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ANDREWS OFFICE PRODUCTS CAPIIOI IIEIGIITS, MD lKl

IT ~ EXHIBIT ~ Ii 65100 7581 CTR MN 012536

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S('IFNTIFI(' ADVISORY H(1AR/1 In 1 he ('nuncil for I uhaccn Rescarch 1/ S A, Inc as nf 1)ecemher 11, 19AS 1 I UN (1 lA( ()IISON, h1 I) , C'hrrrrman ln.rrh Rrcrrltrrrn r,.r/rturr n/ MrJtrnl and 1fr.rlrrKu nl .C..r nrr~ (rm.•rnui) /'r,./,'tt,n u/ thr• J)rreprtrnrru rr/ MrA/rinr (rmrr/rn.1 Iln.vrrshy u( ('hicaRo ('hrcaRn, I/lrnms RI('/IARI) 1 IIIN(:, M 1) lh,r•rrur of f t/yvlmrnlnl C'n•Jrnlncr and Srrrnrt/.r I)rrrlnpmrnl IlununRlun Medieal Research Ins1i1u1es, Pasa(lcna, (•ali/urnia I'r.er,nc A.t,n-.ntr ('al,furma InN,lute of TechnolnRy, PasaAena J'.n/rt..n of Afr4rrrnr(rmrrnut) Itnivrrsily of Snuthrrn (alduenia S.hrN+l or Medicine I os AnRrlrs, ('aldornia I)KIIMM(INI) I/ 11OWI11 N, M 1) rtnJ l/rnJ 1).•t.aHmrnl uf PathnlnRy I /nivrral Y n( Mani/uh1 I leahh Srrrn. ea ('en(er WinniprR, Canada h11(•IIA11. 1 IIKI NNAN. M 1) 1'rrtlJrnt nnJ AfrJtral Anrrhv MichiRan ('ancer fnundalinn /'ra/rtt,n n/ AlrJtrlne Wayne \talc I/niversily Sch.N.l n( Medicine 1)ctrnil, Mi.hlRan )(K/ P11 I) 1 1 1 1)MAN, M 11 f.du.n rn ('A.r/. )nurnal of ImmunnloRy _ S.in 1)ieRa, ('aldornra ((rmMr (rmr•rrtu.). Research Institute nf Scripps ('hnia• Sa r irps ('hnic anti Rrsrar: h I uundah..n ( a 1.JI., ( alr(o.nra 1 I i / I MANI Kfl) I. KARNOVSKY, Ph 1) IParu/J IT // Mtr J'r.rJr•a,n ,r/ Ri.rlue.rnl ('h. nutlrr Ilarvard Mrdi.al Srh.wrl I1nsUln, hlawachusrUs III NK 1' I I.YNC'I I, M 1) J'.u/rt~rn orr.J l'hnrrman I)cparunrnl ol 1'reven(ive Medicine and 1'uhlic IIr:JIh Plu/r•twr n/ Al.•Ju.nr /'rrin/rnl. I lerrdity ('ancer Institule ('reirhton I /ni.•crslty St-h.wd o( Medicine (hnah.t, Nrhraska (i I/ARK Y I'll K('/ , M I) Arnrru nn ('nnrrr .C,.rl:lt• C'rntrnn.nl Rr.rar. h I /niveraly of ('oloraJu Ileallh Sciencec ('enlcr 1)enver. ('nlurado 1 GOKI)ON II SA 1(1, t'h 1). J).rr,7fu W Altan Jones l'ell Science ('enler, Inc. Lakr Placid, Ncw Yurk SI11'1 IK)N C SOMMI KS, M.D. S,7rnN/rr /)urN.rr lht• ('ouncil for Iuhacco Researeh•lI.S.A , Inc. ('hnrrrd 1'ro/ri%w .r/ Pruh.dnKr ('nUrRr of 1'hysicians & Surgeons u( l'nlumhia tlnivcrsity New 1',uk, New York. ticlealUie Slaff of lhe ('nt..cil SI1I'LIX)N C. S(yMM1 KS, M f) Scrrntr/rr 1lrrrrMr IK)NA11111 1(11(1), 1'h l) IIAKM()N l' McA1 I 1Cl/ lt, /. 4.vNunr At.,nunr Rr.rnr, Ir /In. r l..r VIN('I N! I I ISANII, I)M 1). 1)AVII)JI(/N1 , I'h I) Atsru'rntr Rrirnr.h nu,rlr.r Atuxrnlr Rrtrnr,h Irnr,rn.

