the rnechamam responsible for Ihe psoilretsive accumulalron of Rh-12) by carcinoma-dt/rvtd cell types for chemolherapeulic approaches /o ceruin types of carcinomas. Nadahavukaren, K K, Nadahavul.aren, ). 1, and CArn, l.. R. Cancrr ResenrcA 43 609)-6099, 1915 OrArr suppofr National ('ancer In)lilule Frem the fyana Farber Cancer Inshtule, Uoslon, and the f><partmenl of PathoH.ty, llarvasd MedKd Scho.d, Uoslon. (1// NIII ICA 11(1N ANI/ OUAN1111(•Al IUN (// A MI S]I N(i1 K R11111Nt1(I I 1(' A("Ils INI)1q 11f //Y M/1 YNtI('1.1 AR AK(1MA11(' /1\I)KOCAKIIUNS - 11%IN(i A(y UN11) 1111MAN ('V 1(X'IIKhMI. hJ30 (71 Nl: (l.e rrtrar,hrrj ha.e .wbtrd (uur o•e.lappma human srmmsic elonrs atsuciated w,r1, rAr p••/swu.lr.. arM.n /1'A//l mJuaeJ turm of cyhKhrnme P IS0 I I I/,r 1..... ..1 /• e•. ... ../.../. .....v.l -h 1•osll ,nJu.b.,n hat been d.~lmrd 8% /~, 1 ~.. / . . . , . .. , • f r . . . .... , „ . , .. ,1 ../ 11 /1 . 111' l.a.r 1. ,ra ,n ~ lroltth with the .,wlmll upuence lying in Ihe center of Ihesr clnnrs 1ran.L.trnn in rnro of I med.yhindanthrrntindwtd mKNA, srkcled with the human P, 410 Remm.k rA.nr, JrlraN a prntrm wilh Are 52000. which rt i111mum.tnec/p11•ILIe by the anlr /nnwse /'. 450) anlilr.dy lht nolaled human •,-IS0 genom.c clunr hyh..dvrt 1.. I nxlhyhhol.nllnrne-in.h.crd mRNA frum rlwrokey l/ver, henranlhracrnr and I n.rlhyl.MJan/lurne/realed human man.may Immnr cells (M/1 y), hut nut to .w.afrole trralyd human cellt. Ilpon treatment woh 1'All Iherr n a pos.Uvr c.nrrl..unn ta•Iwrrn .mluard arylhydrocarl.un Aydruaylate (11avrquolrm hnMeJ mnnu.yRena.rl a.hvay aml /hr an.nunl uf mRNA that Ayhrnh.rs tu U.e iwlaled hu.nin Rrn,.nu. .hmr lur /'r IS/t Ihe avr u( n.KNA, Imluced IN.m human celh and monkey l.ver by PAII, n a..wnd I I 1 tOr haae pairs, which rs the samr as /ht l.rger of Iwn mKNA rodu.rd Ly 1'A// in Ihr inhrrJ sua.n of .nnuse ((•S/U1 /eN) Iheir dala alw shuwed /hal Ihr ...d.ur.1 IsNA tAmt an drlrsl a mRNA sve of ) 1  1(1r h.ne pa.rs la•.n phyluherna/tLlulmm act.vated beneanlMacent /realyd human lynq.hnrytrs Irrn,rh,mrlrr s.'ammmiR rmlw'a1rJ the prestnce nf a 16 fuld varialwsn IhiRhesl /nwrsll in /Ar h-r1t of lymp/nw y/e for 4t0 mKNA conlenN anw.nR tr. .ml.vw/uals tluJlyd 1 1 I Kam, 1, IsrnR, I 11 , and ('M•n. y'-T f'rnnr••un /.w.nnf n/ NurArmrshr 1311A9t93, 1911S (7tM•r supnar No.th (-arnlina Uni/ed Way. Y I rum Ihe Ih•parlmrot nf Pedialries, 17uAe Ilnivrrsily MeJ.cal ('enlrr, I)urh.lm, NI' i tsISPARAI F plll t RFN11AT1(/N IN IIFMUPO/(11C ('UI (1N/1 S I)1 RIVI I) I KUM 11(1MAN PA/RI U PR(Ki1.N/1(7RS ~ 1he researche/s analysed /Ae diffeanliatinn of hemoMsielic colonies JrriveJ hom human paired JauRhser celh. CanJiJale MoRenilne cells were isnlalyd hy use of a micsnmaniputali+m technipue from el/lares of My-RI anlsRtn pnan,ve co/d bhnrl cells N.ne 1o 16 Aours lahv the paired dauAh/er «lls were sepankd with a mia•rnmanq.ulnor and allowed to form enlowits in me/hykellulme medium eun/afn.ng erylArryw.itlm, phylohernaRRlulmin leukocyle-eomlilioned nsedium, anJ platelet IM.o pl...nu Ihr cellular eumpusit.nn of the colonies was delermineJ by ddferenlialina all the cells of the May-(irYnwatdliirmaa-slainrJ Lreparalion. (N a Iu1a1 of 75 eval.uhlt pairs o( culonies, )S comhlyd of 21 types of disparate pairs revealine nonhuauJnRuus l.nraRe eannl.in.s/ums. I o/ly pairs were hMUm•InRow in lineage e.preta.pn Iluwr.er, Ihe paqnnlumt nf Iht individual cell lineages were s.RnificanUy dJ/••rrnl in the mrmlrrs .J wrnr of Ihe honn.k.Rout pairs. Snme pairs reveakd sqnifn•am dd/rrencrs .o rnhmv svr Ihesr oh.ervalmnt arr similar In those rerynleJ fnr mursne p.used proRenanrs and ace conuslenl with /he slr.haslie wwdel of huma stem cell Jil/errn/.,sn.n I rary, A(l . Saaus• I C,( rvrw. (" I and (1ffawa, M Nl.n44N2) y2/ 111, 19115 r)ohrr sr.pp.nt Veterant Adn.ini.tra/inn and Nalu.nal tna.lutet ul Ilrahh I tnm Ihe Veterans Adminitl.alinn Medical ('enler and llut IA•p.ulrnrnl ul MrJ•..J Itnrvrsuty nf S.wlh (-arol.na, ('harlestan, and Ihe 7uho. Ilnps.m Ilu„d,.Ry ( enler, tl.r /uhns Il..plomt (/nmversuly Salnud ul Mrdamr, 11a1t.murr, MC) 11

SIKIt(-ItIR/ (it 111t HAt o.-A(•If)(a Y(Y)PRnT1IN(i1N1 the cumplrte nua/enlnle xqurnce of the rN no acid gIycnprWein Rene hat lern drtrrmmrd hnm an n.dard IamMla reenmAinanl hacterir.pha9r tiuulhern hlot anatsa.c and 1)NA drqornc.na rn,l«sle Ihal Ihere is only one gene per Rrnumr; .1 cnmima ..e rrnm and n Lhalyd w.d,.n a 1•!f10 haar-pa.r ftaRment slarlinR Irom a IAIA lu.c and r.trnd.nR an Ihr (M.Ivadrnvlalinn vRnal AAIAAA Iranscripln.n alarlt 1) haar (airs uparr:m.lrumlhelrkuuuna.d,hel.an.latwtneudnnAl(: the 1A1A M.a 1IA1A.\A) Lrs :A 1va paa1 upahrnm frnm IMi ti1e. The gene contams several µ.lrnl..d Rlu..rorlnmd rea•rp/nr hmA.na sdtt. MNh imide and oultide Iht a1rY:lu.al gene 1un, V('), lat/nr, I M, Vann.ce, I 1,(7.wr.w,4 A andSm.nlhr F A Alnlh.nlnr nnJ f rllYlu. RndnRr II1;) 1611 1619. 19AS 1 rnm the 16•I..ulmrat nf /'Nhnh.RV, $ch.rd of Me.bcinr. I/nivervlv .4 ('at.fmnu. Srn t un. i,... f.LJUunr I nnn.l u.no San 1 r.m, ncn Grnrral 1 Wyn1al, an.l I4pa.l.nrnt n( Mnlra.A.r Ik.uh•Rv- (:rn. utr. h Ina , SGUdh Sin 1 ranrnan IN 11 KM1 1t1A I I Ill Ah11 N I rR()/1 INS IN PARA I IIYR(/11) (:1 ANI)S ANI) 1'AHA I IIYRI11I/ ^1/1 N(IMAS Ihr inlrrmrd.atr f.lamen/ prulrins n( nn.mal• hvperplaalic, and aAennmalnus 'paralhvrn.d RLmM wrrr arn/yrrd rmmunohnlnchem.cally and by imntnnuldulhnR .dh m..n..yn•, d.i anht.wta•t In Iwdh m.rmal and adrn..malmn paralhyronl Rland., we Lnmd leralins w.th mm,1lrcular wr.f.htk of S.'. IS, snd 10 Ir4Klaltuns (N.n R 11, aml 1'1, rralw.lwrly V,mrnl.n pmtr.nm cnuld M nlenld.rd nnly .n saua.al eells, whdr Rhll /dn.lhrv ac.A.: t..utr.n v.a% nnt luund In na.mol paralhynnd Rlandv, nrurnldamenl l..a.l.vny waa arAn .•rdy in nrr.e a.nna In l.ve .d 1% paralhy.uut Rland a.knumaa aomr /rralm- p.nrlr.r eetla ry..rtaed neurafdamenl like immunnreatlrv.ly alan In cyln.lrlrlal rc/ra.ts of nnr a.ltnnma• the 7110 /.1.«l.lt..n nrurufdamrnl pr..lrin was idrnld.rd by tommn.Jdonm~ 1hus, il apPras Ihal tnme parathyrnnl Rlrnd sdrnnma arllt auy scqoae nrur.dd.lmrnl pmlrms and cneprrss cylnkrnlm and nrwnldamrn/ IY/IylYPlulr In a way cnmya.ahk wilh 1ha1 rrp.uled 1n crrla/n neurnrnd1W11nr IYInu1a Mietl.nrn, M,(1ark, K, I rh1o, V- /, Vulanen, 1, and f/um(unn. I ArrArrrt n/ PnrAnlnRr unJ 1 nlvwar.wr MrJ/crnr, 109:9116 919, 1915 from the 1)el.arlmenl of Palhn/nRy, and I aMnlory Mr.licine, Ilahnrmann I lmveraily SchYd o( MedKrnr. I'bilr.Irlyhia, and the IMparlnvnl of PalhuloRy. Itnivrrsify of I/el.mkr. IIAa.n\., I u.laod IIKh:/N /11 I Ah11NIN IN 1111 I X 1 KA/ 1 1 t lll AR MA 11(I X ltl IIIIMAN t1/h111K X1 NfH.HAI I\ IN NIIIH M11 / Mum.clnnal anlAwu6ra rtscl.nR eeclutrvely w.th Iamin.n nf human m1Rm nd a rydycWnll anlJ..nly .rartrnR w.lh both munnr s.u1 human taminm werr uard tu UIImUeUhnl.hhrmnilty ah.A• the ruracrllular malns of fuur human tunmon arnwn as .rn..ll•.fla rn nu.lr mne a lung eaac.nnma an,) a ynik sae car..noms becauae thry pr.wlal ed l el/ sa.... ule,l 1 vnrmn .n rrr..