Council for Tobacco Research
1984 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
Fields
- Depository Date
- 25 Sep 1995
- Master ID
- Ctrmn00010849-2859
Related Documents:- CTRMN010849-0887 Deposition of Lorraine Pollice [Deposition of Pollice in the Matter of Allgood]
- CTRMN010888-0889 Scientific Advisory Board Members 1954- [Record of Names of Members]
- CTRMN010890-0892 Curriculum Vitae [St]
- CTRMN010893-0919 Curriculum Vitae [St]
- CTRMN010920-0926 [St]
- CTRMN010927-0938 Curriculum Vitae [St]
- CTRMN010939-0956 Curriculum Vitae [St]
- CTRMN010957-0958 Curriculum Vitae of Dr. Mckeen Cattell [St]
- CTRMN010959-0960 Curriculum Vitae of Dr. Julius E. Comroe Jr. [St]
- CTRMN010961-0974 Curriculum Vitae [St]
- CTRMN010975-0990 Abstracts [St]
- CTRMN010991-1010 [St]
- CTRMN011011-1020 Curriculum Vitae [St]
- CTRMN011021-1056 Curriculum Vitae [St]
- CTRMN011057-1082 Jeffrey Robert Idle Curriculum Vitae [St]
- CTRMN011083-1092 Leon Orris Jacobson, M.D. [St]
- CTRMN011093-1116 Curriculum Vitae [St]
- CTRMN011117-1123 Curriculum Vitae [St]
- CTRMN011124-1126 Curriculum Vitae of Dr. Paul Kotin [St]
- CTRMN011127-1128 Curriculum Vitae of Dr. Clarence Cook Little [St]
- CTRMN011129-1132 Biographical Sketch [St]
- CTRMN011133-1160 Curriculum Vitae [St]
- CTRMN011161-1161 Ctr Mn 011161 Is Unused [Record of Bates Number]
- CTRMN011162-1163 Curriculum Vitae of Dr. Kenneth Merrill Lynch [St]
- CTRMN011164-1166 Curriculum Vitae [St]
- CTRMN011167-1176 Curriculum Vitae Gordon Barry Pierce, Jr., M.D. [St]
- CTRMN011177-1178 Curriculum Vitae of Dr. Stanely Philip Reimann [St]
- CTRMN011179-1180 Curriculum Vitae of Dr. William Francis Rienhoff Jr. [St]
- CTRMN011181-1190 Curriculum Vitae of Gordon Sato [St]
- CTRMN011191-1219 Curriculum Vitae [St]
- CTRMN011220-1239 Curriculum Vitae [St]
- CTRMN011240-1241 Biographical Sketch [St]
- CTRMN011242-1243 Curriculum Vitae of Dr. Edwin Bidwell Wilson [St]
- CTRMN011244-1245 Curriculum Vitae [St]
- CTRMN011246-1274 1956 Report of the Scientific Director [St]
- CTRMN011275-1325 Report of the Scientific Director [St]
- CTRMN011326-1359 1958 Report of the Scientific Director [St]
- CTRMN011360-1396 1959 Report of the Scientific Director [St]
- CTRMN011397-1430 1960 Report of the Scientific Director [St]
- CTRMN011431-1467 1961 Report of the Scientific Director [St]
- CTRMN011468-1499 1962 Report of the Scientific Director [St]
- CTRMN011500-1500 Ctr Mn 011500 Is Unused [Record of Bates Number]
- CTRMN011501-1535 Annual Report of the Scientific Director [St]
- CTRMN011536-1576 Report of the Scientific Director [St]
- CTRMN011577-1619 Report of the Scientific Director [St]
- CTRMN011620-1662 Annual Report of the Scientific Director [St]
- CTRMN011663-1720 Annual Report of the Scientific Director [St]
- CTRMN011721-1765 Report of the Scientific Director [St]
- CTRMN011766-1815 Annual Report of the Council for Tobacco Research U.S.A, Inc. [St]
- CTRMN011816-1870 Report of the Council for Tobacco Research - U.S.A., Inc. 1972 [St]
- CTRMN011871-1871 Ctr Mn 011871 Is Unused [Record of Bates Number]
- CTRMN011872-1921 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
- CTRMN011922-1968 Report of the Council for Tobacco Research, U.S.A., Inc. [St]
- CTRMN011969-2011 1975 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
- CTRMN012012-2057 1976 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
- CTRMN012058-2101 1977 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
- CTRMN012102-2156 Report of the Council for Tobacco Research, U.S.A., Inc. [St]
- CTRMN012157-2210 1979 Report of the Council for Tobacco Research - U.S.A, Inc. [St]
- CTRMN012211-2211 Ctr Mn 012211 Is Unused [Record of Bates Number]
- CTRMN012212-2268 1980 Report of the Council for Tobacco Research - U.S.A, Inc. [St]
- CTRMN012269-2329 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
- CTRMN012330-2386 1982 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
- CTRMN012387-2458 1983 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
- CTRMN012534-2534 Ctr Mn 012534 Is Unused [Record of Bates Number]
- CTRMN012535-2647 1985 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
- CTRMN012648-2744 1986 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
- CTRMN012745-2844 1987 Report of the Council for Tobacco Research - U.S.A., Inc. [St]
- CTRMN012845-2859 Partial Listing of Research Institutions, Ctr Grantees at Those Institutions, and Dates the Grantee Received Ctr Funding at That Institution [St]
- Author
- Hobbs, W.D., Ctr
- Request
- 118
- Type
- ANNUAL REPORT
- Box
- 006
- UCSF Legacy ID
- vvr30a00
Document Images
.knaty hpiq.dttn 1 VI hl ./ awn'cnlr.ltnrn. A u.ttclalinn c1uJy u.u1K 14 Iminan .nh
htl. %h.IwtV1 Ihal M'rU111 /(: tv.fnenlralnrn wa.lhe he%l (xcdahN Ir - 1/971 P
II IK111/.1. Ilal' ulM.dr by .crunl (Lllawr.f by phinrhl.hplJ (r /1 f.Kt, 1' 111/1/ alml
ur.1.h..k.tru.Ilt 1/SI1,P' OI)SItPrllrnlratltM\ I~h'tlSUIhItMhtalelhat%lrulll
iG CINIarnlliJlNw1 Ilyp,tj0y VI.uI. I(:/ /nay he the pmlary Lntnt allr.nnK Hal'
ulw,dr hy .rlonl I.I' :Iml ay~lx.t thrt a.mull t h.nl;e tn.crunt I( i t allcrntrauun ..MdJ
I aua a.qrnln an1 /lw rc.1.r ul 11a1' ulw..kr by .cruln I.P, ctwltrlhutung lu an uw /ravd
kvtI ol t nloLdml; c:Irlllw.Frn
YL.. I\ 11 , N..rnlan 1() and Itwl.rr. /) l..
1'r.r r.JtnXl ../ I hr .C..o rrh /..r F Ilrrrimrntul NL.lr.gv ttnJ MrJn mr 177 414 4 III
1')K 1
IltArr tupporf: Nahunal In.h/ulr..4 Ilralth 11 S Ikl+anmcnl t.l Ayr/.uhurr and dlr
Irsla. Alr/luhuF]I I'mi14'/Inlrnl tlall.on
1'r.Ha dll 11rp.utnlrnl. ul Anaamly a/1J 44 1'11y.nQl.Ky ant) {fiattnaroh.Ky ('ullrKr .11
Vrtrnnary Mr.lnulrN ltca. /USM Ilnlver.ity, ('nikRr Statl.nl, Vrterinary It,.N.d
flgy aINI I ntIw/M/h/ry {(l'%cJrl h I_.ahlMaauy I InurJ Ytate. Ikpartnlrnl ut AKfwulturr,
(1.Ik4r Stminl I X
A RII.A111/NS1111' NI 1 WI+N 'llll, YI,AST (l l.L ('Y('I.f. (:1'.NliS (IX'J ANI)
(IX'p. ANIy 1111..r. SI,I)111N("1:(d (1N('(Xi1 NI(' VIRI/S L2A
krlrnlyd hrtc /. .IRnllitanl prlul.uy .ryutnlr hnnwduKy anlwnK Ihc prcJlcletl
Ira/I~IdI11MJ/ IN11111N'1\ LI Illll'r I,'t'11r~. ( I K 4('I K((1, arlt/ rN ('1 X4 and (1 X10
.ur
C.n, hunnrltv.'t rrrrrilnrr .cll dlv/.nal t yclc I:rrlr-, whdr rf. 1% a Iran.hwntrti.wl
.pc.lhi Kyurlce ul avlan rrythnthla.toa% vinr.1:lh llrc JrJurrJ pronary .tnw turr.
nl thc dlnr FnK lIHnhKll were ttNlll.]rl'11 by lt1r111qllel t/l a Iarl,'r llala h11Ve t)/ I M/wn
antl ptrdNlcti prturm .eyurncr. lhr varch nvcakd 22 11 22 S'4 iJenlily .uvcr re
Rull/. ut 1411 21kh alrk+nv fr.perlivrly. hrlween Ihe J/Ilrrenl p:lnwt.e cawnhinalnm.
1'tM Ihl'K Igr1MUIN V tlul'rlCe\, Ihe.c «krllily .auret lall 1.4 4 11.IarltlarJ Jevi:uanlc
ah/vc Ihe rnMarically tklrrlnineJ nw an value. td Hu(uNtluc vimrlarily. S. rrr.rr.ntr
4,01% rcyuire l 1 X lA and ('I X'4 in urJrr In ctlrnpkle Iwo early events in the cr 11 /ycle.
r.ra u1Mln ll/ .tarn (('1 X' lh/ aritl ywnJk plllc htK/y aeparalinn /('I X'4/. In viru.1:26, the
rlv vyurrlrr ts hnkcJ in Irame wilh JK.ex and /nvN rn Ihe Irilwlitc slructwe S' AKuX
nrvH rrt- 1', rtlnqxi.inK 1he 1:2A Iran.hwminR tmtt>gene. lhr htmwdnRie% tk.crihrd
hrre .uKgea thal Ihr 1nt.'hr nlical lum W/m ur /eRulalil/n n( Ihc (Y XA, ('1 X' SA and rn
pr..luao may hc related
1'Nrl.on. T A, Yuchcm !, Ilyer.. N. Nunn, M F . I)urlMrR. P Il. 1hdntlr,
K 1' .uwl RccJ, S 1.
Nnrurr MrNS'Ndll S% }SK 19R4
Other sMpperrt: NNw.nal In.tilutes u( Iiea4h, Naliunal Seience fnunJNitxl anll the
Anlrri.'an Cancer tita lely .