((INItNIti hn....lu. In.n AI-N.... 1, ..1 Ilrp...la 11 Ihr Nry...al•nv \rcrrm 111 llr.ul .m.l f u. ulNu.n IV Nru.uph.umia..1..Ry .nd V 1'harmi..J..RY anJ 16...Ar.un1.Y VI bnnwn.d..Ry :rnd Ad.rpl..r h1r.h.nnmt V11 Me1~M.b. SIU.Lrf V 111 I hnkmuduRY I 1 a•1 III A.licr 1'rnleaN • 111) t'nmplr/r.t /'rujr.N . 190 In.lr. ul 1'nn.ipal InvrcliRilort .`Il. INTRODI I('TION I his rrpnrl rrcnrds crveral nnleworlhy events in reRarJ In 1 he ('mrncd lua/, il crta a('uun.il reCnr.l for a tinRkl yea hecauar ll cun/ainc al..ua.lc ol 1_1 prd.lrchrd carrnlilk dlKumrnla acknuwltQRmg l'uuni8 clyqwrnl Mu.r ..1 IArar rrlv.nla werr puhliaA.J in 191{S white olhers wrre puAliahavl Irca reft rnllv AI Ira.l .'JIS2 rrpnrla acknnwlydRinR f'nuncil tuplwnl have apPrarrA in Ihr lurralurr amar Ihe /'uuncil heRan prnvidinR (unda 1.o indelw•n.lrnl mvrcUgaa.ra duurR rrcrarth m am..t,InR and health 1 hn indhslta 1ha/ 1 hr (uuna d'a rrcrar.h proRram is uur u1 the minl tarnsive ul rh kmd anywhrrr (tnr rd Ihe ahclracla repteaenla whal may l.e aa.nhrr firsl putd.caliun uf a Cuun. d aupl..rnlyd aludy rn a scientific tournal in the Pruple'S Hepubin: o/ 4 1,01,1 IlurinR 1941, William 11 (:aldnr., Ph 1), rrlired frmn the ti..irln.fia Advruny huud whi.h he joined in t9/2. ' he alcn srrved suhcequenlly ac Ihr (•uunrd'a krrnlifrc 1)ueclor. loininR the IloarA in 1985 was anolher AiclinRui.hed cc•irntial, Man(rrd 1. Karnnvwkr. /'h1), whn is 1latuld 1. While /tofrauw uf (Ii.rh.Rl<al ('hrnualry a1 /larvald Medical Schtwrl, bWnlon. Since ila eslahlhhmenl in 1951, thr ('nuncil has nradt svailahle mnre Ih:m $IOO,flt)f/,000 (..1 reararch by 551 scientists (rK 9:4 miginal projea% in 290 medi..11 .ch/Nrla. Mnpilals and teuatch inslilulinns.