•, snd Iwn hrpal.r rl/ubr s ar. mnmas ../o, h Anl .u./ r. ell a...,...v.l 1„n,nm ...n... 1 he r au. r/l..l.. m..rrn u/ 1hr .rnua..JN ol I i t I the tunR carcinoma and the yolk sac carcinoma contained lamimn of hnlh human an.l mYrlne Mltm. Xenl/Rra(IS nf llver carcrnnma conla/ner/ only Ia/nIn1/1 nf mnYK nl~/n/ IMS shnwt Ihal /he ma/iRnaM celh capabk uf Iamrnin pr.wlucli.m m.u..r cnMr.Luly dua Rlycrq+rnltm lo Ihe taU]cellYlar malrla of Ihe s..IY) /Ymnr formrd by Ihem .n rn.. Dnmtnnor. I N nl 1'ncAnrt ArcAr. R/Crll rurM./oer/49 .ISS.', 191S. OIArr sYpp.nl Nalional Insl'ilutes of Ileallh In.m the Ilahnemann Ilnivrrsity Sahrd nf Medicine and the Wnl.u PAAarklph/a, anJ 1 a 14,113 Cancrr Kesea.ch 1 numtalmn, 1 a 1u11a, CA Irrmldule R1(:111 AI()RY IAf'11)RSSP1l'/ll('1(1R AI)111 I ANI)IMIlR1Y1N1( /i1l)111N (:I NI S M A Y( i( )V I R N 1111 1R I X PK I SSIUN IN I R Y 111K1)I I UA 1 M IA ( I 1 1\ In nrdrr In leal if trnnt-acling reRYlalnry facl.us q.rcifK fur Rlnl.in Renra .d Ih# adull amt tmMynnic alaRn of drvelrytmenl e.i.l m er)throM) cella. Lan..nptu.n.Jlt acl/ve enltNynnK anll adult 6hdtin I{rnet on Ihr same ehrYrm.aomr wrrr h.m,IrneJ 1.1 cell fusion fhum the human Irukrmla cell KSA2 inlo phrmHyp.c.dly ad.dl nHn„r erylhrulrukrm.a cells Realriclum IraRmeni length IMdymrnphltm. nf /Iu K Su.` ( emhcy.mn; 6h.f.m 6enes were used lo esubinh Ihal all Ihrre cupn•. o/ huur..n chn.mnanmt 16 present .n the KS62 cell sho.eA Ihe tame pattern o( hum..n Rlobm krne e.press:on aller lonafer 1o the moux erylh.nkYkelwia cell. AJYK (n1 Ibut nol rnJnl.mn- (() human Rh.bin mRNA .as Ae1elled in aK nine of the imlrprmlrnlly .Ir.ivrd nnmw erylhsukukemia hybrid cells, each of which conuinrd human chn.m.numr 16 Restriatnm endunwikaae slwlies of she KS62 e and (-gh.tun Renti aftrr Irao.frr rnln 11n• rnnux trylhrnkmia cell showed an evidence of rearranRernenls w drletmns Ihal cnu41 eydaim lhis Irnt ol (Rlrtbin {ene ealuesainn. Thex da/s suRResl Ihal rrRulahon u( Rk.bie Retx e.pression in Ihex erylMnkukemia eells inv.dves (rnns a.lin{ reRuhlmy faclms specific for the adu/1 aMl emMyrmK ttage1/1f a/evehqqnenl. AnaRnnu. N r, Ynan, T'. Y, Lim, F., llelda, 1, Wieder, 5, Glaialrr, /) , MsrH, K, Wanll, A,('olberl, I/, and fNrssrrwh. A. 111rrrJ 6S(1) T0S-T12, 1991 . n(Arr surpnl I/niversily of California, S.in /-ranciscn, Ihe Velrrans Adnunnlr..hnn, an.1 the Natumal 11ror1, Luna snd Ill.md lnslilu/e Irom the Ilniversdy of ('alifmnia, San Fraacisco Ilemalnh./ly/(McnlnRy Itn.l 31 Ihr S..n I rancran Velerarn Admmnlra/ion Medic•al ('enter l'11A/lA/'I1/(I/A 11(1N /l/ A I/Nh)11/ KNA IN111A 1/111/11MI I//A 111 Y lll'SI HI AM 1 KI/M III IMAN n1 (il ()111N (i1 NI IN 1'II (! ANI) IN I ll Nrt 1'1/1 YMI KASI 11 1)11 I•/ NI/1 N( 1., 11SC111 11'11 1111'11 V. ANI) N/IH -1 / 1 111 AR IIK"A1111N The authon have «Lntified an ahYM/an/ transcrrpl inil:aled upaura,n /ru.n u., cammical cap site of human nl gIuFrn gene in bone mar.uw cellt an.l m 111] /.rI/, lransfecle.l wah an nl ahfi.n gene conlammR'plasm.d S.m.1ar lu 11,r .o..r.r ..I al„t..n lunscnp/. Ihe uPalrram RNA n prr{ent ahnust t.a/ua.vrly .n Ihr.ytnpl..m nl 11.1 I..o. 14 1 IS

I feclcd (Y7S 7 cr/ts tl is sho sy.lhesired efficientty to rrrrn by RNA pnlymeraar 11 in the nuckar tclrsctl prrparM f'rom a tlela « 11 tint snd sn trylMnlrukrm.a cr1l bne. K 762 RNAt nolaled frnm Ihese cr11 Lne., hnwtver, do nnl comam Ih.s upurram Irsn.cript the puul.vt S' tnd of the ol al..hin uptlurarn RNA n mapped by p..mer tslentinn to base eS, which fn localed is bnwern Itu: CCAAT and /AlA A.nars the syn/hrsis of Ihs RNA .n trtre snd .e trro. and /he clost prorim.ly of its S' rm1 lo Ihr prmmoler of Ihe ot efbb.n grne tuRRest s common mechamtm rrRuliunR d.e trsnxnphunal .mIwlN.n of M.Ih Ihr upllream snd Ihe malor ol Rlohm RNM /lras, 2, Prrrr Slahle, C, Drr.vrawA. A, snd Shen, CK) Nurlr.c ArrJr Rraro•.A 11(t7160S96015, t911S (1rArr .upryrr Naraonsl Im1i1u1es of lleallh, American ('amrr S..a.e/y anA Vrlrrant AdmimtualN.n Mrr.l Re.aw 1 rnm Ihe I)rpulmrlN of rrMlKt. Universny of (lldornh, 1)avis, an.1 Ihe tN•/i..Imrru of Mrd.cine, 1).v.nnn of Ilrmatnh.~y anA (MColngy. Itnivnady nf (..Id.-rn.a, \,in 1 rsnca.... AVIAN I RY111RO111 AS1(SSIS VIRIIS 176 NI/('I 1(111/11 S1Q1IfN(-1l/1 llll IRIYAR Itll nn. (.1 NI AN11 (N /tll 1 IR, AN11 ANAI VC151t1 1111 ( t'11 l11 AR PKll1<11 YPI UI 1/11 VIRA1L rr. S11)Itl NI 1 An inlacl S I kh prnvuus nf Ihe a..an erylMuhlavlnta virut 1,`b hat hern rnnltcularly cloned (nr enmpsrsons wilh a•un myeluhlattnus vuut (AMV) and ulher avian lumor vuusrs f 76 sm/ AMY Iranafo.m hrmury.itlic cellt e.clutivrlY 1h.1), v.1utr mytl..hlaatna.s, bu1 176 altn cautes erythroMasMUa Sequence analyt.s ut the pr.uviral IINA thnwed Iha1 (.) the Iripsr/.lr IramfN.mmg Rrnr cuf 1•`6 furrnt a cN.mKu.nua rea.hnll frame ..f 1046 cminnt, imtuding 717 te[ 721 mrAy, amt 4'+1 .rt c.Nt..na Nu tuhalennmut rrr sprc.f.c mRNA was delecled rn 126 mfeard er11t Ily cnnlraat, the w. Rrne of AMV cuntnls slrm.sl emuely of s mtAa srtturnce t.prsard v.a tohRrnomic mRNA Ihal ra/ends ovrr the Y sml 1• endt of nr.Ap* (u) mtA/• ia nnly ttqthlly diver{ed frnm A.e mrAA h.moloR uf AMV snd eren leat (r..m /hr cellubr pr.no mrA sequence wilh no CharaClrllNtK mut.ltNln Iha/ aett aparl the twn v/ruart Irnm prNlu wrtA (iu) /he IIS retbn ..( Ihe huMg Ielrnlnal rrpral /LIR) of 1 26 and AMV are cubnrar am1 d.ffer only in Kalrerrd poinl mu/alinnf the 117 regios of the 176 1 IR n ddf.•rent (rnm that of AMY hul is colinesr snd closely related with Iha/ of avlan carinnma virut M112 snd atto wi/h 11131 of I'n6ue Rout tsrenma virus (RSV1. t.crpl for an untapecle.l 16 nu(kol.de tub4/1lulion of 22 PSY nurleolNles. I/patrram nf Ihe 1' I 1 K, the r reRiun nf 1 26 appeart to be Ihe sarne at 11,31 of KSV fnr 70 nuc'leothdes an.1 vrry Simdv In Ihnae of AMY and M112 f.u aMwl 20 to 10 nuclenlNles. S.nre Ihe Ifls uf /`6, h111.` snd RSV s.e very clnsely rrlaled snd nei/hrr MI/7 nor RSV shna a par/NUI.u erytlunhlatl /rrM.iam, t is pmsihle Ihal Ihe Itl dNrt nol play a rrnNal rNM m the .,ythrnhaa trnpi+m nf f26 flrclrnphwetK sire snatysrt ol chNlsen ItNA .bRrtlyd wuh rtstrwlN.n enrymea .nd.cstt Iha1 ONA f.asmenls loulbng nver S(7 k1A hyhaNtue avuh ,,irsl rta l)NA Nunn, M, Weiher, 1/ , Rullock, Is , and Aw.Mrlt. P Puo6.R r 1 19 110- 119, 1924 l7rMr .rp(wr National Inslilules of IIea11h. 1 Ilom Ihe (kparlmtnt of Molecular RioMgy and Viru. I.aMualn.y, Ilnivrrsuy nf ('al.fornia, Ikrketey A(")1V A 11 h PRUTO UNC GENt'.S Sill FR'11 N fOR NI l'1 SCAN Y 1(tR 1'AN( l RI PrMo onc {enn srt auwal cellular genet that are relatrd /u the lrantfNrmmR INnrI Renrs of reunviwsn. Reeaute of Ihis rrlalicunhip, the.e genes srt nnw wN/ely hrhevrd lu he pnlen111t cancer Renes In tonx Irmmt, paNn onC (enes are mulaleQ M r.p.rv.rd m.ue than rn normal cr11s. Ilmler thrse d.mtiliunt, Mnlu-onc {rnet a.r hyrN.lhr.vrd rn M active cancrr grnes in one of two pMsibk wsyt. The one Rrne-unc can.e' htlNUhr... IuRRrtH Ih.H nne acliratM prnM-one gene is tuffN'irnl to cauae CJn,er. Ihr mu/1.Rrne uoc canctr hypothts:s tuRgrsN that as aclivatrd proNa unc genr is a nrcot..uv. bul nul a 1u(fn'.rrM. Ciute of cancrr 1lnwevrr, mu/aled or aanacnpl.nndly a:ta..urJ p.utu ..nc Senes are no/ Contialenrly saMCN/M wilh Ihe 1u.nurt in whnh Ihrr 1.r /KCatN.nally f1Wed and do mN 1raMfmm primary cells I u.lhrr, n.a set ..( an acl.v.ur,I p.Nln onc Renr and a com(.kmenlary eancer Rrne wNh Iran.l.nnunR IuuauNn haa t.t hrrn ranlalyd Irom a lumnr Ihln, there it aldl no p..Nd 1h:.t artrv.urd p.nlu t.m- prmt are suflN:.rn1 ur even necessary to csuse cancer. noor,lh rR. i rr Snrmr 228/4700/669-677, 19~5. OrA.v .upp.wt National Imlitulet nf 11ra11h 1 rum the 1)rparlment of Mnkcular liok.6y, (InivretilY ..f l'a/.fnrnia, lur.krlry MUTAGI NfSIS QF AVIAN CARCINAMA VIRIIS Mt12' (1Nt Y(tN1 (11 1 W(1 r(tll NI/AI. IRANSIORMIN(: (irN1:51fRaR•m.r) 1RANSI I7RMS I I11K1q11 AS1Y Avian earCrmqlla virus M112• eonlains Iwo pnlenl.al uan.