Ilom Itle I)rpanmenl.d Hlnh.ltical Sciernr.. (/niversily of Cah(I.rnia, Sanla Harhara;
1 kpartnn n1 ul (:rnrtN .. I Inlvet.ity t.l W a.hinltlon Seaak;lkpartmcnr n/ Mokcular
Iladnyy arwl V In/.I a(.Hat.a y, I lnlvrt.ay u/ ('a111.wnt., ilcrktky a/wl the 1 kpannlrnl
4.1 ( llr.ul.try I Ilnvrr.ny 4,1 (./ldunua San (/lcra, I a I.r11a
IR11'ARI111: .S"IRtt( 111kI O1TIIIiAVIANI:RY1111((1111AS II)SIS VIt(I1S
I:!b 11(AN\I l /RMIN( i (il.NIi
I INtr :rrr la/ly tw., avl:m nnt,.gcnir vim.r% that .Ixcihl'.Illy t auv .a tnr kldr
oua. \t'1 Ik. IMM I/.IIIAINIIt t hll Ll'/l IIInn11Ia%1\ 111 CIIIIIUI' (1) 1t2ll wI1N h C:Ita%r% r/
yltl
udd...tn.1.:uMl a L.w kvrI tll llnlt'1N111Ial/t Ulyt'krhla%tlhl\ /II lltlcl.rth a1M1 (21 avt.m
mycl,dd.l.tua% vltu. 1AMV/. wkwh cau.r% nryrl.ddr.u.a% c.t Iuavlly. 11.U1/ vlnl.r%
arl' IrpIN:111.111 lk'IlY Ilvr IIMI \harl' a%rt111rrIlT Il'r/11r1I /n\11 (aIV.I,IM.WII a% 11011 ) )
Wllll I1
IV 111111'I.11lYI ../ l'V4'1111./1 virllnl rr/N% aMI /% Ihl'rrhMl' IIMM/r111 1.111r p./r/ ..1 Ihl'
11.1/1
lunmruf dvr. FtIll'] tul IIN'Y' Vlfulr\. Ih.wevl'r. IIN'lr11r11C VtnN'tUreUl IIh' 1W.1 V/lll,r
dlllrr ('t'Mnllll RNA o/ t 7 kiklha.r.libl alwl rnr.rk. a 1(t,IMMI nM.l.t ul.u
wrl/:lbt cur Irl.ucd pnlaru11p11S1 wuh pnlh.lhlr Ir:n/.Iutnnnl; lulwlMU1 I Ilr mvr.llp.l
LN% %IN.W IM'rr by tll 17H..IId/1~I:NuNI /ha1 tlle S 7-Ah (:!f. KNA thrcct% dl. .ynUk./. M
pl lt /)I1F.NII/l Il'.N/lk' a//alylN IMIN'all'] q/at 12b RNA ctwuain% an rnlrtnal 11 K Ab
mIhN'1.-1IIN'I ! (1.AMV frlatrdvqlMnlr/n/l/.y.lrnllrtlmvlr A! 1/.Abna.lrllJ.u
lt6Nh /nrllI/l'li IHnll l1yNA I/aowrltttl tn t'rn., hlNn 1:2fr RNA cleu:ul/rd :m 1!r.
Ir.m.l.wln.un.a .prt d/l Irrl1 wyucncr IIanLrtl by nnh' arrl an.m' rcl:drJ ..qurnl c A
.unryrktc 11NA uyul/k r.ll thre ckmr irwlit'atr.lhat Ihr I S{,h ru ..ytlcrw r ra1c/K1% tllr
IMtcn rcathnr laullc.d rmb' Iur 4'q auintlx n1.. 7 hu. Ihc p11S I;rrlc ut 1.!h t, a
Flrll'tlr
IIyMh1 ul II11rr tIN111nt lIrlllrnl% 1.2 lh.k'rivcd Inw/ /hr S' nFi.ul ul Ihl rruuv/nr.
1.C//X rl'/h' .n1/r' a111I Illr Pr..cyurrove. linkrd /1/111e rqtkr S'-A(n,r In111' .'ll t* 1tN'
ulyrl.nJ Irul.ruw.ycntclty .harrJ by L216 arnl AMV rtlrrclalr. wnil thr aumnl..n .n.h
vvpwrllr. whlly dn dl.uncl crylhrultl k'uAcnll.gcnirily ol 1:26 t'twrclatr. wnh.r. elal
111r 1:!6 yw& d/c bnAal:r 411 .nt'h lo AgaK.
Nunn, M 1: . Xcrhufy. P. II . Mtrvuvici. C.. arwl l)nr.hrrg. P. ll
Mrnn. 11 INMkN1I (IK/ I'll 195. 19113.
(kbrr t.r/ryrrnt: Natemal Inwtu/es t/l llcallh antl llk Mcdical Research lrrvitr ul IiK
Vrlrran. M1nlini.IraUun
lnnn thc IkpanuKnl ut Mukculat Rinklgy ant) Viru. Lalwwaday I/oivrr.ny ..1
(allhunra, 11rtl,rky, (:rr/cntr.h. /nc., Stlwh San hramri.cu; ant11111 Vlru. Rrvar.h
Irlxwa1Hwy, Vclrran. AJlnmi.tratitlu 1hr.pNal (iatnr.vilk, 11.
.
QIIANlI'I'All(/N (1F 1111KON(XiI:N INhI.IIX AN111111RIN 1)1 P11ti11111N
AN11 I'(IkNI1Vta( IN LINIi I AN111.IN1:1//(iUINI:A 1'lli ('Alll'IN( IMAS
lbc dala Ilrcx rurJ here IMnvilk a spanlilative analy.i% u/ hhrinl.ycn inllua :Iml
/IM/n al'l'1111n/I:11MN1 anll lurnnver in line I anll line Nicarl'IlNnna\. 1/1rl'111caIIy I:MIUIIJ
hrkd Kurrlra prr /ihr/nl/yrn HiMl wa, u.eJ NI mea.we /ihrl/Mrren mltui arwl hMlo
at'l'unWI:11NM1 1/1 hne I a1NI Illlr 141 he/laln (Mk tlU.'11 t'arvllMMn:N rt..w/nl,' in IIN' \('
y.:nr t/l .ynKrncir .utun 2 Ku/nra piK% uver /hr ntNU.e td 7 Jay% h.lk/w/ng trau.pl.i/lt
l lu% tnue .twuvr aplr.eM. an ullrrval .d /tnti.lh wnImplhd alcd by unnnmuklyu al
IInIMIr Il'/1Y1Nn1 M by lIgn111aarN IUmIM nK'nN 1'mIMr /IIUIIwN1111NMCVtI/Nr dIN1a'
revealed hhrin Jrp.alc in IwMh lunwro with lun' I s- Une 1/1 In ara Ilyd wnh thr.c Jatr
(:Ph accumulaleJ in htwh Iwlwlne in anrwM.Ihal nukheJ rr eacenk tl pla.ma blNUU.
Fcn kvel. Linc 1lanltw ( il'1 a1MeM wtnr 4 f.411 Ereakr than that o/ line lu tunww. a/1J
II .3 1-IuW thal td MNnlal % a li..ue. The c.wnpu.ililln rA lunalr /ihnm.Frn //Arln wa%
nlvelt/Kalet111y al1Ue.MN and Urea ealfal'INM. The Irat'IMlrl /./ UIIaI atlunlulatet/ (:I'1'
that was urea imt.luhk, and thcrelure prrwmallly cn/s-hnkeJ lihrm, wa% c.ul.rant
uver lime hul slriltrnKly tlrlicrenl hr line I IAS'I/ ant/ lrne 10 (4N'R) IunMN. a\ tiun
IK 1 19
P.ucJ wt(h contlul o c tl..uc IIR'1{ / Hy 7 Jay.. line I(unha. (mean wcllIq 11 77 r)
-/11;I11xYt lx-.nIy 2 r1/F' .11 (IlNlrx.ra'nh)Y/n a1NI line IO Iu11NN% II1Nan wl'/FIII, (/ 62 y/
arx161ncJ rN.n ly 0% In)t Intlua rd ( 71'1- alrl mn61I a kN11nK wl'll' 11NN1At11 UMlt 111ll
aINI
tywv.Jrnl In/ 11x Iwu In11xM\ IlCnac the Irrrc JdlCrentt. In (iPl- :Ilau111uI.1INN1
rsharvlal Ittwccu thc.c lunxwo a/q+:lrcntly n11ca1 Jl/lctctxc. in tlMlnldy.r. Ixw in
hirt/nla)qn u111ut rx .IUFulrlNm the Jala (xc.cnhJ ItNhtrtc .uMlrnu.ll tra11N ul
Pt.l.nw hhr/m/ptn Intrl a/N) rxul ul Muh hrnrw., u% crxnparcJ wllh conUnI tu..ul..
cqulvcdcnl lu Ix.nly 11/ ,rNl 7 nJ nt Pla.nt,r uvcr 7 Jayo ol rrlrwth hM lla I:IMI IIIx' It/
IwrMw. a.Ixtuvcly, l'Nnp:ual.k vrllx's hw dlrmal s c t/.ax% wcrc 1/1 tu 1 4 nA
Pl.lan./ hlxnN-ycn
/)annd lI I. ll.uvcy V S nrNl M.OtulaRh, 1.
('nn~ rr Rr..,nr h 1-1 111N I IS4 1994
I)Ihcr.tulyrnri: 11 S 1'uhha Ilcrlth Srrvxc rrNl lhc NrlNm.ll I rwnJ.nNln h-r /'uNCr
KevaltIl
I nan IIh Ik'lar/t/lhnl rrl 1'athrrhryy. Hcth Lr+cl Ikr.pd.d aal IlrrvarJ MtJr..d
\llN.d- Inol dx ('hrrk. A 1)rnr Rcarrlh In.ntult Nclh hlacl II.I.PII.J Ihr.IrNl
('l11 Ml('A1. VIRAI.INTI.KA("fl(1N\ IN(TI.I. fRANSI(IRMATIUN
At Iht )tFlnnlnl; rd Ih/. h,rx M N'/xa rl'vN'w. 11 1% tNrll'II /IIaI the aarlnNr/rnx
rrrxe.. I. Ihl' aun..ylh'nat rd I.rNUlltra nua/.NtNm Ixtwlrn Jlvar.c cnvumnnNnlrl
:/INIIMr~ILhhN AIIIhNI(Illlll'u1Nk'rl)111y I1N'1I4nIN11Nh./vtINdlll'l'tlJkhnl.drr'.a.uly
an11u.J .tuwhr. h./vt- rkm..u.u.ltt J Ih.a ~ IN nur .11 a Ml nN1p'/1, a rM1111 tIIIGIIx a' /N'.
-Idrar
rc.uItto/Ilrnnrtlrr.nrr N. 1rNrwnrwh.)ruN vl.uav A.q!IIIIII:IMIClh/11trI.MIv:11N1
w/lhh Ix'luln% a/rNUr trlht.J :m.Jya. nI IIN' IIN.hY1tI.1r h.1.1. 401 lartuN l;cn vn.J
.y/xlyy h:l% heen tIN Ilr vcLyxlx IN rd wl ll J.laxJ r a11 utllnrc .ytlc/u. tcyNmS/vc ,a
mulllPla l,xU.t. m tua.lrNmrrl.m In dla a.rv .d I)NA vnuv. .Ih'h a. SV 111 ;uNl
:Nknl.vnu. IwcctlNratrc n1 the IrtFrl t r11.1a 11x tarttaryen ha. t/atJly Ixrn hMUNl thl
M r(wctaym.uC Irw cnh.rnlc/lxrol yd vnelltrn.l.wln.tlNN1 Itus laI/qxN:1111'Iahun.lup
hn. Ixtn Intcrprehtt a. I/xlaatln1: Ih.d I)NA JrmaFc a1Nl tty+ait m./y Ix /nqrwl.un
nNJradN.ul Ihl.cnhJlxtnhM flnwtver.ltx'ahallyUrt7tclnlh!en.It,Inlhlatu:In.hN~
In:11n N1 11t R NA /u11N la v lru\ InICaltll Ca I k hp. hel'n LM/nl( I/l rl'lhllte a ll/(ICnnl
h'/111x N:A
:qN.hertnm.d aFam.lhan in lhr 1)NA vlru..y.lcm. In a.khlNUl ha hclnr n/ullJacllN
Ilxrc 1% nasw ev/lkntc /rlxn.rvaral in art...y.1co/.Ihat Ihe canvwtgenic Pux:e. alw.
/nvrdvc..cvcrrl.tW):c. ln uo akvckq+nlctnl In 11K Iwu .IaFc nNlu.c .kln a.ay .yICIa.