I I I I AB.STRACTS OF REPORiS 1. Ca.eer-Relaled S/.d1ee PLATf1 I T-OFRIVLD GROWTII FACTOR: A I.INK TO MAI IGNANF 7 RANSI ORMA fI(1N Plalekl-dnived Erorlh faclo. (PtI(;F) is the major mitogen of human serum Ir shares slruclura/, funcUnnal and inlwunolrKical pruperlies .ilh Ihe prediclid pro/eu pr-n/ucl of the vird oncolene (v-an) of Ihe simian sarcoma virus (S\V) /luman aLAlauoma, fihrssarcoma, and osleoorcnma celas, which eapress Ihe proln onculrne (c v.) Mrnndng of v-srs, produce and secrele Initosenic molecules Ihal ..e recoenurd by slwc.fic PIM:1 nliserum 1M parlral seauenca of e-s.s cUNA from human ouernarrnma crlls rs shown 1o code for the carhoaylrrminal region u( the PIKi1 2.haun of the biologically acli.e molecule of Ihe drmerie Plrtil . AnawraMs. N. N e/ af. ('anre. (-ellt !/G.arrA Facror/ an/ Tranr/uemation. Cold Sprmg 1larlwr I ahMualury, 145 -1i1, 1915. Oq1er rrplr..r: Nalional InslitWles of Neallh, the American ('ancer Society and the LeuYemra Sociely of America. Inc. Frnm Ihe Center fo. Blood Research, Soslon; Deparlmenl of Nulrilion, llarvard School of Pwbin llealth, Bns/oa, and Ihe Divisinn of Biology. Ca6fornla Insnlule of technology. Pasadena MOLE('l1LAR BIOLOGY OF CYTOCIIROME P-450 The cylochrome r-ISO-dependenl wo.oeygenases are widely recognired as playing a primary role in the de/oaifKalios and/o/ aelivalqn of aemlbiwNics in hepatic and eelrahepalic lissues. t11 the eaperillenN reporled here, it is shuwn Ihal prelrealmenl of animals .i/h various inducing a{en/s resadH in increases in 1he acti.ity and specific cnntent of parlicular eysuchrorne P-I30 isotywles and may sesull in drereases u the speeifie eonlenl and actiei/y of olhen. heGOinary iM'es/i{alions in se.erll IaMralnrKs have shorn that the increase in eylochrone P-ISOc, the /najor )-nse/hyl:Mltanlhrene inducible isoayree, and cylochro/ne P-ISOb, the major phenobarbnal inducibk iwryme, is preceeded by an increase in specific nsRNA kvek, sultnlinR a rok for (ranscrrplnma/ relulalion Inveslila/iuns .re eonlin.inl into Ihe mechanism of rryulalion fur Ihe inducln)n of IheK two proleills. tlines, R N, e..ImrA. E.. Omiecinski, C., and Levin, ). ' In Rydsl.om, 1, Mun/elius, I and Senpsson. M. (eds )! d.ahera.r f).ue AIrraA.dnrn onJ (hnnna! (acrrnaernnn. New York 1lsevier Science Publahers B V, 1411, IM 119•122. Other srplorr. Nali..nal Inalilules of lkallh and she National ('ancer Ins/.lule from the Fppky Inslilule for Research is Canca and Allied 1)isease. 1Jniversrly of NebraAa Medical Cenler, Omaha, and the Ikparlmenl of I nvuonmenlal llrahh Scunces, l)niversisy of Washington. Seallk. 1

CTR HN 012541