( a..u.na lJrnrs. ARnR-mM snJ tRwR•myr. lbus. M112 may be s rnmlel for 1wu RrM ca.c.nu Renesit in which Iransfurmatinw deprmh an Iwo tynerbitlic Renea Manl o/hrs durarlr oncnRenic virusn eontain sin{1e, suhuwuwnw IranafMminR (..n.) Renes and a.e nN.d.1. (M tingk genr carcinofitnesia. le deleamint whNh ude each pulent.at ..w. Rene nf /att) plays in nncngenesit, we have preparM v/ek/ion md f.aoashift mutanlt of raah Nf Ihe Iwo M112 Renes by rn atre mWagentsis of el..nrd prusual 11NA snA havr te.lyd IramfMmiog functinn and virw prrduclion in t'u/lurrd primary quad crlta Wr k.•r fnuMl Ihal mM drklirM mulaMt anal wiM lype vuw trand.um pr.mary .ells an.t Ihal mly delelu.n and frameshifl muqnls do m.l Ihe nNnphu4.6irt o( crlla Lan.fwmnl hy the mAr rktrlion mutanl/ sml by wiMl type hlll) are s.nular yrl .a.y aNn.Nln,l.ly Neveahe/rss, fyrKal mu/sn1 trsnd.umral eelh c.m .dlen he d.aUnRu.vhr.1 Irom arll. Inn/fn.nKd by wild tyM M112 We eom'lwte rh.tl Ihe 1R.q nn, srnr r..n.Lem, prrmary crllv by INNf, wNhoul Iht areoml tio•ttnatl .Nw arne Ihn n..o rr1.HrJ nrnr .v /he smatletl Ihat has duee/ Irsntformine IunHN.n ARnRmAr is wuhour dHr,/a1-1. /undMmiq functinn bW may affect UanlfMma/WS hy AR.Ir n.rr thus. Mll' hrh.vrv l.ke a virus wiU s singk om' gene, d1/uwRh it taprrnrt Iwu fN.ltnl.al ..Nr Rrm•a, an.l .1 apptsrs 1604 to Ibe s mm/el fog two gene c,rcultHewesis /urlhrr wn.k .1 nnraa.y u. Mder lo delermine whether /he tene ponibly enhances oncnarnN fun,/n,n of {teir •mm M has independent oncotemc funclNln in an/rllat7 16 I I7

%hou, K P, K an, N, Papas, I, and f)urlMrR, P Pr.vrrJ.nrt n/ the Nmuw.el ArrNLmt, n/ Stlrwrrr of the (rwurJ Amr.Na 12 h109 6111. 1911% Orhrr .Npl..ul Natmnal ('anttr Inslilule Slerrt ol Irnm l/.r 1)rparlmrn/ n/ Molecular IhnlnRy and Ike Virus lalwranry, 11m.rrsiry rf (-al/lnrn,a. 11r,\elry, aml Ihe I ahmalory of Molecular (1ncnl.,Ry. Nahnnal (an,./ Inshlule, I rrdrrN i, Ml/ AKI At'IIVAIII/rKtll/l .wu GINIS('ANIiR GfNf.Ss Ihr pcrfNmdt/anct of \)1 ce11-Irsnsformatinn nep/ivet amnnR the lumn a deacr/lr.l /n /hls paprr suRRrsn /hal rnher nn Rrnet havt ewsed the nrRStlve tu/1Nns ur Iha1 the aavy /adeA In dtlrcl them thal nnly rtrl relaled prnlo .N,. Rrnes have tvrn drlrc/ed /n human lumms uRnals annlher hmilalinn nf the 111 asaay Slnce /1.e p,.•tn r.lt mu/a1Mna fnund by the 111 satay /to n01 lrana(nrm p//mary Cellt, 1/ Is plNt/blr Ihal thes a/r nul rrlevanl fnr Iomnr (orms/u.n Avadabk dala wRRet1 Ihal these a.t c„In,Nlrn/\/ /w tnnarllurnllal mulaluNlt ralhrr. Ihan tanter ClWatlve rnulal/ont IM'Cur11nR in tumul IrIIa, IY(autt Ihr mulalN.M see not conalalendy enrlela/ed wl/h specdlc lumms and hetau.r /n cnnw taart they prece.k lumn, Immal.nn and In olher they evnlve AucinR OrArr tupp.nl t/ S Publlc Ileallh Srrvice and Monsanlo ('orpotation 1 r(4m Ihe 1)rpatmrnl of ralhntoey. Beth Israel I/ospital, Ilarnrd Medi.al ScMN,I and ('harles A 1/ana Research Insllluk, Ileth Israel 1lospilal, /hntun. MI1/ A 1 I()NAI ANAI YSIS tN 111E FI/N('TK)NAI. IX)MAINS 01 1111' AdS I 1.a (:I NI 1'K/ llrl/(~IS 1/1 I('l ING ('l 1.1, IRANSIiIKMA 11(1N In Ihs paper, the data descriMd uainR viruset with aptcific muutiorts In Ihe fNNINIn /.( the pn..me emvrlmR the I la SI ld prWein imply i1 is Ihe vital Rene prndu.l Ih]I /s nhra.ary In mamla/n Ihe recnRnired pa.pHllea uf Ifanafnrrnrd cella 1 hr sun.lilNlnally lelhal, culd arnailive phennlype esprrsaed by Ihe mu/alyd Rennu,r. whethrr inlr,NllNr.1 min / KI I cellt by mfeclinn wt/h vuinnt or by Iranafecuun with Inuc/ Rrnamrs n. plAanlNls, Impllrl Ihat the Ils SI hd prulein inleracls with a hna macrunudeculr nr Il.e / la 44 hd pnlypeplillt lhe eold-trnsilrve phrnuly/r may rrf/rcl  dtcrraaed MndinR a'unalanl al 12' C hetween Iht mutanls' Irunealed p/.nlems and a sldl unNlenll//td hnat and/or vital macrnmokcukt. hkn/ificslnm of Ihe putalive hml cu.nfn,nrnt inv,.lved and Ihe characletialiet of I/le viral prole/n-husl macromoleculr mlelactN,n shoulA rrvral crilical clues to nmkrslamhng the mechamants of vlul /ran.lnrmauun i Rahias, 1. 1,/ r.Arr, P R 21.1 Ginstrq, 11 S lu/nur p.nRresaN•n luryurr /11 tffrclUVrness In Iranstu/m 111 cetls, il would fnllnw that In Trr.n.Jrr nnJ / s r •ss F l mulatrd pluln ro. 1t nnl a dum,n.lnl t,nRu1H c snsrl Rrnr, umda/ In a v1n11 .u1r Rrnr, anA ,.n.,./ P , u atvNrr Grnrs, 247-2A2, 1984 that Illt leat H InsullK/rn1 tn Jrlenn,nr .hrrluv pn.ln .m, Rrnet cauae lu,m..a In l h snunata 1ht e/lN.rnty ,•( t1.e aaaay in ,ArmJy camrr Renrt umrl.,IrA In ( r rr surP.ur 1/ S Public Ilealth Servk~e. p/nln unr Rrnes rrma,n. u. M dr/r/m,n.,l / tons the 1lrpa/tmenl of Micrnbinh,Ry and ('omprehensive Cancer ('rnler, ('n11eRe uf PA l)ur,M-.>; P ll rl uf vut uns A SurRe/uns of (blumbia llaivenity, New Vntl, In Nrlh, (:a11n, Grrsves, lansa (r.la I llarw.nrn/nrr nn.l 11L.nJ 1.nn/Juvnw Vul 29, A(.wlr.n IrrwJt rn llumnw fru(rm,n 1I St.,/nRrl Vr/1aR Ilrl/m Ilrldelhr.R, 1761, pp 9 2/ Othrr lupput Nalinnal Imtdutes of Ileallh I rnm the 14parlment of Mntecular Rinin4y, Ilniverslly of Csldornia, tlerieley, lhe SaIM Inalilulr, tan thrRu, ('A, I sMnatory nf Molecular Oncoh.Ry, Nat.nnal Canaer Inv/lulr, I rt'derirl ('amer Rttearch I acdlly, I rederich, MI), and Genrntech, Inc., South S.sn I tanclacn RI(:I/I.AtI(1N (11 I-XIKAVAS('111.AR ('OA(it1/A11l/N ItY MI('ROVAC(1/1AK PI 1(MI A1111 II Y ftlravascular cnsRulst,nn is a prominenl feslurt o( tuah imputanl pslhuh.RNal ptrKrsset at ce/lnbr mmunlly atul ntnplsva and hat heen IhnuRhl lo resull (rnnm prntnaRulanls sssncratrd w/1h the inflammatory or tunNU erllt peCUIur lo Ihesr, enlitles It was fnuml that incressed microvaseular permeabibty alone is sufficirnl to mduce erWlvsknl tatravascu/ar cna{ulatmn in tevtrd murnal Iitsues lhe retults md.cale t),at saturallnR kveh of prncnaRulanl .re preseM evrn in normal lissuea and Ihal m,crn.asaulac permeabd,ly n s,ate-limil,nR step in earavatcular coaRulatum /1...r.n1 )l I rr ol .,), IM'/ INn, Prgi ('/ll MI/'A1.. VIRAI INI I RA('TI(1NS IN 1RANSI ()RMAl1(IN I NIIANI'I M1 NI ()1 1111MAN Al/l-NUVtRt1S 1 RANSI ORh1A l11)N (11 /'I (lNl t) KA I I MIIKYU I 10'(1)I[I.ASI (CK11 )('f 1.1.5 RY Al.K YLA I IN(i ('AR1 IN( K:1 NY A mainr advance in studying carcinngenesis hat been Ike develupment of well defined cell cullurt syatrms whieh mimie rw eur* eareinuRenesis as r/ occura w r.e... UlilirinR these syatems, sta{es analnRow to indialinn, ptomolilln snd p.uRress,un have 1wn i.knlifred ernl Imp/nlanl insiRha into Ihe mokcular evenls cnvolved m Ihese prncesaes thnuld he forlh:ommR In Ibis review we drsc//tle snmt of ..ur rrcen/ slud/rt using the hiRhly Itansfnrmahk ('RIF cell line 10 inves/iRatr Ihe inlrrac/ems between MMS and Ad1 in re`ulalinR the frequency of viral Itantformalw.n and r.presaiun of the Iranslormed phenotype /hrr hndinRs indicale Iha/ catcinlqpns enhance A,/S Uanalormsli..n, hu/ da mu dler the pa/lotn of viral 11NA inleRralinn intn ce/lular I/NA or the pualllalwt r.prrsaron of the trandnrmrd tta/e A IiAelv hypMhesn is Ih:u crl/aln c'u11m.Rens t.rN lheu enham/nR e/feel on UNA vuut bansfn.rnaUUn t.y inc/raunR the payNnlmn n( cells ,n an .n/e.lyd cullure whkh can tlably mleRrate vual I/N^ an.l Iht/rhy het:omt laamin.mrd In olhrt casrs, caccrnnRrM may tnhance I/NA .uus /ransLnmatnm by allrrmR the raptessimr uf viral an.1/or eellular genes rrqunrd f,u ealabl/aluarnl of the Iram/urnu•d stale. Iluman T-cell kukemia virus, herpet viruses and Ilepati/is It vlrns hivr brrn implicaled in the dtveh/p,nenl of specifie human maliRnancies, hu/ a dllec/ llnl (Ylwern vuases anA the maNuny of human neoplasms has nnt Letn demm"ab.Hrd A IN,.a,blr trason for thls spparenl nrpt/ve correlatnm may be Ihal m/nual hum.n ma1,Rn.uNU-a, putallvr virusrs caust lam-rr v/a tynerRrtUC mlera,lu.nt rl)h In,/.umR Il.rmn.d 19 14 65100 7591