Iwu qu:dllrlnvcly Jullcrcnt ./aKcc havc htrn nknt/bcJ rxk ItrokJ °Inlhrli.xl" arNl the
,rhtt I+t,xl«Nnxl "('au tullurr .y.lenn nlay tclxt.cnl vatorhk nxxkl .y.hm. /rr
an./lyiinK IxH61hc nnQlll.xi.w anJ tnultu.lcp n:durc nl t'ar.lrxrycnca. StathNl u1 (hl.
laItxY :Irl .k'varllYl ha Inhrna'Cllll'IM n/ V/trl II:n1\hM111./1hN1 by Ilulllat/ng
('tN.I/IN.II
('Jrt Inla/!t'M IIlhrnl a'llx'nI LI V/tlll l tan%(INn/LlN/ll by I U/IhN I'LxIhN/11/! A/C/II\
a1Nl
KrlatcJ ('.NUlxrurxl.. I'ropc..nln ol tlx I trn.hwlneJ 1'helNeylw : a/xl Mld(/.laP Mr" k1
u/ Al/t'/xlvlnh I Ian%Irxn1a1N111
/rahrr. P H
('rlm rr Mrr.n)<.ne..n I(h) 495 S1)4 1')M I
OIh.r tup/u.rt: N:dN.n.d ('rncct In.ulutc arxl Ihc Amcrlcan ('antcr Slx-lcty
1 uml llN I k 1~rrtoN n/ rd Mx n4.nuhqy .('ulumhrr I In/ver.dy ('otlc)e..( 1'hyaa l.nn. A
Naw Yr.rk
A(('U1 I:RAII:U ONtiIT OF VIRAL TRANS('RIPTION IN
AI)I:N(1VIRI1S 1N11:('fla) I/cl a('fa.lS'I'KI:A"1'F 1) WITII TI/I: TIIM()R
IM(11M(/11R 12-u11:'IRAIN:('ANOYL-PII(H(IK/L-11-A(I:TAl1:
Ih(clry eN Plxuftid caer wlrxu prtunlllan, wch a. I? t1-ttlralkcaru.yl-PMuhlal 1 t-
al'alalc 111'A1 Ilw'rca.r the Ilan.hlrrn:Nian frcyucnty .d ccll. inlcclcJ with type S
alk/xwlnl.lAJSl..mnlan vlra.411 plly/xna I:P.Icin-B:Irt viru., arlJ f+awiue I.apd
kNIW VIIII\ InaulanMrrd vinl.Iran.lurmrllcctl.c.p/.urcln'1PAha.lran.Mlwatn
IIxYI'JN IIM :n/NNllll ul vital RNA anJ in Iminlwavl ccll. TI'A nqritlly Itxlucc.liK
.ynthca..d .IxadK KNA.:axl /xalylxplNk.. Tu Ic.( IIk hypMllra% thal aaa'clclrtcal
INr11hN INNI t11 A1IS /IIKNA rRa11IIl'J It1xn eLly IMact t1/ 1r:pIN(YI(1tNM1 Ihc invc.llFaaN.
IlxJNI/CJ /IN.'IM(11N:IInN1 P1 I'll/unJlllc iMu viral KNA tk/nnfe a S-min /x/l.c al van.m.
hnN.:Illrt /n1ctlN.n n 1 I"(' 1ady vital NNA wad tklat'taJ lu'11'A-IrcrlcJ ccll. 2 ta, 1
h IxLwc /t wr. lk(cllcJ in .r/nplc. InMn cnnlnrl cullures. Jlxcdic ralln.acllvnk. -d
KNA Inwn bc.ucJ ala/ raNmul lcll. wcrc .inlil.tr at eWh Itl1x pnnl .uygc.un): I]c.n
ularca..J I:dxhng .d vrrrl KNA JiJ mN rc.ull InNU t hangc. in Iran./xw( ul (11/uudnlc
/R IltNll .II1a'/:It/1N1\ 11111x' 1111' IxxJ.vr tu avadaMlily Ihat (avtlrcJ o1KNA .yntlka.
IxN1%111Y IIIC:1IIy II Wa% 11IM.IxMC/I Ihat when AJS-I/Ilel'ICJ Ila'I:a a-eII% WCrI C111x.yJ Irr
111a It/11NN IMaNlllnl'r II'A aalClat:NNN1 wal rNN /kqt:/taknt ulxm claxurrcltl PlaNCrn
fynlhC,l% aMI Ux/kI Mrl ht a11//lhanlJ IHt ra(N1I Ctllry a1( vitlla In1U the cCII /11N k'l/\ 1
PA
lulMxr.aJ 11h Iran.a ryuhul lklay plx/xNypc lJ the 1'.la uwlanl hrl, w/1INn/1 Il'~hR111F
'n. ahilny 11/ rcl+lx-rlc
('rrtcr l 11 . Mik.vrlxwic'l.. 'l.., NaM.a 1. 1:.. anJ Frthrr. P Jt
Mlrlr-r rllio arwl ('rllulur Hiroh..et 411) Nal-StAt, 1984.
(Nbei arppn.(: N:NNNI.J ('arxa'r Inl1IWe 01141 I11C N:tINM11I IIINII/IIIa hu Allrrr.y :InJ
Inllt1Nx/. Ui.ca.e.
I rum dlc 11l partnx m nl I(iuk.yiaal Scictxe..1/ lnhn'c Univcr.ily ):uuaica. NY rnJ
dn 1kP:n(nxn1 ul Mxnllxr.hl~y, ('anccr ('cnler ('.dkpr o/ 1'hy.iclan. Jlk Slny,nln.
('ulu/nl+cl I lutvcl.ny. Ncw Ylxk.
1)hl 1:f1(/N ANI) INSIiR1N)N M(/TATI(1NS IN IiARLY RIiG/(1N ta OU '1 YIM.
S AI )IiNI )V IR(1X l 11A1 PK( )I N I('C (Y )1.1) SI:NSIl I V I: l)K UI 1 1(' l I V l:
PIII:NII"fYIM:11<)R 1KANSIt1RMATK)N
l IN C:IIIy tc/,'NNI Ia /I:lal l,'e11e t/t atll'nlW/tu0ha\ Itla'n %hnw111U wrvl an c.xnnrl
nde in innialmK hl-lh the vltal lulx/w'/ive ayck in Ilarmi.vivc ca/1N and (/N ttrn.lrxnl.l
INNI tlI NNkYN cl'11 (M the ha.i% al carllcr IinJing..Mrwrnr. Ih:tl 11Shrl shall 1. crdJ
HMlhva last IranoohN111./tlIN1, a aCt/C\ Il( nBnrMo, WCrC CaM1m11h IlJ M/ Ih.11 Illl'y 1 rNl
tyuxJ lkknrmm aK tnarln/n% in JJlcrcnl ni(c..d R1a In avertrln I I) WIx'lIN't /Ix' t rd.l
atmhrvc Idxmrlylt nl ttll wao the tc.uh n( Ihc hknlthcJ .rnglc hav Pr/l akkINN/ .rl
nut kvNNk 1//SS ur Jul lo a nn.vcnst nwtalxm al aawNhcr .ilc aml lil) whal r.F Nxl rlN)
hltw /ouail ul the (ar SI klhhlrtlun PaMC/n atc arlually rcall//rvJ lu Iu.rlu.r a cll urn.
I/MIna1NM A mulanl. I IStlll/ll IJ11/11/. wal can.uuclcJ ho cawnaln a S hr.c P.ur lk k
IaMt o/ nurltaNntc. 1.111111 lu 1.1112. whtth (walucaJ a fra/nc.hill anJ a.uhvqt/lnl .t,qa
coJnrl rl nul kl11Nk 1,?41 I hlv nwtanl whith.lurulJ cnax)c a IrunratcJ It I,d.NLJa.n
Pnweln in ptxc ul the wJJ lylx' SI AJaxlah.an Pnwcm. had a culJ-.cn.mvr pharNqylx
Lw van.LwncnNln c..rn(trlly Nkntxa/ hr MI ('nn.unaru w/d. /hh I11N/ln1! a /IN/IJall
1113/n1Uta/ cnKnxrcrcJ k. a r.nlam 116 hr.c past inv nNw1/n11ia/cJ .Illcr nw kannk / I ItN
11) 1 21
wllh ;1 .11.11 Ytskm ltk/nnlng at Ihc newly mvncd nw IcrNNk 1.011. ;11.1- h.NI a lydd
NIlatlvC IrtN'/NNylx' like hrI ./IMI11111/I II 1~ YII1~111/', IN/Ml'Yl'1, III:11 .I IIII/LIIII
III~IIIIIISI
with a M1 h.lv Il.ar tkIchun Ix'1InnmF a1 nurlc.dnk 1,4111 1 :IMI h:n111F .1 ~ahl l.xLn/ Jt
r1uN k'l.ulk' 1.tJ 1 wJ. L.lally Ik IclUvc hK um.hnnl.lunn al .uly IrmlxrJUUC I/.m.
Il'111NN1 YIINht'Y wnh I/I./N1111IY itNllJtnlnF the I:Ia IN I'I.1 :IIMI I'.Ih 1!lYN'Y III .oh UP).
1,/1.
a1Nl .111111 Innhir nvcakd 111.11 tll. Y.Id .en.lllvc /r.u1.11a1nJhnn IdNn.N10lx /rh.aIVid
l'..IIkI lx' l'\IIIh/1C1I 111 1IN' Jh%eMl' t1I vlra) l'.Ih rl'/N' t'YINI'%%NNI
NJhn.. 1. 1. . I rJerr, P H a1N1(kn.h.rr. 11 S
Jnurnal..l t'rrr.lnct 4'11 1/ 7 11 7411 1'q1.1
lAhrr .upyrorf: N.IUnaJl In.htulc o/ AlkrFy a1N1 Inlct rl.a/.
I r/N1/ IIN' I Il'I../r1/1N'nl ..t MN rldaok.gy. ('.IM cr ('cnlrr r In.lnutr ul ('.n11 rr N.v.n.
h
('Id/i 1c ul 1'lly.N IJn. di \urMc.al.. ('r.Iunlhl.l tJmvcrvly, New YtNA
M111 A I I/ INAI ANAI YSIS ()1 1I11 1(IN('Ill )NAI It(lMA1NS (11 I tlli
AJt I IJ1;1 NI, INt)INK'1S Alll l'IIN(:('Lt.1. INAN\I-t )NMAIIt/N
lIN' 01NIN'l Ikv nlxd m thl% p.qxr Ikal with takuthl)Inp :1MI uMk'r%1.11NI1/1r IIK
tylt S.wkMlYln1. I Ij .In.s t lb rcM' I.HMIIN IP Ihal afc INY l'%\:Ily tU.n111J11' :IMI 11/.11111a1u
(ht /r.1nLalll.t1.c11 I.IN'MNyI\' IIYIIIF IMNh AtlShrl ItNI J1kI11NNIJI v11JI IIIIIL/III\ 11M/
t.1111111r 11/V'1IN111 /N /k'h'lIrN1 IIt/11JL1/11Y dllillllll,' IlN l.hhlll! 1:117.1111y 111 IIN'
1'1.1 11 N
u/NNA. Ihc Inqrnl.uNi ld dl. Yu.d sl kJ p.lylxINuk l.tkrnr/n.tr.ucd Io/1nJUd.umor
IIN' ILI1/,Ir.titN-.I 401 14N'n.Nylx' .I/NI It. L.,.IMc Inlrr.aurel. wNh Ihc 1'IJ 12 \/rllc
IMlwlllll AA hnNd r.ll t'nlht%// Illu../'Ll.t trll line Il RI I I wa% u..'d 1.,/ .111 IIN' .luclnY
tka Idx'd IN/i I IN hi.u/ ld Ih1.11J1r1 1. Jlvnkvl /ntu tlnu n1apH vlluln. I I I11N t NI 1
( l'II Atk9NrY11t1% I t:m.hlnnatawl A..Jy.l _'1 I rrn.a.rmahan StMlhr.l 1.Ir.y AdShil a1Nl
( KI 1' ('l'IIY; l I/ C.N/YIIIN-IN1n nt I',IJ I)Y'knIN1 aN1 InN 1111111 Mu1:/n1Y. .11N111/ 1
rJt1Y1tM /ILIINNI(~11.16NIt'r1Y1N'YnIWh11M/JMIt.IJI1CkINN1a/NIInYI'rINNIM111a/11 In.u/nuwty.
thc tlJt..k v ulx'd u.mk vinlsc. wtlh Y~ll'tllK' tltut 1/NMIY 111 thl' INM/IIII I.I IIN' F!l'INNIII'
ta'tNhoy Ihr 1'la SI k.) lvlllcm imply that d Lthlr vital ycllr /vtNMN1111J11./Nccssary lu
nwunlam dle rcl l/ynvccl ptqr rl/rs ul translnrnwd ccl1. I IN: t'1NNIIIItn/JIIy hII1.II. l'nhI-
Ycnallvc nccMNyry cspresstJ by the Illul;tletl RlrNNlll'l. whcdwr IronNllwed uNn
t'Kl:t trllY by IniCtINM/ with vIr11M-. IM by tranYklINN1 with tMi/l'1 ItinN1N'] tN IIIAS-
rllllt%. /111111M.'%thal Ihl' 1:la SI kd IMtNe In InlCfal'I%wlth a INN nlair11nN1il't IIh' ur lhc
1?la
4x kd ludylxqllNlr 'Ihe culdvn.illvc p11eM11yl+C nlay rrlk.l a JrcrcJad InrNlinK
ttrlsCmt al 12'( 'IxIw.tn dlc nwlarNs' ImncahJ pnllciu% aMl a.lill unirkntlhcd INrt
a1NIt11r vltal 111:KrInlNlh'luk IlhMIhCa1NM111t the (NNJllve IN/Yt CIN111MMN'/ll 1./v1/Ivl'd
aMl (he tharallt'rIN/CY nl the vlfrl IlrtAtin hnY) mxrlNMlkcuk litll'rNIM.n .Mwld
reveal Crlll.al 111NY Itl uMkr.landm~,' the nlechanl.nU OI vital IrrnAhHnlJtNln
ItJhhs. I. L . FLhrr. I'. 11 and GinsherR. 11. S
In ( imshcrK. 11 S and VnFcl. 11 1(edY /: Trum/rr urwl F.+Inrl.iun tr/ F.uldt~'atr.'