1 I 4 / _.._! ~,r I 1 I I *r.ek .~. 0 01% t71 7 1." Sr.' 1 N m m 1 J (!t W t AR,STRACTS OF REPORTS 1. Ca.cer-Relalel Sta/iea PI.AT f 1.1 T-Of RIV ED GROWTII FACTOR: A I.INK TO MAI 1(:NAN f 7RANSI (1RMA fl(1N Plalekl-derived powlh factor (PDOF) is the major milogen of human serum It shares structural, funcliw.nal and irnnr.nologicd pruperlies .illb the predic/ed prolein prAr/ucl of the viral onco@tnt (v-sra) of Ihe simian sareowa virus (t\V1. Iluman Rbhla.uoma, lihr.narcoma, and osleosarcnma eells, .hich eapress the prmn oncoarne (i ...) hormdn1l of .-rrs, prodace and secrele rnHosienic molecules Ihal a.e recolln.red by spec.fic PIK:1 anliser.m, lha parUal seduenct of e-ur cl)NA faum human o.remarrom. cells s shown to eodo for the earhoayterminal reftidrn rd the P1K31 2.ham nf the bn.logrcally ar/ive mokcnle of the drmeric PIl(if. A..nwrafn. It N rl af. ('nn<er ('rllr )/GrorrA Farrws and Tranr/wmwrsw, Cold SprinE Ilarbur LaMnaaaY, 14f-1H, 19tf. OrArr ruppnrr: Natinnal Inslitaea of Heallh, the American Cancer Sociery and the 1 euhemia Society of America. Ine. From the Center for Rlood Research. Roslon; Department of Nulritinn, Ilarvard School of Puhlic Ileahh, Brnton, and the Divisinw of Riology, ('a6fornia lnsutuse of IechnolvRy, Pasadena MOl E(-1/1-AR BIOLOGY OF CYTOC/IROME P-430 The cylochroiee P-4SO-depeadenl naaoayEenases aee widely recogni,td as playing a primasy tok in the delolifieNion and/or aesivalion of aenobMlucs in hepatic and talrahepalK lissues. In the taperinttats reporled here, il is shuwn thal prebeatmeat of animals .ilh .vrious indacial qenls resde in inereases rn the acuvity and specdic conlenl of pulicr/ar eylucheorne P-4SO isotynses and may resull in decreases on the specific contcnt and activNy of others. heliminaey ievesliplions in xveul lahe.a/nrres have shown that the incrtase in eytocboae F-IyOc, the majo. 7 meMykMdanthrene inducibk iso:yme, and eylocArowe P-4SOb. the wajw phenobarbotal inducible iwryme, is preceeded by an increase in specific mRNA kveh, suggeuing a rnk for Iranscraptiunal re6ulation. In.es/iga/ions are eonlinaing inlo the mechanisrw of regulalinn hn the induction of Ihese two proseins. Ilints, R N, d.esnrc4. E.. OMieeinat<i, C., and I.evin, J. In Rydsl.om, I, Munselius, I and ReqNson, M. (eds / EerraArMqa• fr.uR Alrnalr.hrm anJ CAreneral fnrrn.rgenrsts. Ne+ York. I lsevier Science PuAlrshers b V,-1v11, pp 119-122 OtArr supprt. National Insliprtes of Health and lht Nalional Cancer Instilute From Ihe Fppky tnslisu/e for Research in Cancer and Allied Distase, 1/ni.tnily of NtMas\a Medical ('enter- Omaha, and the Ikpartmenl of 1 n.unnmrnUl Ilealsh Scrences,lln..er.iny of WasAinfilon. Stattk 1 (/1

IrNA 1Y)LYMI RAS/- A('11VITY IN A RI PAIR 1)1 t 1('11 Nf 1111MAN l'f1 I. 11N1" A human low densilyhpoprotein (I OL) receptor-dtficirn/ d,pt.ad fiMohlasl cell t.ne 1(iM191S) was Jelerm,ned to be shorl patch cnmpettnt (IINA (nlymeratr O) and lona patch defstrwnt (IpNA ry.Iymetate~o) for DNA He.sw.n repa.r Anatysit of DNA fn..n (,M101S crllt o, frum W/1/ ennlrnl eells, fulbwinR Iretlment wilh a mutaten An,.wn s,t rn,tralr h.ng patch escninn rrpau, showed Ihal 1iM191S crlls e.h.h.lyd rk.rrot.J rrtynthet,t n( ob;unuckntrde srgattnls eacised Jurnng repait When ellt