tar. mnment• lumnr prnm.ntert, hormnnrt or olher yet to he drfinrd ...f.u In.a Mrtl .haratlrrvrd crll .ultu.r Syttrmt thuuhl prn•r mtlrnmrnlal .n Au..d.a1mR Ihr r.de ul ro.Jlq.lr fatl.•r inv.a.l...m to Ihe rlnd.•ty of human cancer, aa well at Ienl b- an undrr.lln.Lna nf Ihe I..a.. pnm •plrs undrrlv.nR the prncettet of tunu.r prumunnn and p.u/rraau•n Ilrrm.., 11 , Ir . ll..h..a. I 1, 1.tw, W S, Pmin, I M, Mcll.mald. N/• anJ I..h, r^ A In al.•fn.Jnr lln... ..f (u...r /'n.l A l/nrrn.nrdrrulnr .Cnu.ru.r (.unnnt•r.n nn.l rh....e.nr. Nrw \o./. Al.n N I rat, Ina • 19tS, (qr 499 512 Irn.u /hr IApurmrnl nl hfi.rnh».IoRr. Iance. (-rwlr./Intblatr u( ('anarr Rraru.h, 1 r.tlrKr n1 1'Lsaa.ra.,11s \o.l;r.ma.•1 (.•I.uuhu ItnivenHy, New S•nrA ANAI Y%IC //1 1111 N11111( I It (.11(1W 111 I A('l(IR //) PI Nltl N('Y 111 SIMIAN VIN11\ .111 1NAN`sIt/Nh111) 1111111% IAr ul/nn. ha.r mrawvd in a Je/.neJ tnum frre mediunm the platelet der.vrd Rrn+lh 1..•r.•r 11•IM.11 an.l unul.n rrqunrmrnH nf nnrmal Swns 111 cella, 7lnuan vuut •t11 u.u.f..rmrA 111 ,r11., anJ 1•.nlul rr.r.tantn nf t.mrln vrrua Al0 IrandurmrJ 111 trllt \w... 11 1 tr/la Jnpltrr.) tt.nnR rrqunrmrnla fnt hnh P1K:1 an.l msuhn 1A. h nl Ihr.r u.pn.r.urnh w1•.e ur.m/..antly dmun..lvd in tanuan virua 40 Itantfnrmrd 111 trllt AuJat., nf thr PIM.1 anA mau/.n .r.pu.nn- m% of 1/M reverlanta rndKaled 1ha1 Ihr t.•.a .d r.rl.rr ..1 Ihr.r Iwn p.uwlh (].hn .Nn.n.'mrnlt wat nnl necetaauly 1.nlyd In the ull.rr, r.Nln r Il.e r.nr dh 1..• 1.n rry..n. n.. nl. +r..- q.rrdn a11y aaa.eulyd wtlh ulher pp..mrlr.. d U.rn•Innu.l•..n /hr rr.n.ln...n..n ..1 ~ 1'IK:1 rrquurmenl cn.rRr.Y..lyd w./h rr.nv..n lu d. n.dy d~lrn.kal K.nwlh wl.rrrtt rra. qu.a.Imn nf a nnrmal tn..J.n .r.lau1 m. ul ....ry7.. ~ d..l w•It. .r•. n...u 1.. a n..na d Kn•+Ih drl.rndrn, r nn t JI terum AnA h.n..Kr d. 1• n.l.n• r w..a •h .•.. n/.l.- I....o 1...A 1 p 1.•r rrq.nrru.rnla IAr rrlar...n.h.p lu•I..rrn fl.e 1'IN./ . q..... .... .•l ~n.l .Lr.•dt .L•Ivo.l.•nl 1;•'.••1h .nh.ArUnn o.r• tnrlbrr anJrrrJ rn nuund 1/1..11. 1•a m. •.un.q• tl.r 1'IM./ rrqun'•n.rnl al JJlr.ral .ell .1rn.J.r. AI h.Kh ..11 .Ln..r... 11.r q........ .rnl In. 1'IK.1 h •. .nnr trRndnandy Rrralrr N'r u.ryr.l Ihr1 .1 Ir..al so 1•ur Ihr .d•.Int .d b.malu.mrJ rlla In Rr..w la 6.r.h aalurala.n drnvhrt rr.uh. f.•.m 1hr.. L-a ..1 a rrq.u.rmrnl Inr 1'IN.I Pnwera, S• I r.Arr, P R. and Pnll.tch, N M.Je.ota, and ('rllula. 11ndnRy 4 1S7` 1Vh, W111 (LA.-r .arrrwl 11 t/•a6ta Ite•J/A 4...ar and Nat.nnal Inslilulrs of IIr.J1A. Irnm IAe Isrparlrnrnl ..f Mieruhi.JnRy. ('ancer ('rnlrr/In+ti/u/e ..f l'an:er Krar.raA, <.•Iurnhu I/nwrrvry ('n11rRe uf PAytK.m. ` Su.Rrnna, Nrw 1fu.A I/l 1'Itl Stt Il IN/1 KI 1 Rl1N SYNtlll C1\ IN SKIN I IRR(11/1 ASIS I RI/M 1I/N('/'AN('1R PA111NIS So, rn fihrnhlasl cell cuttutes Mti.•ed frnm mak adult lung caneet patienls, an adull cnnuul M•pulal.nn anA a nrwtrun (u.pulninn• were eaaminrd for the.r susceplihd.ly to Iranalornnr...n ..nh Kualen munne ta.u.ma .inut anti Iherr ahd.ly In ret(u.nd lo an .nlr./rrnn .o•lu.r. /l..lt I Ir.ly / 1 An aaa•nura.n Mlwern traad.•ay to viral 1 Iransformaliun and induction of interferon was ohaerrrd ('uhures drr.ved l.nm luna cancer paUrnls drmnntlraled aw increased tenbtlvily to virua It:.n.la.m.llmn anJ a drerraarJ ahrbly lu reslnrnd to iMerfernn rnJuclurn as comp.ved wqh aRe ma/.1.rJ cunUult and newlw.rns Winlers• A 1- . I.ea: h, M. F, Ihulun, F: I, aml F.nn4rl 1 I/ . /.w.nol n/ lnlr. /r...n Rrsrur. A{ 163 1/0, IOjS. I rnm the /kparlment nf lleahh and RehahdilaUve Sr.vraef• Vrlrr..ns AJmnoal..mnn A1r.lnal ( rnlrr, 1Impa, 11.. 51111)11SUN(:1N/ IKANSIFR ANI/NIVIKUI/N II1tIV Rt\IS1AN11 IN XI Kl l)q NMA 1•IGMI N'1<KItM 1-11 1 S Ihe aulAati have esamined wvrnt paramelen which address I/.e /.•aadohly u/ cnmP/rmenlmR Ihe IIV-srntqive pheno/ype nl aer.wlernu piRmenln...m (\I'/ Idnubl.at by Rrrr /ransirr We ptesrnl a cnmparali.e s1uJy arhrcA skmunNralrs 114.11 rrlalse 10 io.m..rlatired crlls, hu man dipl oiJ eells are fMYV trciprenls for Rene Iran.fr. As nw•asurrd Ay tn.lh Ira nairnt ar nl tlahk ea1Nt•NaM aataya drplarJ Id•nJd ntt wrrr enmpM/rly refraclury to bNA ltawtlrr , . hy eakium phmphale cuprr:.pAU1.un a.ul e.Aduled suMunlially redrrced kvels of eapres.wrw fulA.winR Rene Iransfrr, try lusu.n w.ilA I colr prnhq.laals We alsn eaamrned IAe srRwdi.7ncr of rr.eraun n/ /1.r hrmd K p )/ uf IIV senai/ivrqy in SVI0-immlwlaliled XP-A cell lines In a.l.lnw,n lu sunlumutR a prevwwt reporl of reversion to rriAl-lype kvela of ('9V retntanae it a(rrqurucy t uf + KI , we Aave at/emp/ed In faedilale /he ilknlifwatinn nf XP A trllt cmnplrmrnlrJ wrlh Remrmic IsNA by employing kst slringen/ sekctwal sthemea anJ cmran.frctmm to( a srlh-tahle marf,rr I/mkr /Aese eondiliunt, we nh.er.ed an mcrrateJ Ireqaency ol .eversr.n and were unahle to ilealify Irne transfecunts. Sahultr, K A, Ilarl.n, I) r. anJ I•nrJh•rs. f•. C. .C..mnnr l'rll rn.J Af.drrulm Crm•UCS 11(6)6U-6!1, pOS. (IIArr tupp.ue. U S Ilel•artrnenl of 1'.nrrpy. I rom Ihe I al.ntalory of Fsperilwewlal (7wcnArRy, (4patlmeM uf P.uluduRy, 51.mfnnl Ilnivrraly Slanford,('A. PRI PAKA f ION ANI) ('l/ARACfFR/7A11(/N O1 MI/N(K /(1NA1 AN 1/1111U11 S A(:AINS1 /•11/ N()IIAK1111'AL-INIIII('11111. ('YIIK'1IK11M1 1• Is0 MnrwyArnal ntrMr/irt against cytncAronle P 4110 .r.e p.rparr.l L.un phem.AatMlal rnducrd ral t.ver nlleroaomes I he Immum.a/..AYLn . 1 nara 214,1 s.d.. 1 ra.es, as well at 1he hmd.na aapa(ily In cyhnha.me P 111/, ol the dJlr.r.N anlJ....l..•s w.rr tAaet.lerued Ihro .1ved4Ny .at veldMd by •a.mua Ir.An.qurt an./ termr.I tn crnreslmnd to a srnitle lorm of cylorhrome P 110, IAe mapN phrn../•arlw~l .nd.nddr form Ilowevet. Ike anlJrdies were unabk to inhiArl comple/ely the nN/mMHyarn.ar KliviliN inveslilpted. 1Aese antibodies may consti/ute .ery s(.rcJ.c and )...wr.lul analytical tonlt for charac/eriaiq and puutifying cyluc•Arome P-130 .urcnrymrs I euwe-Goujnn. 1: , K rtmers. P, Sra.wr, P, Paye, A1, and G.rlen I E' Rr..rAr.n..rl onJ Rn.pAru.o/ RrsrorrA ('onrn.unnamn. 1191)) /JI )SO, 1•/11• 21 65100 7592