(:rnr/. New Ylnk Academ/r ('rrss. 19144. Iqr 247 262.
OlArr rrpprrf: Nnwwud ln.ulule 1.( AlkrRy and Infeahnus hlsca.ec
I n.m Iltr I klvnn.rM /1 MI. /..f.a.l..w .Iwl ('tanl>,rhrn.lYe (.M cr ( cnlcl. (rdlcl:c r11
/911.a Ln. A \urI:r.-n. 1nl.uac/.na I/u/vcl%/ly. New lrak
1;.NIIAN('I-'.MI:NT OF VIRAL TRANSFORMATN)N ANI) I:XPRI:.SSI()N ()F
111ti TRANSti)RMEU IMIIiNUTYPE BY TUMOR PROMOTERS
In the .ummary nf this wide-ranging review alf carcim.Renesis. it i. MNed 1ha1 any
clmlrrehcnave nNNkl altcnyltinR NI describe the mukcular evcnts invnlved in car./Ml-
I;l'nC%l\ ntu%l IncM(uMale the IMewnlly available tnlt1m1a1/1M nn the v;IrNW% IIhaK\ n)
lhl' cafCllN/gc11/l' InIK"e\S. i e.. /niha11n11. IIflN1NMNM1 and (MOgreS]NMI. Ihe hr]I evCnl in
Chl'1111Cat C:RI'IM1Rene\IS. ICrnINI "InIt1a1NM1." Is IN'l/eved 111 Inv.dve the IYWJICnI
hIM11nK u/ a rnclahalically aclivaled nr direct acting carniMlfeen /t, cellular 11NA lh1Y
mtcraxtuln with tarl;el 1)NA can result in a permanenl change in 1)NA scyucMCk ac a
rc.ull 1.1 pnnt mulatNlns. nr it could re.uG in a Kenclically allered cell by IMlu.lng
cI1;InKe. in /lx e+pressNm uf tklined 1)NA .eyuenl:cs widNlul rllertnR the strucuuc ut
I1NA In tlle spec/Jl case ol intlividuals eshiMlln6 cancer pnlne syndaNm.. a IJrKc
plMNdalNln tl( /ntl/atrd cells may Ile pcesenl at binh.nd a lurther increa.e in KcncllYally
allcrcd ccl1Y may deveAq+as a rewh af suhscyuenl espswe w inilialinR carciM/gcns rn
/hc env1a11muM . AhlNwRh MM clearly de/ined an a hNN-hemical ur nN/kcular kvrl. lhc
.uh.cyucnl cvenls in carciM/Wnesis allpear ht invrllve chlnal nulKruwlh ol an inlthalcJ
ccll plqlulalitln. Thls pnlces.lermed "pnInNNNM." has been studied in numcnlu% tn
fnY/ aMl rn virrl..yaem% . lhr cnn1/1/eslly n/ lhe IIt1lnNllitln (IheMmsCM/n has re.Cnlly
been cnylha.iied by thc uhservalinn that there may bc Yeveral.lages in prunNnNwl 1 hc
hnal .lape in the nenq+laslic pnlcess.lemled "parylressiun.° inwdves Ihc Jevcl.qNncnt
ul cklnal variants that have acyuited yralilal.vety different pheMNylles /nan the tlrrKr-
na) Inll/ala'd t'etl Iln(IUI;IINM nr dl4llay enhanced ett(Mr.l>,NNI n/ the IraMhlrnN'd YIatC.
With the JevekqlnN:M ul INNh in siwr and in vir.oo nNlde) sy.tems that e><h/hn the
"11n1~,'re\\NM I1IKMNIIeMM." lulute sludics may pnwide a nNlre preci.e nudccular
uMkI.IJndlnk n( the pnN-cY.s by which a lumtw tell ewdves inln a mclaaallt flct./llasm
Prlhrr. /'. H
In Slaga. T. 1(cd 1. Mrr /Mrniunx nJ 7wrw.r r.nwnNirrn. w.l.rnrr /II. Turou. rawn..nr.n
uru/ ('.ot innxrnral In Vinn. Ituca Rauln. hL. C'R(' 1'ress. 19114. pp 37 121.
(hher supilla1: Nalillnal Cancer Inailule and the American C'arKCr Stw iely
hn lu the Ik p:/rtnNM n( Micrtd+iuh/ity. (i+lumhia l/nivcrsily CnikRe 411 1'hyslcians A
Surt,'CtM%. Ncw Ytwk. r
I:XI'RI:SSIUN (7.ONING 01; NI/MAN FGF RECI:ITOR C(1M1'I.IiMGN"MRY
I)NA- (A:NI: AMI'LII7C'ATN)N ANI) TIIRIa: RI?LATI:/) MENti1:N(:I:R RNA
PltOUIKTS IN A411('I:LIS
t:pitkrmal grnwlh (srttx 11CF). a pepli;k of S) amiM/ acids tk/1veJ Inan a 111t
kl ) precwstw IIrcdN 1ed by rectwrlhinaM 1)NA .naly.is. e1/ecls IuMh Kn/wlh ald /MkN
tNNI ld yrcil/c dll/crenliagcd fum'tirwl.t in target tistues. In order lo dchne nNlrc /ully
the Inct'hanr.mY by which pldype/Mde Rnlwlh (al:Nlrs regulate gene tranxtiptNln and
cellular I(rnwlh. eslwes.innckminR /cchniyues were used in Ihis study tu.ekat huwwl
I:CF recelNUr cr/mnlcmeMary I)NA cMrles. 7TIe !;(:F )' eldinR dlNnam shnws Yulk inR
MlrlNlh>Fy Iu the tran.ItnnlinR gene pral/icls of avian eflhynlMasltnis vrn.. Ovcrcit
hrl.slrN1 n( 1;(:I' reCe111tNY in A4II Ctlt hnef c/lnelale4 wllh ml'n'aYtll I'(il' retrlMln
mRNA kvelY and anpddicatNln (up 1u IN) lltnes) nf the apparently YlnRulu 161,
recepllw gene lbrrr are Ihrce lyNq.lasnla pdyadcnyl.ted RNA p/.NhN 1% ul 1 GI'
22 1 71
0
r Y
...i.
~
rrleptN Fenc c tprc..n.n in A4t1 tclla, r+ne ut which ctxualns INdy S' O GI hlrnling
JtNUam) .eyorntca and is (It..tulatcJ d+ rmtsk the .ecrrled (:(& rercl+uN rclaled
1lnttl'In AIC.Nlhlll, to+ rhl']e au1hlN\ Ihe use UI catINe..nNl a'kN11n1,' and :111 RNA \a1MI
wtth arrcn+nll aMNUach ha% luadr avallahk rcl'afN1N ti)NA whr.h t" Imllc
catAIO11ero.Ik.1r11a'Jlnevaluale.truliurc IunCInNIRIa1NNn.lltw/Ynretl't1NN IIrarIII
i/ncrxiaNl ytadK rene Iran.criplinn and Rrnwlh rcl:ulalnNl. Ilk.r ttlnlK% alw+
Jt n«+n.u.de thal ampldlt aonNr uI a t+/t'/n-tN1aRene Jrlcrmmc.lNr+du.tnm ul a hn+wtb
Iat.N rrlelMtN arwllcltulrr rcy+tNtae.lu Ihi. Ennvlh Ixl.v!
I ul. (' K(lxn, W S, Kro1Krr, W.. SN4ar.ky l. S Wchcr, W Fvan. K M,
Vrlula, I MGtll. (: N anJ KuKnfe1J. M G
1tlrn.r 224 R-11 M4R IW14
(hhrr rrpport NatnNUl In.titulr% u/ /le+lth Anrcrlaan ('anicr S.KNIy, IkulvlK-
I.N.a hunp./:r nK +nv hah , antl lhc 1)ula h(Junn W llhr m/na 1 um)
I nNn tlw 1uLary.wt. Rcrula.Ny 11NdnKy Pnyrnnr, (/mvet.ily l+f CaldtNma San
Ihey.+. S.Iw.d.tl Mrdnlnc. La Ldla, M.tkaular Nlolupy anJ Vin+k.yy I.aMN,wwy,
/hc SiIk In.tUtNlc I a/.Jla, ('A. and the 1)/v1.1.Nr .d 1mlhourim.k+Ry. lhnvct.uy al
( .dAtNni,t. \nn Il+tR.+ $th.rA..l MtJll/nc, I.r lulla
1111MAN AIW.N(/VIRUS 21:111 iVK stn! 1 IFI t1K TIIMI/R AN11GI NS
AN 11I'I P111)1. AN I Itt( /UIIiS 1 AR(;1 11 I) 10111U. NII, ANI) (Y N)II 'fURMINI
In thl..tuly. anhtrahe% thal wcre pnp.nrJ aEam.1 .ynllwIic p)Nak. R tu 16
a11111N1 at IJ. In k'/1r111, t-M IwlrJ .t Ihr IIN, .nwl 11 K)11 /inmat .uI I1N- nupN I-llt WK
wN) 1:111 S 1K 1111114911 ,mlqcn. I IM' Inlll['1I/.tr JnhIMMIn' nuomrwywc. tpltrl. J tlM
IarKrteJ lah 1'JK N 1 I11 is IK hnmN an1.Fp n% ln.m i.ux n.d A.12 rnlc. IcJ arll. '11M
.pradnily ul Ilk anapeplnle antd..nly ria.Innnm t.l /IN t'II1 II///MN ,m.t/:rns wa.
ctNdirnr d hy IN plnk uNrq+ruu..n .Uwlh. Annl>.plnk' ,uuitr.dlc. JueatrA lu IlK NI1,
aMI ( Y K/I I Il'flllllll 1111nnIM11Nl'l l(Nla/ed IIK 1'.Ih S IK Iu1/NN a/llll,'Cn. IltNll Iwl+ Ad!