del,crenl .n hNA I+drmtrne a activity were perreeabiliatd to perml I bl en/ry, rrpair tynlhetis ,mmrJ,alrly .ncreated lhttt JaU suggesl ,ha1 IsNA pnlymeraK n rs mq s.l.van.1 t.y mutaRen uealment in GM191S eeth and that .nlnNtuc/urn of I Isl mto tLe ce1/t rrsuht ,n a, r,val,nn n( Ihe enryme fne. C 1), Norman, 1O, 1rv,n, 1 R, and BwMr 1) L. RnrArmrol anJ R,npArurnl Rrseorrh fumwrw,uanw. 129(2) 1S4 .150, 1985 /7rA.v .,.prn.. National Inuilutrs of 1/ealhh, t/ S Ikpnlment of ARriculture, nd Ihe le.at Al.,cullural I eprr.mrnt SutN.n From the I)rpartrnent of Analomy, and IAparlmrnl of Phyt.nloRy and PharmacnlnRY. (blleRr nf Ve/er.nary Mrdurne, Itsas A A h1 IlmvetatY, ( ulle;e Stalum, snd the Veterrnary ln.n-o1ogy and Inlomolngy Rnrar.h Iaburalury, l/S Ikpartmenl uf AI{ncullurt, ('nllrRr Slal,nn, I % I , l..rrrdrn;r of rhe Surrrtr JM Eaprrrntemaf Srolngr and afrdrtrnt 179.116-122, 1985 Othrr ruppnrr- National laslilutn of Ikallh, Teaat Agricultural l:.ptrimenlal Slation, amf the U S bepartmenl of Agrieullart, College S/ation, 7 X I ram Ihe tXpartmenl of Anatomy and Ikparlawnts of Phys6doRy and Pharmacolngy, ('ollr;e of Velennary Medicine, Teaat A A M llniversily, ('olk6e Sulrun AI K YI-A 11ON (>t U1(1XYGUAN(KINC DY 711t. SLSOUIlLRPFNF LA('IhNI IIYMI N(1X()N llymeno.nn, a/oeic sesquilerpene laclone found in the ruminanl fnrage planl Hrmrm.trr ..Joraa, binds deoay6ranosine in a eell•free system and (orms adJu.'/td guanrne rrsidues in sheep lymphucyte UNA-` Mdunen-slimulatrA I/NA synihetu in lymnhncyles was inhibited by hymmnuaon st eoncentralinns Erealer Ihan 100 r.M t/nscheJuled DNA syMhesis in Iynq.hoeyles wat inituled by hymenaton concenlraliuns eecreding 50 pM, and inhibited by eoncenlrNions above 100 YM We drsceibe an IIPI.C method which sepuales unmodified hynsenoaon and deoayliuanm.ne from Ihe hymenoaon-deoay6waosine addr.cl and albws the qranliulion of adducts m hymenueon Ireated cells. Sylvia, V. L, Joe. C. O, Slipanovic, R. U, K im, 11. 1.., and tiu.hrr f) l. 1'onrnln; r l.rrlr.. 29 69-76, 1915. P(/1 Y('111 f)RINA111) 111P111 NY1' 11P1 AK 1 ANIr IRANSIY/R I IIY I Yh/l•11 ANI) /'l A`1h1A ('(IM1'11N1 N1oi. The upta\t and vatcular Irantporl of ngetlrJ Arnch,r 12N:, an INlnret/c m.uure of pulYtAl,rnnsltJ b,Phrnylt (IYI/l, wat rnvrtl,aaad m e.prrm.roul animals Il,;h cVnte111NIM.ns of mRetltd P('R wert founJ in Ihr chylnnuc.un frmainn nf IMnaiic ducl lymph When the lymph ltow wat ealeruuueJ. P('l/ wrre nul sul.sequrnlly founA n the vsatutae eirtula/inn When lym/.h wat nat e.letmrisrJ plasma 1% H eonantrnurns rrached ma.imal kvels 6 hr afrer inRest.un I ets than 1% of h,tal plasnn 14 11 was delecled in ctllulac fracin.nt of b1ouJ over a 10.hr ptrid fulluwin6 u.Reslu.n ('hyM.miernnt eonta.ned 11% of 10121 platma Pl H 10 min afler m`ettinn, dec.eavnR to kst than 6% a/ 6 hr A masimlrm of 10% o( plasma P('H at I hc, and <ytt at 6 ht, dler in;esliw.n was nsociateJ wilh very low dentrly hpnproteins IV11/1.) ur low drnuly lip,yuoteint (I lf/ ( Although P('R enler the vatcular circutatiun with the chyh,n.wron ftsctrnnt of lymph, detq.,prn/tinaled platma ennlaintd S2`1L of Il.e tuul 1Y'IS in hh.wl co11ec/eJ 10 nrm after .nRestwn Ihn k.rl m.traxJ to 1!