(hhrr rupMwl I ondc de Is Recherche S.'.rnlif.rlur Mrditak 1 rnm Ihe I ab.ualory nf Medical (-hrmhlry, Irnlilule of Pa1hnlnRy. I/n.vertily nf 1.rRe, 1 .rRe, RtlRrurn III N71>In1l•YKI NI MI I A11()I ISM IN h/l)11C1 I IVFR. ASC(X IA I I()N 111 11() 111 7.1 I 1Y1r11)A III1N ANIf ( l)VAI 1 NI I/INI)IN(: (/1 A MI 1 A111)I 111 l)1 1111 7,8 11101 WI111 1111 eA 1(K'11S lht 7.2 rpoit•,lstron of brna.4a1t+yrene, and Ihe 9,10 ep.uJal.nn uf Iwnnst•./rrnw/l,R Jrhydrndal coupled .•ilh tovalrnl hind.nR uf Ihe h.Rl,1y rraiu•r .linl ep•u.•1r, air Iwo aey P 410 me.l,alyd rtacl.«.ns brl.evrd In ht impnlaul in c..n.rr inH,alron, muURenel)s and IersloRenrsit New aauyt fnr Ibrtr Iwu rea, tw•M werr Jt.rh•1•rd wah munar Lar m.clu.wn.rt Ihrv Iwn acl.vn,rt hrve spna.rn. K vlhn•a (appr.u..nalrly A rM) ean.Aar lo Iha1 of aryl hydr.narhun hvd....ybar a.l../y ~I uenlv 1...n.I1.nIWI I melhyl.h.,lanlh.enr l.ratrd.IA1•/AA4 and tA 4,. tA'1 proarny •d Ihr (1 \/111 /hN) (t111A/7N) t/ e 1/11A/JN ha.tunnt wrrt sludwd R•.th of /ht nrwly dra,.,l•e.) saU•n.rt appea. /n rrp.rvnl P t10 p.nle.Ma/ Ihol are rrynms.htr •.. aryl hpluwa.tr.n hyd.n.ylsar s.bn.ly an.t that arr r.wn•1•nalrly a.•m.nllyd by Ihe AA" :11r1.• Van 1 anyfu.l, )/ f snd NrM.I. It W R.n,Arnnol PAa.w.n.nlnt. II11n)tR71 IR,`h, 1•rRN f/tArr ,upry•.I I..nda dr Ia Rr,hr..he 4.rnid«I•.r Me,6.att I rnm Ihe I a)rnaloue Jr ('h,m,e Mrdu 31. Ina,1u1 dt Ps/h,•iuR.r- I/nde dr It .w h.uur, I.rRtI hrlRwm, an.1 I aMralury of IN.rI•.(.mrnlil 1'harmaauluRy, Nalw.nal Ina a,dr n/ 1 hdd Ilrahh and Ilunman 1yr.rhy.mem• Natw•n.11 (nu,tult. nf t1ra11h• hrlbrlAa, h.l• I//1 ta(PRICq(1NO1 hI/11RIN1 MON(N)XVGINASISS111•1Y)K111111Y ( Y1/M IIRI)h/l P 1%01N NIl)NAIAt KA1S ANI11N /'RIMAKV 11 1A1. III PA I(K'l 11 C tN ('l1I I I/RF In ral livtr, lht perinslal develnpnmenl of varinus mnnno.yRenate acti..l.rs follnwa dlfferenl palleros, depend.n@ upon Ihe rtsclnal tludwd lht nntuoleny of Ihe hA-, 7n anJ IOn lea/mleront hyd.my/ase acbv./its ddfe/1 vtry sipnifi.anlly Aldrin rywuidase and tlelon/ mtlatwdrrinR mnmm.yRrnaiet are eprrsard in pnmary Itlsl ral livtr cells in cul/urr sfler, hltalmenl rn rrtrn wdh dr.amrehaaone (tslotltrnne is nnl meldxdired by Ihe cnnlrol ctlls and is hydmsylalyd on Ihe h/• snd IMo pnvt.om foltowlnR IM addi/ion r.f cnrIKOMII In the cuhvre med.um Ihe .1mr an•I lnvr turvrt vuy s..nrfinR In IM hydauy/sNd M•sllirm of Ihe tterv.d Ah/r.n ry.••..d.na a.l.v.ly n wrsrly vndr/.cuhM iw /1.r conlrwl crlls bu/ Is p/rsrnl twJ N.n•/,.. •hlr 1•y phrm•harh.lal (v1lnw.nR Irealment wdh /M .•uln•nnI PhrmJ•arbNSl .wdu,rs •1•bro epq.nda.e .n Ike ahsrwce 01 decamrlhatont Iw Ihe cullWe ncrdwm. Mu.n1.nR tlh..l Ilhr cellt art prruesled w.lh Iht cnrlicn.d tor 42 h Ihe Ine of anblan8rt aRa.nml Ihe m+.n cyarhrnme P•10 aprc.es purdirJ frnm adul/ and pbrnoharhila/ bealeJ 1391 cunl•.ma Ihsl a s„n,lar t yl.n hu.me P 00 can Ir mduceJ in fe/al crlls in a ullure lhr pr..naul ,rR,uluw•w of h.uh•Raa/ e•rnn, su.h aa /he esprrsau.n nf t/.r .n ..w..... a•w..r. ..w 1. ..Pn.l..,..1 .w trlJ al 1•.ea .rll. ,n a.dt.ut au,h a m•.,1••I . .. .... 1....~ ,r.. 1 ....1..•.... d ,nr,h.u..ma .lu,h . r.b..l Ih,.r . ...,..... . . .1 , . , t Krernrn. P, I rtuwe-Cuujon, F. OeOraeve, l., I)uvivirt, 1, and (:n•lrw. l/. Fur.q•ran lnurnnl.r/ R.aArwuu" 1.176(I1-6pR, 19a1 Oth•r rupryvr I onds Jr Ia Rechercht Scienlifipue Medicak. 1 rmn Ihe I ahnraWry of Mtd/cal ('hlmnlry, Inslilu/t of Pa1hnL.Ry. I lmvrrs.ll ••( I irRr, LreRe, nrlRrum ('1t)NING ANhSIRI/(•II/Kf ANALYSISO1 f111. RAl A/Y11 11'(/1•K()111N A I c1/NA Ala•hpnprulrin A 1, the major prnltin in mammahan hiRh denuly lipuprnlern• a,N as a culaalor f,u kulhm-cM.ktllrul "yhunderaoce durinR Ike /ornaatron a/ clwtrslr..d es/rr aml aa tuch, .s IhnuRM lo prm/uNe cMdevnul ef/luo frnre prr.phrral arlls Io Ihe bvr. In thn (VIK1, /Lt aulhOrl Ir(Mrl Ihe p.1.IqI pMLIn.11mn n( r.a hrer aP••14u•p.ult.n A I mKNA by a µ•1ysu.ot rmmvnoaduvplmn IrthniVue and /H c1/NA clura.nR Iw/almn nf Iwu n.r.l..pp,nR t1)NA clonte enaldrJ Ihe rrsearchtq lu drn.r Ihe wholt ral alblllMlprnle,n A 1.1)NA c.rling sequence ('.m.paria..n of Ike dr.tuard prulrm .rywn.r w.th ita human cnunlerparl rereals a senlinR ho.mdoRy 1wl-rrn Iht p.rp.uprplntr precurSnrs 1/n1h malurt pro/ein aminn/Tlminal rrRwmt are wery hamnlnR,.ul• auRRralmR Iha/ tlus parlnviAr .lomain cuuW he invol.ed in lynJ p.u/ruo hmJmR .n Irc./h.n chulesirrol acyhranafrratt acliva/n.n Pnn.in, I I, Ma.1n1, 1 A. and (f.rltw, J F Furn/•.•nn l,x.rnol n/ OnrArmrurr 110 191-198, 1924 OIA,-r .uph.n M.n,tttre .tr (a Pulilique Scirn/ifiqut/ Ilelg/om Crom the I alw,ratnne de ( Ainlit MeJicak, Inalilul de I•alhoh•Rie, I lni.rn.er a/r I irRe• 11t/Rirm, and I aM,ratoire de Crme Centlique/ Inatl/ul .le (•hinur, I/e1R,va1 SIRtI('llrKl: ANI) K1OtI1.A11(1N (IIllll: 11•11)IRMAI (1KUW111 I A( IttK Rlt IPI()R 1 he rpnlermal ofrowlh fXlnr (1 (:1 I rtceptur it a/ramn.r.ot,ranr, R/ycnaylslyd phMpM•prulrrn wah inainsie prnlt.n-lyranin! phosphulfaM(rraa acersnv Ihe amimnerminal cr11 wrface parl of Ihe I(:1rnrp/nr, whnh conu,at ammoamled orlmhydrale, has a sinRlt 4G/-bin.bn0 sile Iht earMny/rrmin..i aylr.pla.nuc ,hro.a,n corrtt/n.ndt In c.A B. • hnown nncoRene tlruclurally bnmulultnut 1u prnle.n /yrnsine Amastt Self-phnspM.ry/a1Mm of Ihe I lynerplor, wh.ch o(cu.t un .1% catlwny/enninal dama.n via an iMranudr.ular nltchamsm• enh.smes c:./rlvlW aalr.ny 1'h.nphory/sliun n/ //.e 1(31 relrpmr by prolrrn hinasr (• tulqvra.ra nt pn,lr,n Iln„,nr &,na. a.l.•Ily llr.Auae (dn.y.Aal.JyhnM./.J Isinaat h/rv11y an Ar arl.n..r.1. prwlr.w 1).nunr am.ae rrrmr 1.• br d,e unly CAIdyUC a.h.ny /nbman 1•• pu.J.r.l (1./ rrceprorl In hu.u.n ep.dr.mvwl car.m••m.. A411 arfla, Ihe ralrnl .J .a,pbl.. ~...•n u/ 1/.r I(i1 rrarplor Rrne delrrmines the ee/1uLu conlenl n( I(31 rr.rplur p.n/r.n Ihr amounl of /(71 receptoa rn eh•nsl varunl At11 cet1. J.clales /heu R.owtl. n.p,msrs 1,• 1(:F G.H. C N, Ilertict, P 1. I homptun, Q M Wrber. W, an,l /Whrl, (' (,mcrr (.ll. 1./..,•. rA I u. 1,... ...nJ 1 rnn. /n.wmrn.n 11 111 , I')R S !I

I7tA.r N.Iti••nll Intnlnlr nf A+11N•1.a. Ih.l•rlt., l).Rr+uve and Kidnry hneaars, anJ AN.rrn.rn 1 an,r. '•w1r1y I ram Ihr Ih. putmrut d Asr.h. mr• Ilrvl.u•n nf I n.l•w 11nuh.Ry anA Mrt.ltMd.am, C. hn..1 uf h/_J..lnr• I lnnrruty .J (.J•lu.n.a al diIn U.rRn, 1 a 1.413. (A NIIAII/1N\I/11'IIIIWIINI'I(1111111IN/N(11 II'It1/RMA1 (:It(IWIIIIAt1/1I! R11 11'1(f1t\• (:I NI A0111'1 Il lt AIIttN, ANI1l IIRI)h11/11/ht1 / INAN\IIN A11/1N IN VANIANI A•t111111i \ynlhran uf the rln•Irrnlal R/nwlh faclor O (il ) recrptnr ha+ IN•rn sn./rrrJ In a sr..n .d varNnl A111 human epal.•.m..nl ca/amnn.a crll alnnea rr/+NIrA 1.e conlam dd/rren/ anu•Nn(s n( 1I,1 MnJrna u/rt )he smnunl nf 1(.1lrarplN. pudr.n, qnln/dar•) hy .n.oNm•..Ill.nqy .tunmasaRNph7. anA I(i/ /rarlN.N mRNA, Y•.ama.atrA 1•y .t/NA hsb..dv..lu•n, +.r/t• \hrvly a.N.rlalrA In the talent uf Ilil rr.rt.tnr arnr aml•L/a uron Ilu. rrlN~.n r.nlyd .n varlantt trltclrA 1..t rrJuae•I 1(:/ rr,rpl•n\ an•1 in rrvr.lNN• I.nn.'1h••.t v.NUnla with in.lraarJ 1(i1 rrceplun lhrre was a/an a c.•r/rlaum 1•rl+rrn tl•r Lrqurn. y n/ Uan.l..aaann nf chlnlmnno.r 7, cnnlain.nR the 1/:/ /r.rPl.n arar• anA 11,1 rrarpln. p.Nle.n Ihra /r.uht aul•M'll Renr amyldlCal.nn a\ the mr.haan.nrnhln,rnRA1lI.rll11.1 rr.rpbNp..N..nsnJ.lrlr.nNninRRlnwihlrqn.n.ra (.dl r: N .r nl .C...wnh. (YII wul a1.A..nlnr (::nrnrl 11/J) 111•1 IIN, /•IIIS (1/Arr o.pryNt N~h.•n.l In+tNUlrs n/ laraslh and the Amerrran (•ancer Srciely. I u•m the 14p.r1mrnl n( hlrAi.'.nr, hni+ma n( 1 rtd..t.inuloRy and h1rqMAnm. IInlvrrsNy nl /:dJnlm] al S.tn IbrC••, ~•Inwd nf h1r.L.lnt, 1 a 1NIla, ('A, Itrparlment .d Mnlrcul.lr tlaJ•.Ny, Kr.o Ilnivnvfy C.'h•nd ../ htr.h..nr, LuLYn. lapan, 1h•partmenl uf ('rllnla/ anJ Isrvrl•.pmrol..l Il.nl.•Rv, IlmvenaNy uf A.vnna. I.naun. aoJ 1 atnN-alury of h1.•Ir. ul N 11.•JnRy an•1 V Nn1..Ry. I hr %.Itt InslN.nr, ( a luIlJ til l l Pltn\I'll(H(YI AIh)N INIIAN( aC 1111 1'R/)111N~IYR/ritNI KINACt: AI'11V11Y t/1 1111 11'II71 NhtAI.1.K17W1111 Al'/(7R R/( 11'1()R Ila eflral of srll phosphuryl.lU.