Iran.hNmcJ tal. ell hne.,l'l7 anJ 14 pruvaltnXeviJear Ihat idcMical pumN anl/gcn%
are .ynthe.iieJ in AJ2 infected and Ad2 Iran./um+rd cells lbese re.ulh slM+w Ihal
/he Iah N)K and 1' Ih-t 1K T anti/,rn. are mll pr.res.cJ IN/Netdytically al cither the Nh,
tN ( Y K N 1 ternnnu.. The Ja1a lNUvNk .tnmK evidenie at IlK pnMcin kvel that the LI1/-
1')K and 1:111 S 1K tunwn anliKen% rar(ially overlap in 1)NA srquence, with the 1:IH-
1VK /nirlalmF Itan.IataNl at the first A'f(; at nut:ktwnk 1711 in Inn.lalitm rcadinK Iranrc
I aml the I:Ih S.1K IunMn anl/Ren iniltatinK tran.latitNl a1 thc w.crnN1 AI'(; a1 nuakauJe
2111b in reaJlnK Irmlc 1. //vera11,11K.e Ja1a e.tah6.h at the pnHUn kvel lh. mlmmum
Rene MwmLurc., Irrn.latitNrmi11a1itNr .de. and rtathnlt Iramee nl the Ad2 1:111 N/K
and 1:Ilt t 1K Kenc. dw% ranlirtutnK Ihe+Netical /kducti+m. havrJ +NI 1)N,\ +ayoca'e
aml /w rlak ntat+ analy.er. 71k annricptHk an/1btNbts .MwIJ Inove u.rlul HN .Iuthc%
on the ryrnlicalNN1 anJ funrlitNl% td the Ad2 h/B 19K anJ 1:1H-S1K T aMiRrn..
(:rrrn M rl ut
LY/MII../ Vn.dr.R+ 41111/ MM 615, 1119 1
lhArr.rM.n II V tbMN IkatthServNr
/..no Ifvr In.ftwr I.r MIr.uLa Vu.,lyY. %I I.ut.llmvctaly Mcdaal Ccnlrt tl
I.~n.
24
i
ANTIIN)/)I1:S l'()SYN1111sTIC IM:PfIIn:S TAR(;1TI:1) T() l'lll:
7KANSNIKMIN(; (;1:N1:ti (KAIUMAN AI)I:N()VIKIISIS. AN AI'I'K()A('lI
1O IININKtil'ANI)ING IiAKLY VIKAL(;IiNI:IUN('fK)N
lhi. culrn.ivr paprr.lart. with a hricf review t* raaeM stuJie% uangan1qKtMnk
anllh.dlr. It. Invc.l/1;atc pnlhkrm in vrnk+Ey. A Kencral .tralify i. then +.uliutrJ
whltfi u.r% aaq"aNk arnlMNlic. In inve.tiKalt the \m+wn AJ eatly Ix.Neal. r1Ml 10
lkl.ct htlt:ulvc, a% yet unnknldirJ, pnMein% whnse eai.kntY Is .uyKa-.IeJ hy tlK
tNe.r/Kt.d thxn Iran.l:uNNl reading Irarrlr% a. (>K/htIIYI fNNn the Ad I)NA 4YIIINNe
Many Iwrlwular .IlNhev are Ihrn Jescrihed whlch can he IJantilred by Ihe Itdl..wuwr
v'a1nNl lnk. (;1'lll'IN (hF!:It11/a1N1111+1 the Ad2(;CnlNlll' I'INl'11t/aI Sties LN l,Nl!l'lll/r
A/N/IM'111/1k AIII/IMNIk-., Ila/Iy Vital (;ene I:qINlNMNI; IJte Vital (.elll I~Rpte..a.u.
Atk'n..vtrll. 'I Id11./tN1111111, ( N'/kY 1)tran//a1nN/. (;t11C I'fl41u11\ i1MI I'1/1N tNNIdI
`IIIO
w M.davular (llara11aY1/JINNI ul I'pNem. IU1lINkJ by
Atk'MWlrll. Itan.l.N//nt11
(;cln. I Llnr. Muquy+lak AnlthnJK.; (Ag:mvalirm n/ Ad2 1:1 Kep+Nl; Slla/a. I l.m/;
Annl+t1+1akAnUIuNIK.1 arFr/avl to the Ad2 Ellt S 1K, 1qK, aml 20K 1'uaeol.; I I.a ..1
AmqKINnk Anuhtwlk. IH+ Analyte the AJ2 I:rgr 1'layue MNlanlh that Mc 1 k Ira Itve
in ('a11 I r:IMItN/na1NN\; l1m: nl An111K'111nk AINIINNIK% Nt h1en1/Iy A112 and AJ12 1IA
I:na-trkd I'rtNrmt in Inlerled anJ Tran.IrNUkJ Manrnallan ('ell. alnl in F
lratNttvllM'J 11y tIA rl)NA ('nnlarmnlt 1'cplitk., anJ Ihu)crlwNM% un AJcrw.vuu.
I ran.ItMll/lt~ I'r/Ml'm.. In Ih1. hNt .eIINNI, e\lahh.hlnfp Ille IurM'IN/II\ III the
:Nk'rN/v/111\
aarly IN+ACIn., and In 1/arllcular Iht early re~nNl I:1-CnlrMlell IraM/+Mll/1n1, IN++IrIM. 1%
prexnlyd a. a chalk n~inK anJ eRCilinK 1a.A,.ince inve.llpattN. c:m+qwnnl.ln ally k~d,
hNw:ud Iu the avallahdlly ut micn+gram yuanlnir. ul purihed Iil (N.Nrul. ItN hnt1Nr
.1uJle..
t
(:rrrn. M. rt trl.
(-wrrrnt 71y+irs tn Mrt rrdnu6tXy nnd Inunra.dnKv K14.1A7-141, 1YR1
(khrr srpperr: Nalinnal ('anrer Institute.
hnNll the In.tilule I+N M+decular Vin/k+gy, S/ Llwi. llniver.ity MrdKal ('cnter. St.
1.tNU..
AN111I()t)Y 1)IKI:('1'1:I)T() A SYN1111:TK' PI:1T11N: I:NC(N)IN(;1'IIt:
NI1. Il-KMINAI. 1(S AMINO A('ll)S (N' 1711i AIN:Nt)VIKIIS '1YIMi 21i111 .S 1K
111M(M( ANl l(;I:N KI:('(K;NI%liC THH 14t1I211K ry1M()I( AN'/l(;I:N
A, rcligoNteJ here. a peplitk. FI,N-(;M-Ars-AtK-A.n-Pru tierd;lu-ArR G1y-Val
Prn-Ala (;Iv I'he-Ser (;ly-l('yK'(KNI. elNNaininR the anlilw+ alN/ acyrknre at the
NI I. Irnniml. ul /hr atkawuuc lypr 2( AJ2) /il/l rlr/nl larre T anliRcn //'.I H S 1K ) ha.
IKen.yMhr.iitJ. Anmiprplwk anlrhta/y was Kencraled in rahhNS and u.rJ /.o immmw+
INecrpn:Ne Ad T antlKen. IaNn Ad2 ttarly tnlelteJ cr11 e.lracts In aklllNm 1u thc
e.pe.ICJ 1:1H-S1K T anliRen, antipcptMk anllh+dy /Nrciln(ateJ the AJ2 1:11t 21)K f
aMiKtnlhalvasprevi+w.ly./wtwn/uherelaleJNwk1N-SIK((lrrrn.M rrn/ ! Vu..l
42, N1-41 19112). AnliprpliJe anlihtdy pepared asains/ the C(!t)11 terromuv t,l the
I:IN-S1K T anliRen /N against the Nll. terminus tA the 1:18-19K T amtRrn JNI rwN
INecipitate the I:Ifl 2UK T anliKen. llrcse data sutqtesl tha/ rhe AJ21:1N-21)K T anuKrn
inNialr% tran.lanm at nuckollJe 2016 in reading frame 3, as lkrc.1:111 t 1K Thr viral
mRNA that encudes the 1:/11 21NC T aMiRcn hn not been iJentifieJ
Lucher, L. A, Rrackmann. K. Il , SyminRuNl. / S, ant) Grrrn M.
23
1'm./nxv I t? 217-221. IVMA
(hftier.rpOort: Nali.mal ln.titutc.uf Ilcahh
I n.m Ihr In.ululc h.. Mvdcculat VirnL.ry, SI IAruia MeJlcal ('cnlcr. St I tiur..
I 1'tl l IN IIARK IlK I VIRION 1)NA IS VERY 1I1(CIII.Y MI:fIlY1.AT1 1)
It 1% wcll e.lrhhatKJ Ihat f)NA ntthylatinn is eenlrally invulvcJ in /:cnc cqxc.
IUMI A v(-ry /nrlrntAm l1UC.InU1 01/w 1% tUrw IunMlr vtrv+e% rerUlalc IhlIr g4nl. /n the
lytl( ao,wcll A% in dK ultcgraleJ.late. In the auJy fxr.enlcJ hcrc. I:HV 1)NA Ir.an IsK
11114 1.Iraln. a rnnwan.hwn/mp variant. wa. I+nsd1ul-crl amt pmllnJ Ihrcc Imx. IIK
hnal Innlhr.l vl/uv fwcpalalam wa.ly.cJ with Iw.acacc K 11/MI IrK/ and vrahl/m.M..k( v)
.u11iIC 11'% I A11ct .evcrsl (Mbcr prepata4.ry a1c(h. the S nkIhykytmirK c.mt,'M ..1
vuanlI)NAul1 ItVanJu.huaI/K I(cll.wa.an.ly/eJ 5 nwIhykyl./an.1.111(.adv
/lw'IIIyIA/(1I haN' in lvkary.Mrc I/NA Ihc tu.cs werc n1cAWrcJ ahc/ LnmN :wal
hy.h..lya% by hr):h pcrl.Kmanre liqunl lhr/aoal..Etaphy T11c peraenlagc o/ ayarnN%
nr/1/y1Aa-J u(17N I-IIV IIK I vitam I)NA wa% c.tremcly hiKh. avlrap/nK llu.e lo ISl.
/.w tlucl .kL /lnnwnun. 1)NA mclhylAtw.n u1 the lur.t llurknl'% lymplwnlu tell hrr
IIK I wa, mu.h luwtr..avcraymg 2 JN% LM t2.k-tcrm/nAtam. 1hi.cRlcnl(d nlcdlvLr
INn1 1\ In 1`r.:11 l.Nll/A\I III L/IKr l L1%H'\ ..( tur/Mn v/ru%C% arMl 1% IIN hll.`Ik'o Ihal 1%
I.(w.w/l
/n:n/y nr.unnull.nl.ydrm I he a/11oK n( w.a.vrvalinn thal 1.11V 1)NA 1% urIhylll(J
lu .ul /l a larkc eatnl tal.c% the fl(wvtr..n 1.1 Iw.w rrrclhylrlam rnay rerutalc Kc/K
calMr..l.wl in thl% vuu. AtclwJmp u/ lhc.r aul/wn.. it i% c.v/dial Iha1 Iulnlc CRpn
mrnl..ktcrnoa whN h/;enls arc uMIhy1.1/eJ aml h/ what ettcnl nlclhylan.m.r<( ur. in
llK vnaMl :IrM1 ultrr( cllolarly
I/r.Ar. 1. S an.l Ih./J.n.rn. R M
l.NUn.d n/ 1'rrr.b.xr d5111 4112-1111. 14A 1.