% afler 2 hr and remamed tnntlanl sl abnu/ 10'K (nt an aMldwna/ / In prrw,d Ik.Rh pe./orman.e Lqu.J ehamulnflr.q,h.c ttimmationt of delrlnM'rote,nalyd plaima from hhunl l.,hrn 6 hr aflrr P('It .nRetln,n SM.weJ elol«,n of r 93% uf plasma P/ 1/ lo to.nt ide w,lh the alhu.n.n peak I kclr,yrhorrlic r.aminaliont of drlrpoprnlrinateJ plasrna showtd Ihe ata.K,ahon of 1'('11 wilh alAumtn tu be noncnvalrnl /he retults suRges1 that a(+olar IY11 a.e abtnrhed into intefanal epnhelial cells /rom which they are staeled inlo Ihe lymphal.c dramaffe sequettered within the apular core of thyl,.mru..ns, that Ihese IY'H transrt she Ihotacic duct anJ enter ILe vaKYla/ arcubtion wilhin chylnmicront and aee melaMdhred nr, nthrrwr.r relrased /rom chyb.mrcroos dutmg hepahc chylomcron elraranke, and 41,31 retuhmS Pe R ur P(L H denvalives eireulate in sssoculion w,rh plasma album,ns 11u.Mr h I rr nf 1 I Orher tuppnrf- National Inslilu/es of Ilealth, U. S fkpartment of Agricuhule and the leus Allricullure 1.a(.erimenl Station I rmn the beparlmenl uf Analulny, and tkpaslmeM or Physinlolly and Pharmacohyy, ('olle6e of Veterinary Mediciae, Teaas A• M llniversity, College Suuon, and the Velennary luaicology Researeh Laboratory, U. S Ueparlment of Aaricuhu.e, College S/atum, 1 X IIPf AK 1. ANU VAS('ULAR TRANSPUR 1 OF INGLSiII) AI LA 1l1%IN ihe uptake and vascular Irsntpor/ of 6aslrically instilled aflalosin D, (AtR,) was investigated in sheep Af/atotia uptake was eompared with /hal of pdmna/e, a water-insolubk oil Ynown to M absorbed isln Iht inteslinal lymphalie drainaRe whith hyhasses the Itver lu enler the peripheral vascular cirrula/inn vis the Ihoracic dw"1 After inttdtatiun in anuna/s with ealerimired thuaeie duct flow. AI 11, was detectrJ in rnler,ar vena cava blood wnhm 10 min, ohile palmitale was not delec/rd in vena cava hhw,.l sl any time Palmna/e was detected io lhuracK duct lymph aftrr approaimarrly 2 hr (:realer than 95% of palmnalt in lymph was associated with the chyl..m.crun /racln.n. wh.k afbtoain .n tuhtr plasma or lymph was no/ deleclably atwKUtrd wqh any nf the ciaculating l.pnp.utr.ns. tn addilion. All/t d.J not parlilron .nl.. platma or lymph Lpnpruternt rn r.a.. Toeie lipophilic arnobmlics, such as brnr..lalpyrrne anJ p,JytMueinslrJ biphenyls, do paalilion iMo IrputNUleins, are abwrheJ .nlu the .n/ru.nal draina6e, byPats the Irver to direetly ealer the penpheral vascular cuculatM/n, aml ate not specifically hepalotoaic. These data indicate that Ihe mode of AI H, aMnrptmn 1r..m the 1asuointeumal syslem rtwlls in its immediate transpuct to the Irver, whnh may eonlnlwle to AI H, hepasolonicily. Wihon, R, 7ipr,n, R, Ragtdale, S, and SurArr, 0 a 1 9 I