•n Nn Ihe prnlein lyrnsinr \inAse adivitS Id the e1+Nterm.ll Rln..1h /•wl.•r rect•plnt h.s Iwen Invral.r.lIrJ usvnR Iminanual(m.ty pulilird p/Nlriw I nrSmr was IN+1 imnhalrJ (nr v.lnnos Umes wilh eacr.a A1/' to pMnfhrNylalt it IN d111rr.nll 11.e atutdy .d tlhr rnrynlr hl IJmsphulyl.lle e.nRrnuul IKptnle suh\l.alrt +.IS Ihen /nr..+u.ed as a I.m.IN•n .d .1s srlf phnaphwyl./lnrn s1,rlr I/c/taainR 1.11 p1...+IpluNylaln.n 1.. I{ I I nl.•1 n/ ph•n/dl llr nud //.f epnkrmat prowlh Iaa1.N Ir.rph•t rnb.n.r.1 1.... frln ly/nvnr /.n.l.r a.uvlty : IInhl /.mywr.vun u/ d.r Imeln's /A INUtr/n lyruvnt /.n.•e a.'slvily :11 I1.11n.•nl AIM cnnienl/.qan1 revrale.l u(ndNaM d.l/rrrmrs Letwrrn unl.Mnphmyldrd anJ ph.rphNry1.11rJ rnryme AI hl.. Irvels uf A/1', a dauldr• rrr.y..Mal p1n1 n( ILe /•.•'Ir.n Iyrasinr Mlnase xlnNy of she unphnaphnlylalrJ enrvlue wat hylw/Md.e, aupRr.ImR that Alr nuy a.1 as sn ad•vadN of the enrymr AI brRhr/ A 1 h cnncrnbatmns, wlwre Rlealer levels of srtf pM.aph(m y/a1N+w n,a.lae.1 du/mp she .eacle•n, the \mrlics aM'r'a.rd llnrar ami similar 1o /hnu of Ihe /.h.•.Lhnlylalr.l rnrvmr Ihnr /ral...nu stuA.n uvnR I(Ntr ddfrrenl IwptiJt suMlrales IanKuNen\N. I1, al•rr•n, anJ a a)nlhtr.c IYI•tl.lr PNININ.nII1n~ In Ihe sAf phu+phn.ylalmn ,41 I sile in pA0' "') shuwed that etollenout subslralet inhibil reteplNr self ph.nphnrylahun In roch caae, half-nucimal inhibilio/l was observed at a Iwpllde rnncenlralu.n apprn.i.nasr/y rqual lo the tubslrale't K A LinetK analysls cumpsrmR prp/nar plwapbu/ybtn.n u+noR unplNnpMNylaled aru) prepho.phorylaled rnryme indnalyd Iha/ Ihr arll ph.n,phoryLllwlrl slle can act as a cunlprblive inhibilor (a/trrnale subslralr) r.-rari prpl.de auba/alrs Ihese results su`tral that self ph.sphuryla1u.n nf Ike epidermat Rrnwlh Ixlnr Irirplur reuloses a cnmprlilive cunslrand so Iha/ eauRrnuu\ suh+tr.l/rt aan he mulr teaJdy ph.nphorytalrA Ur/lw.• r 1 and t.J7 (: N I Ar I.n.rn.r/ n/ Ar.•!.•tunf ('Armrsnr !W(?7) NM2 11G•/7, 1'1115 Irnn. the Ih•par/rnrnt u( Mrd.cine, fhvi+Nln nf /n.t•rrinnl.rKy an•/ htrlalw•Laol I/nl.e/.rry ul t a1Ju.n..1, -.In It.rRo, $ahlNd uf Alr.ta Inr, I a lu11.1, 1 A htlt"kt/l lltltll S, 1 t 4C11f' AN('/l(1RIN(: 1'11h11'11N1 N1% Itl 1/11 I X1NAt 111111.AK AfA1RIX, AN1. AWNIA111) WIIII IIIIR//NIt11N IN 1111 %/IN111 1 t/1 /1NN ANI1 A(/N /'A hlwlnhb/ds air slnalrJ tubuks Ihat ptay a rulr in the /ulnabun uf tlanl.n fdN•la .vnllurmRala aal(..Id S/ upnnIHwa/snwA h newly svn11N•+vt.l el.l+an n Jr1~nNrJ byI/IIaNpuI w I' anJ sl.umnR WI IH/1e11n.nNrale ml:wllhrils /h;H L•uoloalr whr.r elaaliw is sl'a/ae ur ahsenl in basal laminae, pl.ls.na mrmbranrs, an.l Ihe an/1aRrnuu\ m.\Illt Ihe musl l11.A1nR acl'umula1i1N111f onvrnllbrJl is fuuml /n the rullalr .u/ /mn, the Ilan.pa/enl anJ elaslic suspentoty IlRamenl /lf the kns, whia'A IunlaNls nN rla+l.n Apl.t/a'a1Nm n( unnlunncyhKhemi:al slaininR wilh a prrusida\e aul.pr.o.iJ.l.r (l'AI') p.rtdure dr/nnnaratrs 11131 fibrnweelin is aavm•ia1rJ wilh Uie micr../.blds uf Il.r rNnule anJ aut/a ARR/rRatrs of ullctuflb/llt alt nlrnliavl lu nylalan /"aad endu/inot'1 IJ•r/s that havt IN•rn drsrrll.ed in I.nidonlal menJNanrs and o/hrt sdrs suh/rct lu mr.hanwal slrres and /hry can 1N• fuun.l iw sites as Al.paratr as Ihe rahbil rnnule, /al hepatlC sla.ma alal human carduc p,l.lnary muselr, i/nlicaline thrl miirn/lb.ils arr a wl.lely d.su/hulyd clulnes(ive listue eh•mrnl wilA a funclN/n /hal r%lends beyund rla+lNjrn.•.ia, /htir asNK/atn.n w/th fdnonrain and 111aa6/•Uilm tuRge\h Ihal dley srlvr a. an r1aNrC an.hlumR tNm/Nlnrnl Of the etlraCrllYlar nu11i.. G..IJ/r\. Arr. S. C.ultulf-S.hJlrr, 11 , aelt Goldfiacher. M 7t\./N•.1 (•rll 17111 dJ1 410.1995. . (pA.v anp(rnf N:Iliun:J Ina/ilutrs uf Ilealth I.um Ihr Ih•pubnrnl uf 1'.Nh.dNRy, Al1.eU 1 iosh•m ('nll.•ae ul hlydalnr, Iht Ib.mt, NY A. 11 N1Y1 A/l I111/1NIN1 0611 IAIIUI (\At ANts I R.\NCMI t//SI AIIIIN IN ('ANt 1 R hlrlll.nnu.e mrl.d.oham a.ul Uawsw/tlhyl,u/un a/e f/eqarnlly In can.r/ \rll\ the allrral/ow is ollrn eclNrsseJ as an m,.b.bly uf the cancer atll, lu R.,.W ./vn methineine is rrplaceJ by homncysleiwe in Ihe cuhurr wleA/uns, w cnnddNm /ha a11/.ws the Rrowlh of n.Nnul cells lhis wselabobt defecl is termrd twrlh.nnme dr/.rnJrme Methinnine drlrn.knce may refkd aw nverall iminlae:e iw (rammtlhylalN.n wh.,h rasulls in Ille O.r/1nelhyla/N.n of sNmt tYh7lanltt and Y/Idr/mrlhylalNln nf ..Ihels w.lh•n 7) I

cana'er cells Many ca.c.notens affecl vatinua slates of mrlhw.nine/Iransmethylal.nn melahol..m Ibe ul/.mate effect of 1ht alteralwn of inelhiunme/tt.-tna.uelhylatw.n meuludnm may M Ihe d.arupUon of Ihe rr{ulahun of tenet involve.t in the oncotemc pr...ras the known p.ulecl.ve effect of inelhw.nine aRa.ns1 cancrr may he due to ptevenl.un ..f ahetrd melh.umne/ltammelhyhln/n melab.bsm nr cumpensahnn of the allerrd mel..h.ham /h.f/.nan R Af ~bnrrnnd e, Kr.run A t 1 10, 1985 (Irhrr turry.r lhe Nal.onal ('ancer tnalilule and Ihe Georte A la.ohs Memn.ul l und lut 1 an.rt Reara..h I tum the 14pa.Unrn1 of PnliairKS, (lntvrrsity of (-aldornia, Can Iheto, I a 14,113 1111( 1 411 ANItPI AI111 f ANf10(ybY (IN f111. b1.Vf1U1'MIN1 OF 1•111 MI INAK V k/l 1 ASI ACI S I1)1 I l)WIN(i INII ('11l)N (1F (-1:6 ('()1 (/N Att1 N(K"ARI IN/7MA, 1 1 WIS I IING IAR('INOMA, ANl) 1116 AMLI.ANPIIC 0141 1 AN1/61A 1(Iht()R ( 111 S INIt) MI( I /hree ddfe.ent murint lumnn, ('1:6 colon adenneareinoma, tewa lunt ca.ctnmaa, ml IIIA amelanm.c InelJnnma, writ inletted tnln syntenere mu'e (l1ALR/e and l $/1[1 /6)1 /n Iea the effect nf rahh.l anth mouae platelet snlibody on the deveM.pmenl of pulmunary melaslaars Antqdalelet sm.bwly, when injected ip, dr.rrawJ the plaltlel cnunl ftnm 1) l0 012 a IM/M/ at 6 hr, which remamed at Ihn level for 24 hr Anl.pl..trlel an/.h.lr t•ven 6 hr pre- and It hr Loat-i v inleclion of luwtm cells dtcreaard Ihr mean rtumhrt of (1 76 lumut mrtulrt per luna by 57% (rante, 47 to 65%) anJ dettra.ed the mean m.Qule vnlume uf lutnor twr IunR by 111 (ranRe, 0 1n 71%) (IN espeumenul an.mala), when cumpared to Ihe effect of nommmune aetrrn nr itrrlevant an11/mmuM.t/nhul/n anlthrly in 116 cnnlrol antmaH With I.r..it lunt carcrnnma, anaplalelel antibdy deuraaed the tnran numAer uf tumor mwlules by 62'Ik (rante, tl to 71'tl/ and decceased the mean nodule volume of tumon by 64% (rante, 6(7 to 7T\) mmR 411 eapetimental 1111.111311 snd 6S cnmrul snimals When lumor celk wece ttven sc , anlq.tatrh-1 anuMwly ttiven 6 hr pie rn/eclion. It hr pnal-injeclinn and evety 49 ht Iherrofler alan decreastd Ihe mean numAer of teelaalaset by I:% in 14 e.perrmental and 13 cnntrnl animals. With 1116 anselanolie anelanuma, anliplalelet anltlrwly given 6 hr p.e and 11 hr /Mu-injectan tkcreased Ihe mean numher uf tumne mwlults by t3X and decrtated /he mean noduk volume of turnnrt by 66% usint 9 tapc'rimenlal and 9 enntrol animalt SimJar rttullt were oMained when all Ihtet lunwu• .ere in)ttled A M afar the injeclion of antiplatelrt antrbwly 11o.ever, netative reaults r'ete o6talnrd /f am.l.talelet anlibnly Ma1 injeclyd A hc af/rr Iht m7ectN/n nf 1wnwN crlls \.n.e anhplatetel am.b..ly hat ill maaimum tlfecl al 6 hr, it is bkely Ihal plstelrls play Iheu rnlr in Iht AraMq+mrnl of prhaunuy tnetsaltaes dutint Ihr (wat 1) hr of lurnnr rmw u/alw.n Peartale.n, 1' , Ambrotio, C, anJ Ka.par(.n. S ( onrr. Rr.rerrAs 44 11t1-ltt/, 1984 1.nm Ihe 14partmenla of Medicine and ralhnMty and l.vintton Ilorte Inttd tle, New \...k Ilmvrn.ty Mrd~: 11 },hmd, Ne. Y.wk I Al'K fll /11 f(-I (11IN 1"ll•c) PRl1STACY(-I IN ON 111E 1/1.V11 (H•MI NI l)1 1•111 MONARY M1 -1 AS1 ASI S IN MICE 1(11 1/7WING INIKAVI NIII /S INII ( 11(1N /l/ 1/'h ( I/I //N 1-AK(7NOMA, 1 1 WIY 1 1/N/: ('AR(-INI Ih1A, (/R U16 AMI I ANO11(- MI1_AN(/MA ('E1.LS Ilnnn rr af have recenlly reporled a 911% reducli.n in the development of melasta.et of 1116 ao.eLtmNic Iumor celts tiven i.i follnanR a sintle .W.x u( pantacyclm IP(ac) snd Ihruphylltne (100 pR each) )0 min prlnr In Ihe injectrrn of lumnr cells Ihe p.rarnl aulhnn have hren unable /o reduce pulnwrnaly tnelaslaset rnduced by the i,v rn7ectw.n ol ('1:6 cok.n adenocarcinoms, le.rn /ung carcinoma, or U16 unelalwrbc melanoma ce1N w.ith a stm.lac reRimea. lhw. P(aa and Ihenphylline given prw.r to inlec/w.n of tunu.r cellt anA .' hr post In)eclwrl had nn effecl on Ihe numher or volume of pulrnnnaty lomur muluks ftw ('176 eellt, Wrns 15 eaper.men/al and /4 conUnl anitnalt, 1 e..n lunt cellt, usint 1• taperiteeMal and 11 conlraA an.mala, or 1116 amelanotic ce1H, rarnt 76 ral•enmrMS/ and 12 eonlrul animals lhe IYaa used wat sbn.n /o he a.9rve tn nr.... tnh.AdinR /wnor-induced platelet aRtre/laann by all Ih.ee /unwnt al 10 t M aml to rrvn by inhibtliun uf (.e.rit lunt-induced IMom6rw-yt.qan.a al I hr, rttnt IW pR IYilc p.wn lu the injeeliun rd turmu cellt. Karlwrk.n. S. AmhtuRin, (* ., and Pearltleia. E. fancn Rrva•cA 44 11Nt0-1tR 1, 19t4. Orlerr aup/rwr Nalinnal Inatilules of IIea11A I com Ihe I)rparlmrntt of Medicine snd hthnloty atwl tuvinRtun Ilnuse Insthtute, New Yulk llniversity MrJKa1 SiMwd, New York. NI I/R(1P1 PIIt)1 K• A MAJOR TACIIYKININ IN PLASMA ANI) IIIMIIK 115.\I11 S I K()M 1'AK( INI)tU PA I IEN IS I.vwfence is preunted foe tke presrnce nf as enture family of larhyktnin•immum.axltve peptiks in pbtnu and trnwN lisaues from palrems wr/h caecln/.wl Iuminl. lhe petNwle4 IrKIWIe, in sddAion 1u suht/ance P and neutukinm A, neurokinin O, an elyduisin-like prplide, snd awnpep/wk K, a 36 amtnn acwl M.nt lachykmin which contains nerroklnin A al its C-lerminw Nertnpepude K seems to be Ihe txhykima which rs prrsenl is AitAesl ennceM.Nwns in plasms n«HI as rn sctuc wid ealracls of tutmn liaaues 11 is highly biolnsic'ally aclive and may therefore coMrihule to the chnical syrnphwnt of earcinuwf tuwbrt. fhttw6wason-Norhaim, 1, Nnrheim, 1. (thert. K, I/rndin, f., M. 1 alemntn, K, anA LtnJRtrn, P/i. I unJM.Ar ! Ilww Arma.d un.l IIw.PAr.w nl /t,-u'M16 l.wn.ww..n arnM\ /1N I1 7) tl 194% (/rMv awryrwr Nnr4..k tn.ulmion.l, S+.rdnh S4k.rty Of Mrd.ctnr, Katnhnaa. In.u~nle, Uppsala Univertily, and S.ednh Medical Kesearcb t'uun.d From the I)rpattmenl of ('tmKal Chemisuy, Ksrotinaka Ilospilal, Ihe 1)rpsrlmen/ ol PharmacolnRy and Uiochrmiary 11, Karolintb instilrte, Slockhulm; and the 1)rparlments of Internal Medicine and Roenttennloty, t)nivetsilr Ilospital, Up(nala, S..eden 21

III RI I•II AKY (1VARfAN CARCINOMA 11H)MARKf R 51111111 S Ihrrr uvanan canarr prune \indre.H wrre stu.lied, lu•o .•f +•hi.h cnnurnr,l wlrnlN.lt L.m anlcra cnn.w.tsnl frn urarun ca/.inuma In nne hinJrrJ. INnh nIrnln it 1w.n ...Irra haJ dauRhlera .nh n.vian CatlrlNlma In am•Ihn \.ndred, one of lle alrnlnal rwsn sntrra 1Aa.1 an u.auan tancer affrcleJ JauRhttr I/sarqn carcrmsna thn..r,t vra1N al /.ansmr..n.n m all Ihrre famd.rt rw a Pallcrn Cun..w.uN nrlh : n a.dusurual J..nun.ml mrwtr uf .nhrril.lncr MrJKaI-genrtK turrry nt cash la.nily unluJ.•J Jrtadr.l qursln.on.rura rrlh /elrary) of ptrmary mrdnat anJ palhata/,• J.aVrorrlls rm 4uprr nf a11 an.n.•wsw' 1LItt 1'utalrte prolwar\er Jrlrrminalums rnalrnlrJ (1) rw .u.o hyl'rr.l.l•InrJr m Jrrm.d mnn.JaYrr eullurtt, aml (:) lu..rr trrum IevrH af a11.1ra 1 lucnarJaar (•?/S Il)/ml) In 211 cancer•affeclrJ paln•nla anJ •lahslu:ally aren.INant h.+,rr krtls in N/'% ris\ rm/1rNW?/s when comparrd t.t slw.usr anJ putd.sh.v1 a..nUnls //'-OISa anJ P•OIIMI?, reHlw•slr.rly) Ihrae I/ndinp are JscuateJ in conlr.l rnh 11.1 rrrnlu.d .L.rl.qnnrwl uf \ rrs\ 1'a./ur prnhk .LN h, 0wen a..rpl.d.k trnanr..,y an.l .IN•.dNdy, .urJ,1 rnah'r nlrnlJ.ctaun uf /nJHNIWIs hn .uutJ bt prunr r mdnldrt (..— ml,nsr.r sar-dlmtr/nuneRrmrnt prnKramt I rn,h If I rl ul ttl?/J10 415, I'/l15 (Ilh„ ,up/'.'a Nrlnn/.. 1h....nn, I ralrrwd /lr•hv, uf I y;trt I.mn the ('rrrrhlnn IInrrnvly Sthn.d.•/ hh,1,, a•an.116r Ilrrr~ln.uy ("anirr In.ulult, (lm.rlq, N) N.Un.n.t ,ntlnulr 1„r 11•,r ,nR .uul \Inv.h Ih.a..lrrt in ( hA,brn, /lmaha, anJ /'...nr11 Iln,.rra,ly hlr,h..rl l„11I hl,r, 1, NY I Ah1111A1 I MIIKSY/NA1 I AN( INtlht.\ IN A I ANI 11l 1•Ifl1N1 AINI.R) lt lamil.al h•tl.:ul.sc .an.r. n r.ne Ihr% rrl»ul JrsarJ.rs a f.m.ily ..nh an unusua/ aansrr sIN•CUmn thal nNlu.trJ Ilrr mlanrJr (,uo.,d rmLryno.J.aau.Orna nt the /rars In the a.m..f ] tanarr Irre hul puUlrrr uhlrr.alr Rene aauwv .nolhet, auJ the adu11 (unu u/ t•.nhsrnnat a]/tua.ma in Ihn wumaws nnlrrnal I.all brulhrr Ilhea mWsul mothrr ha,1 rnalrKuanl mrlan,.ma anJ urrnary hta.tJrr 1 ucrnumal IlrreJrl.uy arn.lr.uule JruRna/wn rr.n.um rtus.rr 1'ru,nly anrnln.n In hrarna.Aer researah rn lanubrt ol Ihis IsPe Iu1 rluc•J.m..n rd :autr an,/ .unh,.t is JraauurJ I IwcA• ll 2 rv ol I Ar hwroo! ul AIrJn rnr 10 891 /9A, 1'/I1S Irom she hrparlmrnt nf Prr•tnlwe MrANinr/Puhlic I/ralth and dse /kpaaruem af 1'alhulnRy, llerKhl.rn I/n.rtrtdy S.A.Nd a( AlrJnmt, anJ llhr Iltrrddary / antn Inahlulr, Omrha, NI ('()I (/R1 (•I AI ( AN/'1 R IN A Nl/('1 f AR I AMII Y1 AM11 1A1 I)R IIIR11r11AKYa Ikcaute of the h,ah incidence of culurrc/al carower, famitial aRltrrRaliows of thit Jrsease are curmm~n IlJfrrtnlr.ll.on Athreen tlmh.Rsf• cun/usl.uling to fanutwt aluaesmg I+hnh mar ha.r rrsulttJ e.lher (rom c..mnmun enruunmenlal ryNnurr nr Lunr n.rrr .hrn,rl ..uJ p.,n.ut Ilrnrlu 1.,1ara .nar 1•n.rr ra.nIt I..Ihr phYU.cm Ih.s drds +,'h Ilv a.su,•1 /.r.•1.Irn.• ru...wn.,.•1 .hrn anruq.lma 1u n..Jr su.h el.o4.tit dialinalwnt in ,nJrr Io provide appropriate lurvriuanse anJ m.rntRrmrnt, ehaard VINIn IV1m.t .1.,_. bwn anJ nalur d IuVOry. Iw palirnlt 31 rM'/ra.rJ .ansrr r.aA / rwrA p 1' ct ,d lhs.wsrs u/ tA.• c..l,w 6/6-, tunr 2245) )10-)16, 1915. I r..m Ihr Ih•p.uUnrnN of 1•rr.rnU.e Medicine/ruhlic I/r.dlh, $urgr/y, ralhuluRy, anJ RaJNrluRr, ("rry;hl..n tlw.•rr.ny 4h,Nd rd MtJkine and the Ilrre.hlary ('anaer tnsl.lult, Unsaha, NI I ill CAKI Y1h1A. 10141 A%1 I AN( I R, 11/N(; CAN(-1 K, ANt) AIIRI N(X'()R 11/ AI l'AK( INUM.\ \S NUltl /xll 1<1 V1"1111) ( 1111 h11()1/I) ('ANl I K Mr ou,1-1 /+.. chd.h, n uh.. 4u1 rlulwlumyn.araunu :u..) rhul.fnluu.a anJ r.hn +rrr Imm a LuuJV ...d. a hrnJn.uy t.tn.rr, s)ndr..ure 1h.s1 ras clbara,IrrveJ by t.uawm.l, Lu•r.l ..m.rr, b, rns lu.n.ns, Irur~ C.ur.H, Lutngr.J t'ar.uN.ma. ........ Iru\rrara, anJ a.hrn.~urlaal s.n.a Ihr J.•I••Irrw.ut Rrnulypr h]1 mr. IN•en rllnesuJ IlsrouRA Ihr fnuah Knn•r.un.n nl Ihr. Lugr AuNhrJ Ihe Irdrrrre emplutvrt Ihe m•rJ /ur an ratrwdrJ Inslnry ..f srrrr.rl /;rneralmua In acrwe a1 a hrrr./.lary-S)mbot Js:rRnu.ra A 1uui1.v11N•Jrr.rr rw.ty /r,ull .n n..n.pl•n•redum .4 the grm•Ia• tumlu.nen/ IIN• pr,IrKrrr Jlwstrah9 IhAI, .w arrl\in . rp un1.L.V.. •.. Ihe hy(IJy 1gw.d w sa/rellra uf tamYr n.ly n„ ur .n. chAJrrn IN•/ure tl it r.p.rs..