(lt6ir .rppnrt: Nau(ulal ('arller In.ulute
I nnn Ihl tkpartnant ..f PeJialrir.. (Inivcraly rr( ('alifrwma. San hlcpa. S.Inrd ol
MrJN Inc. I a LdIJ
'IIII. I:M II.NT UF I)NA MI:TItY1.ATION IN f1UMAN TIIMOtt (I:I.IS
Inlhi..ludy.111f hNa) FcmwnN I)NA nR'Ihyl:Mllnl.l C. lln'rCrcCMaRel/l nlclhy.
latctl ryh..nK., wa% nkawrcJ in 21/ ccll Iuw. IkttveJ tnNn Jdlctcnl lyluc nl hunurl
lunw.r. I hc nw a.nrcnk n/. were uhlanleJ by calnwl c1<lhangc lnrlid rhr(rnanqtralhy
(.1 ha.r. rclrA.cJ by I.wmK acill hyJrnly%l\ I IIC%e C111(r1/tM'nl% wC/C J.N1P n..k/i rlltnlC
/I ./ht-N'11 nM'111yIJt1.M1/% a Iwevalcnt and IarRc (kkcl in.nx.qcnia lran.hwruatn.n A
nl.lpully (.1 Ihl tunMw ccllo nlea.urcJ haJ lklrea.eJ kv.h ul nlclhylalcJ IrN/1 in
l.nup.ul.un tn Ihi, a/Mt.whcr IafrKal.wrc.' puhh.hlIl nlca.wcuunt% ul mwmal:t 11% wr)
1/.ln.. In Ix1. lunw.r rell I)NA ranged tn bw ac I 2'% ul cyunincs mcthylalcJ
t umparcd la a valur .r( 1'R6 rlr nwwe hw nnrnlal cell% and tieaue. 1(pall anJ M.pl I)NA
t('mnN II. M CII/ynr(' :Inalytli lIwf1/nM'11 IIM all 1U11MN l'CIl I//1C% h\Il'll that thelr 1RIA
wa\
hll.ua Ihl Lnrd /u...n11..u1~.M lu II11' 11NA IL.n11Nn/14.I11//1IuN1 hfNnhla.t% fc.a J llk
~. uh, ./.~ ...,, .11.. 6y....1 ./.........r..... qb% eo.l r..11n Lnn. nrluM dltAtv%.. wr/r
%Inl,
..y ~. .. 1 ~. ...1...../ ... .... ... .. 1 .1. ..n.... .. 11 I I'v 4 ..w..lA1rJ ...dh lla-
rCCCnI Uh~lfvallull PI .NIKr IJh.NahMn'\ Ihal IntI/vNI11aI Itl'rN% arC url.knikthylatrd In
hunlan canl ct rclll anJ Ih:lt a nanltwr (d Jdlerenl carc/m/Frnm ca/l h.wc/ 1)NA nkllly
lateal anc./ly
1)I.Ja. 1: 5.('hrah. M S('.. Kuwilch. I)., and Hu//rrr/n. R. M
Irannul.J th. Nutr.nn.l ('unm rr lnlrrhnc 711d):755-7M. IqR I
Othir tr/y.r.rl: Nali.rnrl('nnrcr In.lilulc a11J Ihc ( i..npc A. IaClilh Ml'/1MKIaI I'UINI hN
('arll cr Kcaarl h
1-nnn 1hl Ikparlulcnl ..1 1'cJ/alr/c.. llnivCrsily ul ('ald(nnia. San 1)/cl:o. ti.Mwrl ol
McJ/. nk. I a ).dla
\ AI)I N/)\YI MI.I IIII)NINV tiYNfllla'1111: IN ('111:111KI-1) N(1RMA1. nNl)
//N(-/M;I NK'M.I.Y IKANSItIKMItI)1111MAN ANI)KA'1 l'Iit.1.S
In Ihi. allcnq+l 1./ rcarrrnvC Ji/lcrcnccs in the rnKtiah.di.nl u/ /11cIh11Nnllc arwl
IMNIM4'y%hItK Itl rMMn1:1I .IIMI Iran\t11mR'J l-cII%. the Cn/y111a/N' h1r1IWInM1..t 1:1J1'IM..
\y1111C1I1NN//1N w.l\ cxauuncJ in calracl% tul s varicly r.l mwmal arrl ..n...ycna-:Jly
uan.1(nnKd hulnan an(1 r:N arll llnc% whKh Jlllcr in dw ir a1wlAy l0 4ruw nl lnlrJlua( In
wh/l II nN'IhnM/nl 1% RlIIIJCC.t by 11% I/IIIIICJIak IIrCf1/rMM IMNIIIICy%IIIIK . I hC%l'
lllvl'ml
KatIM% havc h.alvcJ /hc hulk.d the S-aJcrln.ylnlclhilnnnc syntllcla.c xbvlly In 111c
p/./ Imawlwwwkial.uprrnalanl. "fllcy.hl.w Iha1 in all cell hner a stnplc klnlIK .p(cll%
cwl.l. in a dialyiavl c* Iral l with a K_ for nKIhMminc of alrnq 1 I2µM. In.cln /cJ /nk.
Ilw y havc lknMnl.tralcJ a rcyuucnwnl IIK Mlt'' in n(klNMnl Hl that tNYIkJ to /(KI/I tlK
MI:All'rrnllrlru /(w cniynlc aliivily anJ have shlwvn that Ihr cniynlc can h rcyu.
I:I/cd hy prln1ur11e.y/A:uk1nhd1ilnm Hecsu.c the invCaiKaluraktn1 n(1J/tlcrcnrco in
Ilk cniynutic ability (// Ihc.c cell calraclr lo Wilvr mclhi(wl/rlc hK ti:wkal
sylnwlhi(wllnc hwnuli.nl in rurn. tlky suRFes/ thal the lailure lll lmtl.l,~.nically-/ran.-
hrnuy/ ccll hncs ta puw in nlclhilmine-hee. IMnlNllysllnll-l'lNNalnln); t1NYI111111 may
rc.ulllr.un the Jcarca.cJ nrclhiunine plrAs in Ihc.r cells or fnnn 1hl hh. (/1 ability ul
the.c celt. ta plMkrly nlelal>,dve honwlcyNCine. alknlwine lw Ilkir cellular /w(Khw1.
S-a(k m/.yllMnrll t y.lcinc .
(kkn. K. I... ('ar.nn. K.. Mccham.l. 0.. H.l(nutw. R. Af.. anJ ('larkc. ti.
Rir.r hirnirn rf Ri.yrhylih rr Arfu 7(#/.27(1-277. W111.
(kNte supprl: Nalilmal In.lilulec llt I lerllh. the Amencan 1learyAsNNlat/(/n antl the
(k(Kgc A)xnhs Menl(Irlal hunJ hn l'arlra Kc.carch.
hrnwn 11K 1)cparlmeM .d ('hcmi.Iry mll Ni(.hcnliary and the Mukcular Ni..h.ry
In.btulc. Ilnivcraty ol ('aI/1.Nnla. I Al. Anpcks. arrl the I><par1nN/1/ u/ 1'cdnNn...
Ilnivctaty u/ ('alrl(wn/a. 5an Ihcpu. lclwwd a( Mcdsclnc. t.a fu11.
Klil)(ICI:U 1RI:Ii MliffflONINIi IN MITIIK)NINf:-1)IiM:NI)hNT
5V10 TR/1NSIt)RMI:1) III /MAN 11H(/111.AST$ SYNTIII:CI/.IN(:
I11N'ARI:NI1.Y N(NtMAI. AM()IIN'IS OF MI:TIIK)NINN
In the kmK running .e:nch hrr JLlincl metahldic Jtf ferenles helween IM.mul Aral
rancer cel1., rnany J/llcnnt lype. ul ( Am'et celle hAve %xen .M.wn lu Iw nnIhuwu.w
.kll" mkm I l1C%c ll'Il%. I/IIIIk(' Mn1/1aI1 CII%. 1!n.w IMlwqly 11/ rMw at IK wlKn IIKIII/.NU/N'
27
1. fcldarrJ by rt. iumicJiale Irccurs.N twmwa ysicine in IIk rrnwth nN'Jlun 1 Mc/ 11cy'
nNJlum) (IM'..' nlv.ml~,'a1Ma have I+rrvNW.ly .}N.wn 1h.J al+(qrenlly MM/IIaI 1..1al
anNernl...f nKlha.mnc are synllksvcnl by nNIhawunc-rkplmkM SVJII /ran.h.rmcJ
human hMnhLr.ls Ih.wcvet, nNthinninc Jcpamlrnl «ll% in Mc1 I lty nKJinur alru
nNJa1e rcJrNtJ .mNNrnls rrl SatkrNnylnMlhNmine (MM.Mct) arN/ ekva1eJ anaMmt% tJ
1 aNkINNyIIMNINm ym.ina'(AJ.rlily)th:Ittlrp'1/1Lflna.hahlyll11111r1.Iw111 Inlh/.lclwnt,
Ilr mvC.hF al.y..knMrr.uala tha/ tIN anwrYM td IteC mrthnannc r% luw in nNIhnwnrk.
akttmhn/ SV44/ traa.hwn~r) humon litwnhlaas in Mcl Ilty nwJoum a.Noy..ncJ 1.0
nIN11CJ IN/111a11 lhf4.aJ btxuhla.l. In atrwfast, in Mc/' I It y ItN'J/um IIN' aINn111I OI
Itcc nKIhumnk rC t.wrK+.Nahk in h.yh t'ell lype.. Thc JlhrNnt (wN.l u1 1rac nw.thannne
In IINIIINnl/lw tkltn.knl tclh in Mcl Iky' nKrhum alti.ws only krw auw-unt. uI
A.h.Met 1.. /r' L.uNd Iluwever. (.aKe a.a.aM..4 hr...ynllwsvrJ n.Itbaaww arc
r h:unwkd nH.. IN.MCm .ymht.r. P....J.k nNY hannro. ar Jrv u..aJ 10 . yda~o Ihe.
..ukcr a...t...tcJ mrla/w.lp d1ra/
SICrn, 1' 11 . M.a han. )O, Wallaa c, C 1) . anJ 11../pwrn. R M
/.arrnul..f ('.Rr.brr 1'hr lr.d..xr 117'/ 14, N)%1
(hArr rrplurrl: Naln.nal ('antef In.lnulc aal lhc (ie.wKc A JalY1h% Ma'IMNIal 1111041 Ilq
('rONar kc.aarah
I a.nn Iht /1.panownl u/ PcJralnl.. Ilmvrr.ny u1 ('alJnnua, San UNFu S.h.rJ al
MrJN Inr. I a 1.J1a
1711iM1 fA11()1 IC 1)1111'f (11 A11'lt/h)NINI 1)11'I.NI>I:N('I.(1('(I/RS
tKlil)III NII.Y IN IIIIMAN 111M/)K ('I aJ. LINIa
A nKlaly dN charaa Icri.lw tw .k /ct I Prc.cnl in tanc/r, c11% hul mw in rwumals may
tIKJ hyhl .wr the IlNlkt ular ha%N r.I rmcarcnk uanLwmatNm 'thi% paltr Jcal% with
.rtch a chararlcri.uc. McthNminc rk'pcrNklNC is Ille inahJlty Id cclls Iu rruw when
I/ll'IhNN111N' IMct) i% rcplateJ by Ils nnuN'Ju1c Ixacurvx INrnNrcy.lcmc Ilkyl in Ihe
cullurc ukJlum Mcl 11ry' uKJiuml. All rNrrnul uncstahh.het) ccll slram. Ic.lcJ lo
dale luve hacn .IN.wn lo hc melhi.minem.kpcndeM anJ thus Erow alnNr.1 a% wcll in
Mcl Ilcy' nwtlium a. Otcy tkr in Mct'Iky nrJrom Resulls pre.erNCd hcrc indiaa1e
Iha1 nul nf 21, cell Imc% tkrived Inwn Jiver.c lypcs Irl hunnn IunN.rs, 11 Ju nn1 lemw :N
all in Met I ky' mcdium and arc aA...tulcly rntHhi.minc-Jtpcndent and Ihree rr.wr .wdy
.hghlly in Ihrm nrrhum. Many ol the IunNrr cell lines IeslcJ have Irak elx in cammNm
rMhcr Ih:m Ihc latl Ihat IIRy are nNthNmint' JcpnJenl 11N hrKh !nyurrNy ul tKtur
rcrNc'n1 melhirNnnc JcperNkrNC in Jlverwe lype% af human IunN» rells irN1Nalcs thal
nKllm.mnc JlPernklNC nuy he.n in+ppntanl aywecl ol rnp'ngemc IransLwmalnrn anJ
1hct:qxulitaliy c+pkutahle
Mecham. 1O , Ruwilch, 1)., Wallace, C 1)., S1ere, P 11., anJ 1l.17iN.rn R M.
Ran hrrnir ul rrnJ Ri.y,hrsirnl Rr.arurrh C.nnnrrniratinnr 117(2):42Y 4}4, 19at 1.
Other srRpwl: Naliamal ('ancer Insluute and the (ieruRe A. Jactrla MenNMialFunJ frw
('anrer ke.ran h
I n.m Ihe Ikpartnrcnt uf /tJnbaa, I lnivcr.i/y of ('all4wnia. San 1)iego, ScINNrI of
MfJN/tK. I.a 1..11:1
ALTIiRIiU MI:TI11l1NINI: MI:TAIN)LISM O('('11KS IN AL1. MI:MN1:Kti OI A
til:f (N I)IVI:KSI: I/IIMAN TUM(/R C'EI.L IJNIS
Thi% hNtlKmiral stuJy e.anlines the (sirKhemical ha.is rJ nklhi.minc tkpln
rknrc, a IIKIaIMrhl.kfl'l1 hNlnll (hu\ IartNJy in IfalUhKnl[J and nlal/l!narN cell% IhC
tk ka 1 i. ncmdcslcJ a.llk inaMli/y t~/ ccllau pnwr in nK Jia in whN h mclhNNruK / Mrl l
i% tcnl.NCJ hy il. Imnkdialc Ixttur.ur INrnNMy.kinc (/kyl IMcI 11cy - orlJ/a). It 1.
tknMm.ualal /K re Ihat wNIhn.ninc-JclwndeM ccl1% rkriveJ fnnn hunwn IunNrr.. c..m
Parc.l 1.# rNK111aI Illl't11NMlnl'-IIMk IKINkIIt lYlla, have hrw kvch ul Itcc Mcl, hrw, kvcl.
44 S-arkrNr.ybrN'IhN.nnlc IAJidNcl/ arNl ekvalatil levels td S adcmnylh.MrNryslcrnc
1 Mhd la y/ whcn int uh,arJ in Mc1 Iky' ua'dium Mclhi.minc-uNlcpcrNknl human
111801409 tcll% al.n h.ivc vrry bw kvaIs of lice Mcl crNrN.arcJ Iu rNKm:d acll. Mn
fcrnr.Jly havr kvcl...l ML.M.N and Atk.Ik'y ctNnp:ualda 1u naMntal acll. in llw
Mct Ilty nNJNrm Alt hutNn acll lypc% uNtwPrNatc anMSIMs lJ Mel uun tw. tcrn
.urnlar 1u maNr.d IIMIIINntlne /MkIk/Nknl human (/INUhla%1\ when mrohalcd in
Mcl I lt y' nNthum, tlNrchy imlN aAinK apparcMly fNKnul kvcls nl Mal .yndtca% ln the
IunNr tcll. '11ic neclhwnurK-imkl.CrNkM Iwmr ccll line% in Mct Ilcy' nKJNUU sacm
able 1u rc)ndalc Ihcir AJuMcUAaGJIay raliox mwmally tkspUC Ihr. Jrlcat rn havuit:
vcry 6.w li vch.J Irce Met Thu., in a divcr.c .c1 rd human lunww tcll IuNs all alc
Jc(calovc in al ka.l wrc aspell rJ Mel mclalMdl.wn, yiving ri.e l.r tIK (n.rhJUy ..1 a
FtirNraI urIahM.IN aklcc/ iN aanter.
SItm.1'. 11 , Wa11:Nr, C 1). and NoJ/nwrn R. M
IrwrnrJ../ ('rllNlur I'hrai.daxr IW:2') 34, Ivl(4.
(1tAer rrpperf: N,IIIIMIaI ('ancef IMt/lule and the (ielnFe A. Jal'11lv, Ml'nNMUaI 1'II/MI hM
(':unccr Rcscarch.
fnrm 11k 1lrpannknt u/ PcJialrics. Univcnily u( Califnrnia, San I)icy,u, Sah.Nd ul
McJlcinc, 1a lulla.
0
ALTI:RI:1) MITIII()NINI? Mf:TAB(M.ISM, DNA MIiT11Y1.A'1'I()N ANI)
(MKYM:I:NI: L'XI'KI:tiSN)N
This we1l-dirumenleJ review fawsca ar the itNcrttlaliamshiP ol mclhi.minc Ine-
taF«rlism. I)NA melhylalNM1 and /NKt~,'enll Ifa1Kfl1fnl:NMN1. ti!l'INnI\ taI (Itls\IINIy arl'
dcwMCd 1u: (:cncral mNhimmine me(ahldi.m: AbereJ nrelhirNlinc nK1aMJicm in can.
eer - mcthinnine deq+cnJente: li/fechvs ul Sark/N..ylme/hinnine (A.hrMel / rnclah.r-
Ir.m: Altered 1)NA methylatine in cancer: Cienc irNloclirNl Jur ht allcreJ I1NA rncthy.
Ia1NM anJtlM allctcJ mclhNM/ne mclalwAi.m: I:/kcts nf inelhylalNN1 nn rNNUKcnc
e ape..NN+: ('IlenNy+nACflive cl teel nl tn[IhNNrine altaina cancer:.fN! ('rNrt tu.Nm. anJ
per.Pcctives In Ihe ctuNIudinR seclwrn, a nudtl nf rNx fwNhway hr caniNqxnesl. Is
prescnkd. A corre.yNNNlin6 liaure dt:pids Nrc retNCd ry.lhwayv ..1 Na~hN.mne and
nuelhylalion melahldism arNd indicates pninls in the biaehemieal scheme wlKre mtcr -
rulMirms nray lead to eatcitN.genesia. Sia PerlurhalirNla in the scheme that may allc. I
oncu6enesis anJ the pnsihk mechaeisms invnived me: (1) CarcinnRens may hnN/
Kuanine resiJues, prevent mclhylationof djaenl eyNnines and thereby INn.rMy a1h.w
oneeogene aclivily. (21 ('arcimrrns /hw art RageMs fIM ful/hylkyl smoPs lan atl
directly on DNA mNhyltransferaxs anJ ituctivale them (1) 1:acess S ademnylMNlNr
2K 1 29
t y.lrlnr. .IN h J. IhJI IrN/nJ in uNthNmnK ak1+.nrknl . a 11.. can trNnlxuuvrly mhlhrl
I)NA nNIhyllrJn.lrr.lv' Id/ Il.r ta/l'llNrl`a'n rIhNN11/N' lJU v'rvt J. auh.lr:dr IrN
Ad..Mrl .yulhc/.rv Wllh IIN ININIIN 111N1 .d \N/r/N..ylrlhamnN wlu.h ru hrrn . Jn
Itllnhl/ IIN'/11YI,11PM1 ISI II nN1hNNnnc /. In .INN1 .up+ly, krw kvt'1. .d M6-Mr1 :uN)
rrdua a d.N In I/y r.l I 1NA oK Ihyhren.lcrav may rc.uh, .nNl Ih/ Iolrl/a la n. r ro 1a nvl,d
11N IIINNII/N'ltlM'IIIyI.11/o M 111t'IJitit11./11 tIN/kI alw/ mla'lla'Ir w11I1 t hr1NINMrN11.1I
IMIoIa'In1
I m.d1y, Iwu mq"N1.ud unldN:mrNl. ul Ihrv nNNkl Jv 11 1. INaw111raI IN'li .I/a /t1/1111/y
tJN rNN~r)rnr. 11./11~I/NIILIINNI ruay hr Ixevaniad hy J alla1 rrNnalnmF
IIKII/NN111N'. IM-1I-ly rdN,/1/M'II IIIHNII!h tlN/hnc aMI d.kuNthyLuNNI ul 1)NA 1. Jn
IIIIIANI./ld a Jla /IM~)'l'll/a rvan1,1/N INr.ahihly arivs.d IrnNd1ylJlmr I)NA :,rNl /rvrr.
Nqt u/N rrl:rrK.r.
Ih-/frnna. X AI
Itnr luma u.l lh.~/dn w.r Ar frr 71N 49 %7 1994
Nthrr tuR//rNl: NJw~n.d ('.uN a r In.Irlolr arNl lha (:.rNyr A/.w rrb. MrnNrr/ rl I urNl I.N
('.Nwr/ Hc..Jrah
1 nNn dK IAp:utnwn1 0l 1'edrJlnr. Ilnlvcr.ny ..I ('aIlllNnla tian I)layr.. %tMNd ul
MrdkNN I.J hdLr
111'1't)MI II11'I A lltlN I)I 1)NA 1111MAN ('AN('1 K(l:1 I.S A SI11. SI'1'('ll l('
('l1ANG1 IN 1111 (' At1( lIN( 1K:I NI.
Xilr .It% lilt nN1hyladrrn.rl 11N Ilu/o.m. onr .NN /11!rnC wa% ll/vl'mIFa1rJ In a u1
OI CIIIIUra'II h11111.11111111NN ICII IIIM'\ JINI IItN111.1I h1111Wn Ilhfrrhlavl .Ir,un. A.
INrv1..Nlly
tclNMad. all lhr IunwN crll linr.. rn a.NruJ.l hl n.Nmal rrll., were hY1.NrNIhyl.urd 1.1
varaNl, tkkrca% rll dKIr Ir4,lI I.N'INNUN 1)NA -lhr prc+cnac n/ nklhylJtu-rn lu .pct dia
rrraNlt r.l dK t Nrrr Ih'nl' Wa\ i11:1Iy/ClI by uK 01 the rC%ItN'INN1 C111kM1N IC.IV lvrv In
hNIM'1\ Mtlrl 'JINI II/Mlll, which rarr.~nvr Ihr x'trlcrwe S' ('(Yi(:1' 1)NA
V9111CINa.1) 2 ayhnuk hav./alh.wrd by 2 Ruanine ha.r.) hul.ldler in thrir ahlhllcv lu
tk.lvr a1 Ihe inirlnal cyhnlrlc rr.whk whrn it i% mrlhyl:Natl '1hr hr.1 Ct.NI, lirst
inlrtvcning vqutnar a/rl .auN+d rum were hylrwnclhylalyd in all tcll lypr. rcKard
k.% ul wINlllrt dk tclls wem mMnal nr .Nrt.rcnically Iran.h>rnlyd a1N) rcyardlrs 411
/hr drKrat'.// /tMAI ~l'nIN11N' nlelhyl:NNln 11I (hl.'t.CII I h.wCvrr thC M11Jtary ('('( r(
.%Ik' lll
Ihe Ih/rd ct./n wa.lully nNIhylJtral in rNNUlal cell mrailu. In ctmlra.l rn 1.d S lunun
ca11 II/w./uKaurcd, thiv.ilc wa% hypNlrlhylatcd 'Ihi. i.1hc hr1.klrNrmtralnN/ ul a
.ilr .pct'dN 11NA nNIhylalnNl tkleil in a cc1lulJr .NNUKrnc. 1.Nnt INr.Ihlr unpl6a'a-
bron% rrl.dmp d1.rulMnm rd I/NA orclhylJuun 1r/ tNNukrrw a.NNtul auN/.NN uKr1n.IV arc
dl..v.vtJ
('hrah, M S(' . Wallat'r C. O . and Nr.J/'rwan. R M
LNrrrNd n/ thr Nerrornul ('une n In.ritrre 7 t(S): 1057 1410. 19114.
(hher suP/ort: N,rtnroal ('anacr In.nlute anJ the (irrNizr A)atr.h. MrnNNial Pnml LN
('J/Nrr Hr.eanh
Ilr.unrlN (>,1r.nurNnl.ll'rJrJbN.,I/nrvrrvlyul('.Id Nn1a,San1)Nyu I a)nllJ,('A
r
I:I.f.VAT1i) t)VIiRA1.L RATIiS OF TRANSMf711YLATION IN ('1'.t.1.1.INI:S
1ROM /11VIiRS1:11l/MAN Tl1MURS
In a sludy of a divcrx se1.ll human lun.>r cell lines fNCvilw.ly sMrwn Io h.vr a
tkfecl in mcthuxlinc mclalN/lnm, it was demwlnsltaled Ihat all have enlunced uvrrall
ralrs .d Iran.mclhylaMNNI ctnl>pnrd k/ mwmal Iwnyn fihmhlaat.. Tran.nlclhyLtu.N1
ralr% wrte tnra.ured by hkNklnR S-a.kn.rcylhunw.cyacine (Adrdlry) hydrul..r a1NI
nka.unnK the Adullcy whNh accumulales as a resuU of tran.ntdryl.U.N1 '1ht alu
hanceJ Irrn.rntIhy1J1Nm rales may he the basis of the a1N.ve-meMw.ncd tklcal. in
mclhaunnc nlrlatNrll.m prevurudy tepMed in huuum lurtuu cclls ioc/udinR 1he Inal,rl
Ily /1( the n1a11Klly 1rt Ille Iu11NN t'ells It/ itntw when n1e1hM1111ne is re/rlalYd by INNINN y%
~
lrlne ?lrr ct:e.% and unhalanced IRNA tne/hylaliun uh.ervcd few thc I..t 25 yrar. in
many Iypcs uf cancer may la a1 kasl in part explaitNd by nur resulls 44 ek valed ralr% ul
uvealll uran.orclhylalNm in cancer cells. T'hc alteralirNl u/ sua'h a fundamrnlal IN.N r.%
aa (ran.mrlhylalNN1 /n cantYr may he indN'NtvC t./ Ils nn/xrrtanaY in (llr rNN..IYn.c
pnK'es.