r o. rrnrt.. y I rnrr 1 1 tO(1 - 2/69. 7a, 1925 OrAcr tup(.nl Nat.nnal Inst/1u1es of Ileallh, 11.S fyepa.tnxnl of Agricullure, and the Ietas ARIKYhure L.prrimenl Scatiun 1 rnm Ihe Vetermary luc.cokray Reualch I ahnralory, lI S I)eparlment of Apia-ullme, (..It•Rt Slatwn, 1 X, and Ihr I4parlmtnt of Ana/omy, aml tsrparlment of Phyvutnay sn.l /'harnn.nh.ay, ('ullrar uf Vrtr.inary Med.cine, leaas A A M U/uveaay, l o11rKe Stalxm M1f(N 11ONItR1A IN 111M(1R (-II IC 1F11CTSOF CY((YKII I IUNUN 111S1R1111/11(IN ANI) AS lAR(:I.IS /(IR SI LL( IIVE KILI IN(: 1hr ha..t far the ddfrrrnce in milnchomlrial rhudam.ne 121 re(tnlinn Irlwrrn (arauu.ma cella and n.,.mal epahtF.al (rllt .a t/dl un./rr uaal.Ral.nn /luwrvrr, .t a ldely .u.e nf Ihe la.lora invnhrd rt Ihe h.Rhtr rnlhahondllAl memhune (wnrnlral in . a...m.m3 crllt It .. of .etr.etl to n.ne th.1 /hn rs the revrrae of what kat hern ol•.rr.rd in no.enal anJ tun.fu.mrJ m.nk f.b.nblatts rletpne the lack of underslanJ.nc .d Ihr hatn mr.ham.m, th.t wurk confnms, .n a pa11u1 and prrt6mmary way. Wa.hu.R't u.lunw.n 11.a1 paf.na aUen/n.n 1.s aot.qhnndru .n lamor cells may uhunalrty hAp the Ilra/mrnt of ranarr ( A.•.. r 9.101 In I r.m, A 1 rr ur (rd. I 1A. 1•un./„•.n../ PA.n,.rylv ('o1,t SprmR llarho. I ahnalnry, (•)a1, Pp )% 16 (rlA,• .Y(•ry•.t N.IIn.n111 anar. In.1.lu1- an,l ll,r Anmrr..an( anCrr tlNKly troa. the 11.nt 1 ulrr 1 anlr. 6r1....v a,•./ .1.r /hpul.ornl ..( 1'a/hul,.ar• Ibr.a.J Mrdn .1 %. 1h,./•,., 1(1(-A112A11f)N /11 1 NI1(tPl AtMI(KI 111 14 11h1 IN I IVIN(: .\NI)(il U1AKA11H11111c1 /1`(1Ir1/I1 S Wllll 11 UI/RIle( 1 NI 1)YfS Cerla.n (IunreMrnl dyet, prev.nudy rrl.uted to localae mil.uhondria, wl.rn used at hi0hrr cuntrmral.oes a1w h.:a1.te a cont.nuous net-hke slauc/ure in Mlh Ir..nR and plntaddrhy.k /rttJ crlla A slm.lar relicular struclure can he deleaed by phav cunlrasl m/cruacul'y and whnk•muunl tkcbon mi.rotcupy in (olastium prrnunRanale (..ed tells as well. lhn sbualure is moally lubular, w.th sume ?ahhl.ke arraa. and rs likely to he the tndopbam.c re1/rYIYm lhe orltaniaal.un of Ihe rrtwular ah...lu.r is vnsdr.r In cohhic.ne and .ulrnone Iwl rto/ lo cylo.halalin R, /s.ul, monra.a, rhr.alcium «.nnphore A21III1, 12 Iltrt/adecamlylphorlMJ 11 aretale, or hyJ.nc.A.v.nr Ir.aoki, M, SunR. /, Wung, I R, Wtnt, M. ), anJ ( Arn. /. It (.r/10101 t01, 1914 O.Arr turpor/ Natu.nal (-anctr Intlitute I rnm Ihe (hna I a.lvr ('sncer (nu.lule and the f4parlmenl oF Palholnay. Ilar.arJ 6tr.INa1 ~aMr./_ h...l..n 1 1 MI1(X'llONbK1A1. ANI) PLASMA MFMIIRANf. POI I N11A1 S(-ALISF IINII\11A1. A(Y'1IM1/1 A11ON AND RF.TI:NII(XJ UI RIIODAMINI. 