•.1 .n Il.r (parrnl ..INr calrirs /he pu/.nr.r Rrne /'rJr.Nrp uns, .w et.Jw:.IwR the uu.r. rJ lh.h/lNwwl Can.'rc, nursl ho CuCni.anl ..1 canarr anN.ur 2,101 rrlr/...... .uwr Ih.s rr..y...r.nn rnay aid in the JraKmnrt uf 1hu.r hrrrdrl.uy can.rc .SnJrumrt Ihal arr thau.Irr..rJ hy :.m..•r nacwlenar in chil.trrn aa ..r11 a. a.tuha I rw,A Il I. KaV, 1) A, Ih.gud, 1' 2, an,l I Sn.ls, 2 1: . 4 wN.rCO.r ../ Ih.r.n..•s ../ (6dJtrw /19111116, 192 5 rdrlw•r a..ppvl Nrbr r.l.t I h. r.arn, I talrrn.d (bJer nf 1 agks e I rurn the 1)tparunrnls uf 1'revrnt.vt MrJ.ciwr/l'ul•Ir.• Ilralth, anJ nf /'alhulr.Ry• (-rrrRhlun (lmstrsrly hShNJ uf hlnlwrne, am/ IhvrJnacy /amrr /na7dwr, /1wr.rha, NI 1111 (IIIANIOIKIVU1111111N111 NIV/INAI'A1/1N1 KI11/ I Ah/ll IAI., A 1*0 1'ICAI , h11/1 111•1 1 MUI I MI I.ANUMA SS'NUK(IMI- 1 w atnun/ t.w ./ri.nlct ut havr fulhrwrJ a\ur.lrr.l•wqb 11hr /anub.d, alY/n,,d, mulfspk nN,lr mrlrnnnu (/ AMMM) syn.lr.wwe Wr Lr.1 t.aln.qrd Ihe pruhawd's IJ yrar ul.l slsuRhl.v nhro ahe was aRe 1 ycast Nr r1,.,wurrnlrJ /he r.uluuun, L.Ih .hna.Jly anJ hrslul..kN.J11, w/ Ihe I AMMh/ phrm./sIN• rn dn /;ul /..r rrKhl y„rra I rw. A ll I r-r .J t'rJrartr I1r.mnt..J..Kr 20139 ?')1, I')AS 1 urm the 14parlmtnM nf P.erenlire MeJicina•/Pul.lrc Ikatlh anJ I)rrnuluh,KV, ('rriRhl..w l/mvrnily $:h.nd of MrJicine, (Muha, NI, /ht hrpmin.rn/ u( Inlrr.aa/ Medranr, l/nrre/srty of Nrhrat\a Medical (7nlrr, /hnaha, the Ilrrcdnarr t an,rr InaUlulr, (Imalha, the Iti-rnululnRy Ikparlmen/, the /'ulychwa, Sratlle, an.i Ihr 1lrparlmen/ wf Ia//n.l.,gy, IYrmran Grnrral I/ual'n rl, Ambe.s, I 1( 29

1u1(IMANKI R SIItDII S IN III NI DIIANY OVARIAN ('AR('INOMA Orarhn cam er hss hetn increas.ng in flequency during the pasl seveul dreaJta, parl,cularly in Wrslern inJUSlria6reJ n.nnmt 11 ha. the IRrnmlln«/us dnUMlmn uf herng Ihe malur cause uf dealh Irom Rendourinary can.er in wnmen in the IlmlrJ Sules A small hul sqtn•fl.ant I/ul•nn of palienls with ovanan cancer ha.e farndy Inalur.es Ihal a.r rnml.al.blr w.d. a pr..nary Rrnetr. faclnr the hereJnarY vananl is helrn•Rtnruw hul Ihr.e 1'r•t.Rrrra revrat a high prr.h.(ahihty uf cancer Ihrr.fine, families 11,31 are prnnr hs o.ar•an canrer mtril the hlRhest priority far Momarke/ rnveat.Ral«.m When cnnaldrrinR Ihr Rrnrrally p«.r wrveJlanct nxawret wailahle lu u% f.n drlrrUnll n•ar/an cancer tuff«vrndy /•a.lY lo irnprove pr..Rnotit, the srv/ch /ar h«anarkr.l nf h.Kh sens•t.vrly anm/ yr.d«n1 as.umrs mapu significance. In lurn, sach h«.markrra nnr sheJ bRhl on the el.uluRy anJ pathnsenetit of owarian eancer in the Rrneral 1«q.ulmun anJ murr im/w•rlantly IuauJr mechamtms foe early dtlecl.on anJ ptevrnlam n/ dralh f•um this tnn«u I/n.A II F.to.hurlkt,l. S,andlyn.h,1 I ( n•...• It.r:ru•'n umI I'•r.r•.now 9 1:9 111, 141)S (hA.. .opl••at Nrh,aska U..n.un, / ralernal (hdtr nl 1 aRles Ir..m the 1Mlnrlmenl uf Prr.rnli.t M.A«'mNt•uhhc Ilrotlh, CrtrRhlun Itnrve/srty S.h,.J ur Mr.l«.nr, and the /ltreJ•larr ( anarr /rtrr.lulr, Umtha ('AN/ 1 N(:) NI t, h(1/1 111'1 1 1'RIMAN t ( ANI 1 N, ANI) VON 111141 1 11NtrAlt 111\1 Atl Von 11q'prl I unltu J.aratr rH nhr.drd ht an sW•a.•mtl A••m.n.nl lenr /hal noy aM,w markeA r.press.a .a.uhdar nf . tn.r• pbrn••Ittw .n ...I.,n Lal.rnvlamd.n We M.rrrM a pal.enl wdh a.I,nnRlt 1»•.'r'.r /nud. .1... at age `R undtrw.tnl ctan«.lomy with remn•al nl a a)aba .r..l..lln Lrm..neu•Ida.auna, a/ aRr eR, he devrlnpr.l tyrrnaamrrlu of the alnnal .•n.l. Ir.ao.e qulJ.qdre.., anJ haJ a prnRrraa/.r da•+nhd1 cnurtr AI aulapty. hnrnanK«.bla.l..nut ul she crlehtl6un and spinal cord werr IounA, n well as a le/l renal .etl carc.nonra, an oal cell carcrmnna nf the lung, a hepanKellulsr s'areinoma, and an alypn•al Ihyroid adennma Ibis tuo«.r spec/rum appears to he unpue, atlhouRh chance cannu/ It eec/wkJ 11 is po.arhlr, hnwever, /hal these fimhnp miRhl repreaenl an etprestiun of the deklerinus grnnlype Ihal Mcame evidenl because of Ihit palrenl s proh.ngeJ turvi.al frnm hit rnrlral cereMllar hemang:nMattuma. l. enr A ll r. K su, D A, Roprd, I, and 1 ynch 1 f (unrrr f.rnrnrr anJ (ll•.er•aarrl 1s 11-M• 19A$ (1rArr auplr••t Nrhra.ka Ir..n«.n, 1 ralr•n.d /b,t•r .d 1 aR/rc 1 r..n. the IMparlmtnls of ('/rvenUve Medreinr/1'ubhc llrnllh snd nf Palhuh.Ry, ('rryhl«n I lnirrnny X.ht«d of MrJicrnr, anJ llcre.6tary ('ancer 6nlitule, O.naha, NI IAN('R FA fIC CARCINOMA AND IIER FDITARY NONronLYK)SIS ('( )1 OR I c' 1 At. CAN('1 N A /-AMILY SIUDY Thls paper describes a kindred s.ith verlical transmission of cancer IhrnuRh S Reneralinns which showed fea/ures of hereditary tsonpnlyposis colorecul cancrr (/INP('('1 in concerl .ilh pancreatrc cancer. The proband is a S7-year o1J w/nte male wilA ven/ied pancrealic carcinoms This pabent, and subsequently his trvallablt r.9aa.es, filkd out delai/ed med.calgtnellc pueslinnnaires lheir signed (wrrnnsnrn Iurms tnahled the autMm to cnnohnrate family, medical, and cancer (a11 sna/umic siles) hnlory throuoih secureJ pri•nary medical and palholuity dncumenli IINP('C ts becum.n; morr fYequenlly recoRmrnl than its dominantly inheriled eounlerpsrl, familial mulnple t«•lyl«nrs cnti il 1'(). a fact which has eonlribu/ed lo the recenl inereastd inleresl in Ihn dntase (Lynch rt nl, 19t11) lhere sre s1 kasl two forms of IINIY'(` (1) hereArtary srle specilre enlonrc can.er, referred to as l.ynch syndrnnse 1, and (21 /he ('ancer I amity Synda.mr, refrtrrd tn as Lynch syndrome 1/ (Ilnland snd lronrale, 19641 In I«nh dnurArrs, one finds m«llipk prim.ry eancers of the colon with an tecen of inv.dvemenl o( thr proamal cuhm I.yack synJ/ome 11 includes eancer of nlher anatomic ulrt, parlicularly the endomeurum and ovsry and possibly Ihe pancreas (:enel.c he/ern{eneily wilh IesIMY/ Io vatqlion in IYInOr speelrYm has blYarne Inc'reasin/{ly more evidrnl in QINMC (I ynch rt al.• 19t2). NeuroMastnms, a lesion mure charsaelrstic of chilJhnod, in the prohand's son at sge 22 is pueu6ng. ihere is a need (or morr biomarker snd prdiRree studies with documentatron of eancer of sfl anawmic si/rt m IINKY' kindreds (Danes and l.ynch, 1982) 1 l.ym11.JI T rtal. Ilrrr.rA Jnornal aJ Canrtr Slt271-27), 1945. 1 rom /he Ikparlmenl nf Irevenlive Medicine/PuMre Ileal/h, Ikparlrnen/ of Inlernal Medicine, f)ivisian of Gastroen(erology, Creighlon I/niversity Schmd o( Medicine and the Ilereditary (•ancer Inuilule, Omnha; snd The Mc(3reevy Clinic. Swux I alls, SI) FAMILIAI. MFSUTIIFLIOMA: REVIEW AND FAMILY STUDY To Jale, with few escepliont, pimary aNen/ion to the elinltKy of maliRnanl Inesolheliwuna has been focused acl en.NOnmetllal faclMS. Ilowevet, uveral reporls of familial aRRreRalians of ines,Nhetama slronRly supporl the suppnsilion Ihal hnst fulmt, in conceit with environmenlal eaposure, parlicularly ssbeslos, may conlr/bult elio"ically 1o an as yet unknown frsctioa of oeeurrences of this diseate Ilowevrr, /n eralualinn nf famihal mesWhelioma, il it imlorlant 10 considrr the possrbdny of 1«wsehnld rsposure In ssbeslos. We reporl a family in which /wo hruthrrs with prohmRed uccupational attwslns e.pwutt manifested malignanl pleural mesolhe6omas of similar hislnMqy I rynA, N f' Katu, 1), anJ Matkvicka, S 1: ('anrtr (::nrNr/ anI Cr/o(eNGrr /S 23•)), 1925. Frnm the Isrpartments of f re.enlive Medkine/Public llrallh and Palhn/ogy, ('rrrghhrn Uni.enity School of Mediclne, and the Institute for fsmilral ('ancer Manaaenwnl and C'onlrol, (Anaha, NF. nr I 1t