121 RY 11lIMAN RRFASI At71 NO<'ARCINpMA-1)LRIVLO M('F-7 ('1 I 1.S Ouanlitatcve sludies of MCF-7 cells (derived faom human breast adenocacinomal and ('V-I cells (from normal African green monkey kidney ep/(helium). us.nt Ihr permeant catamc com(found telcaphenyWrMrtph.m.um (/PP), in cunryncla.n wnh 1lunrea:ence m.crmcopy srsing rhm/amine 12) (Kh12)1. indreale /hal the rniuwhumlrial and plasma mee.hrane potentials affect both uplake and cetenlion of Ihese Fompnun.M IImler lrlndll/un7 1ha1 dep111artre 111t p1as111a menlb/ane. Yplake and relenlN.n of 11'P an,l Kh121, driven only by Ihe mduchnmlrul memMane puteMUl, are grealer in MI'I 1 Ihan in ('V I An .om.phore that dmipHes the mituchonJrial rllembrane pulenbal of M( / I cellt calut them 1u resemble ('V-1 « Ih by decrtatin0 uptake anat relrnln.n Iry(.rrp/.lar.rinR the miluchundrial membrane of ('V-1 inereases accumulalion and ryruh.eits rrtenlwm, hyptrpula.ua/intr of the plasma membrane furlher heqhlem Ihn r(Je.l, cau..ng Ihe uptake uf CV-1 cells to tesemhle /hat nf M(7 -7 cells even m.ne clnsrly Iht Rreatrr upuke and retention by M( I- - 1 appear In be a cunte.luenct a/ ekvaled ma.khnminal and plasma rnembrsne ppNenlials lke plasnq memhranr potential a(frrts m.h.chond..al retenliun uf l l'P and Kh121, anJ its role in enhancing 16e elfect u1 a ddlerenie in m.uwhondrisl membranr Iwleni.al s eqda.nrJ Isavn,S,.vuf ((Arn.(..R) ) Ar J.wrnu/ u/ Ru.l.sn or ('Arm.l. r 2a0.1)IJA-1)tSO, 1985 1 rnm the hana-1 arber Cancer Inslitutt and Ike Depaualrnl of Pathology, llarvard Medlcal S.huol, Ruston MI I(K FI(1NbR1A IN LIVING ('C1 I.S. 1.111 ('1S Ua(:R(/W 11/ / A(' I( /K5 ANU 111M(1K 1•KOMU11 RS, ALl l RAl I(M1S IN ('AR('INUMA CI 1 1 S, ANh 1 ARGI IS I ()K 1111 KAPY Rhodamine 121 is vseful for Mleallrinif milochc'nAria as well as lor reflect.nR ekconthemical R.ad.enls arross mi/.ahnndria in l.vins cells. I he laller is sulnlanlutrd by truaphenylpho.pMwium (IPP), a widely usea/ memhrane Mnenlul pr.ul.e 12 0 1elradecsnoy/pMfrbul 1)-actlale (1PA) eonverla fdameMUUt mil.wtnmdna ml.. a Runular s/upr but d.les not affect Ihe elecln+hemical grad.enl. Ptalekl dercved gruwlh i faclnr kads to an increase in milochoedrial anenlbrane putenlial as WQII as to a clYS/erlnd of mialchondria at /he petinlrclear re0inn 3 hr a(ler uealment uf reslin0 RAI R/c 11 1 cells Whereas the majority af t.mur eell lines do no1 have allered ekclr.rhrm•.al graJirMS aa.ns nulochnndna, the Awms of t.prestion between mtmhrane (mlrnlul an.l pll {radirnt can be varied Fot nunlerous aJrnncarcinorna deuved cells. Ih.t Sralwnl ap(•ean 10 be prefrrenlially etprtssed as a anembtane polenlial lhut. the mauwh..ndrul ncemhrane Iwdrnrol is Meher ia adenocatcrnoma eellf lhsn in normal epaheh.l .ells these carc/numa cells lake up S-fokl /0 20-/old mo.e rMM/amine 121, IPP,ur nrhe, hpnp:ul.c, rahun.t compwndt that can rraah maochundrra than du normd rp.uhrlul eells IMs phenotype may be eaplui/eJ fnr ehrmo/htupy of adtnnayrcinnma tells A /pM.pMl.c, eal.onic dru/. deVualiniam chlor.de, v.nfely useJ fnr surr (Moat in humans, n h.{hly Incic 1.9 carcinoma tells anJ tahlbrts a tr{n.(iaant anlaa.cinnms a.h•.ty /n an.mak ( Arn. t.. R tl nr. ('AN(F. R(!([ S )/Gru..rA F.Norr snJ Trun./.unmuon I aM.rato.y. 1'/kS (-ul4 Spcinat I/a.lwu In