Stem. l' 11 and Nr.Jj'nwn, R. M.
/n Vit.u 2(NR):(rhl-67O, 1984.
(hlier suOPoA: Nalirlnal Carr er Ins1i1u1e nnd 1he ('.e.Kge A. )x.rhs McnwN1a11vnJ IrN
(ancer Rcxarch.
Fnun the Ikpartlncnl td flnliatrics, l/nivenily of C'alifixnia. San 1)icy.o, I.a l.dla
1IIE CYl(1SKIiLIiTON (W MURINF.1,F.I/KIiMIA VIRIIS (Mu1.V ) INI'7i('"1 P.I )
M(11IS1: h11(R(/111.AS'fS AS UBSI?RVI:1) UNI)IiR VARYIN(i ('ONI)1I It/NS
(NF N)RMAL1)I:IIYI)I: hIXATKNV
In the wark reppNted here, nwaase 8hnatlasts ehnmically infecled with Mrd.NUy
murnK Icukemu viru. IMu1.V) were 6aed u.ing variable annwnt. 01 Lx/n.hlchyde,
then ctalnmetl by Imlirecl ilmnwudlurxe.eeae IiRhl miansatq+y Several anhara
welc cnq+l..ycd lo dclecl bdh ealernal atd intetwal anliRens a.ww iatcd wnh 1/K cc11.
.R., Mul.V pp711, lulwlin, vinll:nlin and aclin Rewhs indlcatc Ihal alK tell nNln
hranc% ctruk/ hc panwlly permeahili/ed hl IR(7 mokcuks duccled aK.m.l the Ihrac
eyhr.keklal aMiKen. tudy allcr 1.7%, hul mr1 196, ftNmakkhyde Ircalmr m('unqdrlc
pertncabili/aliun wa. achieved by suh.eyucM aceHme ItcalNlcM nl ccll, after 1 1'i
/nrnulWchy.k haalam In wch cells, ruNmal all)IearinR cyhnkcklJl netw.Nk.../ mi
cruluhks and iaennediale lilameMa were nhserved. S/te.. /ilkrs wcrc alw ven
M/wever, they appeared ks% numenwa and Ihituln than Ihl..e uf unin/caIcd nMrov
lihnrlda.ta hurlhet, a.Ilrnficanl anuwM of F-aclin tlwrevtem'e wa. kN'ali/cJ m
pranuks in the cyh/llla.m.r( inkcled cells. Similw td+.ervalNin% were mark u.inr 115
V9/mru.e cells chnNlically in(ecled with 114( virus, an.Mhet Mu1.V 'lhea ratult%
laken 1..gtther su1:Re.t that suhlk dllfeances r aisl In the trKanvanun ol aahn wnhm
Mu1.V udratcd and uninlctlcd mlwst fihruhla.ls.
Salaka, M., Lu{.1,1). and IrJtig, R. R.
CrII M.aillry 1:567- 577, 1981.
OtAerlY/pR: Na1NMaI ('ancer Insl//u1e.
Fr.wn the Ikparlrnenl of MN'nrhadrqty and Immunuk/gy I/nlver.uy ro( Grulh ('uu
hna, StMNd.d Med/crne, ('u/un.Ma ~
11) 1 31
GI NI rI(' 1'KI 1)ICPOSffH)N TO11RY.AST ('AN('I?R
AIIINNIph l.lnnh.J t lu.lrring .ul hrra.l tarNCr was lir.l rrc.w.kJ in thc R.Nn:ln
nxJit J IUrr.llure rr.ro/Nl 11111 A I), il% puhhc tNallh nwEmlak atNl .IKniht rfx r:uc
sl/ll INlllfll111.111t 'd, t.l l/lls tlJy In Uh llresrnl rI1NI.m/11hlr Na1 s11Nly. 11 1s
sIN/w11111.11
Mta.t l.oNer r1.A LNhN\ arc ekwrly, tnlcrlwlnlJ wqh tlll p.ltlcnl'% cuhur.ll h:ltk-
pr.nNNl, whah m.1y 1/N11I1141t1 tll lwr.l.l carltcr :1'I,1,'fl'1,'a/llnls wllhln lannllr Ih.
lhlht u1/.p1c.1NN1. ur I I I.MIt. a Iruly Ix rcJll rry Ilrca+l t'arxrr uh.cl ca.t''.1:1 whN h
l.l/udlel ap~rcFauNl, rfr INrcJll]fy-/. JMI ( ~I is Ihe herethl%ty llw,n Jt.lnx-llvr tflNn 11.
NNN.Nhf llNllllrfllifl' lhr.c yurric% will he res..IvcJ lwN'c huwll:uiscr% arc itknuhcJ
Ih.N IN.w Intih.rn.Nlvny :u1J.pecilw'Ny wi/h pe/wllype. 'flle autlNw.lNOvnh a revicw
1.1 /hl..uhh.1 a.Nl will l.tu...n Itlcit rccrrN Ji.covery.d uNfca.cJ nr rrl..- hyl+.r
JydulJy /n ru111nrJ.11a htwld,la.l.Ir/Nn Pahrnl% wi/h.w at tf.A hw hcrcJu.ny INra.l
cr.x cf I111' dWINN\ (IIV IN~ IIIMhnI,'s tr.Mll llx'Ir stlxly Ut 1:/n11Iy I11stINN's In 2~~ t/41s.Y
uthvlly a.a rnanN.1 P:NNnt. wtlh vrt/lieJ Mr:r.I . anlYr R.Nn IIN ('rrlyht.nl 11n1vcraly
S. h.Nd .d Mt JN Ir/c / hN..l..ley ('hnx l-oNhnyl t.lna.lcrlt wnh an IlctcJN-ory hrc.l.l
t a1N ct .yn.h..nN wcrc NLnttlit.l ln t~{ ul Ihc p.111cM. ( ilvcn IIN' I/? INM) nl w t,IV. ol
Mr.l.l i anl rr ul lhc I lnllyd SI.NC. in PnIZ. (IM a1//INws es11111Jt1 th.lt with a t'Imlidrrlce
..rIht Nnl .11 O'15 hctwrrn 2./111 anJ K.7V0..1 Ihr.c inJlvlJu:d% wdl nlandc.l lxtcJl
t.Ny Mr:nt . r/xcr Sltrnct .urvcdlr/xr/Inan.lErnrnl pn.yr.Inl..MwlJ hr ycarcJ tu
h//:h u.L nN mfn r. ul Ilx.r /amdlc. in whit h t arN cr yleNl will hr P/cJNiahlr
1v.nlr Il 1 4-1.01
( tln. r1 S 11 11 hl? f.; Z. N/I{d
Ia.nl dN ('Irqhlno IInlve:r.Ny Stlrrd ..1 MhdNlflr anJ 11N In.lltutc t.w U.Irud1.1
('arNrr M..n.qvnNnl.aNll nnUul. IIN .IIn1.J1...('wrx11llnlvtnlty McdNal(lJlryc
Nrw 1'.NA I In/.rraly uI Mrrl/tnN anJ 14 urnrly d Ncw )rrvy. Nrw )rr.ry MtJNal
StlNrd. Nrw.IrA .uN1 dN IAP.n11.Nul nt INA.aynFub.l:y, It.ly. 'luwn In.l/lulc
0111.111.1
IS ('AN('I k l'OMMIINI('Altl.F.-I
Thr c/N.l..yy Irl i.lnlrr renlainm cluivc Nevcrthekss when nwucuhlu% cl naal
Iahlwallwy IwantrJ nxJl.al ~rnrtlr/rpNkmudl.~/c .lulhc% arc petltwnxd .NI larl;c
.rnc t.l I+a/Nnls wNh yvcllic hi.Ir/1..Kw hwm.ld rr/xcr .uh.cls enkrrc whu'R lend
stll.lrwt h.:/ vJrlr/y /.1 e/ll,h.giC hy111AFNsr. A.INCSCbICJ m thitlc tlllrl. fClYnl tkvrllp/
nxnl. In t arxcr clwtkfmolugy llavc II:J lo tht psiMhty nl arl cscecdinKly c.wnpkx
t.lnm/unla aldr /x l.wl.l /n a atw'rr clNlh.Ky 1 hr Ir:m.mis.awl lJ .uch an rKentl.! m.ly
rcqulrc .1 .u.cclNiNc gr/NNyp arNUlw sillier PrIN/NMNwlat evl'nI\. likely CJ/NIIIIJII'\
whNh .ulyMwl tla. sul"IS11Nw1 IIxtINh (I) IINlcln Ilarf v/tu\ InaM/Pharynrra1 tar
l'l/Nlllld. lllnLtl/ s Iy111111NNlla saf/vary 1.'IA/NI tnnNw anMNll,' I:sk111N/s. X hnlirll Iy111
tdNqN.drlcrahvr .yntlrlNlK nf Rutdal. 1?/ human I cell kukcnua virus Ixluh Y trll
kuA.nua).1 t1 xylnrcd lnllnunc lk lir/elxy >ynJrlwne (AII)S1, c.Nlry/lx a1tJ by Ka1M1
.1..arclNna (cINduFx agenl rrnwm% elu.ive. IIN1uKh ePNknuati+gy wggcd. LL./htc
inlrclNNl. Irrn.ull..nln): 14) ahawrnal inlmune pherNNllena in MIu.eMdd% ul
I l.alyl ln'. Jl.r.l.e p+11crN.: am11 ti) a IuslerlnR al varillus typc..4 cancer in +Lw.e. the
~clll'td LIqNJah.+n, anJ famdx. lhe aulh.w% have.elrttlvcly reviewed Ihc INCralure
JMI lvUlvlJ an tIN.IOI!N hypwlNsn dul ultr Kf ate. a elNnmunxahk aKrnll.) /n c.wlrrrl
wNh /rlxtN irn1'.w 4 nv.r.nnlcnl.d ..ua uN.rcnH mlrrax IN.n wlnt It t..ul.l I.NN eivahly
r.p;.nn ./ .qndl. Anl 10- bMI a.1 Ifr I.a.l . uN.% la/t.kn
l.lm h. N 7' , Schucllc. G. S and O'11ara M K.
Il1r.Gr.d IIIyNNhr.trl 14.IR1 1'!R, 14Kt.
frtan ('ilIlabtlwl Ilniver.ily S.IN11.1 uf Medicine. lltpatlnrnls uf Prevenltve
McJlcltn /PuhlK Ilrallh anJ McJical MxrnhillkKcy (hnaha.
( c1 NI 11( S, 111()MARAIiRS, ANI) (1)NTROL uF NR1iAST ('ANCI'.R A
k1:V11:W
11NwKh thcrc h:l% hrn mw'h inlcrc.111Nauyh.lul the yrxt in Ihe cINJtmi.d./4Y ul
Mea.1 cancer. lady very hllle anenlwm lls Irrn given lo the r.lk nl plrNINs In N.
chld./ry ( lx rrvlcw prv nh J IN tr. lNlwcver. repre.rrN. an altcoqll hy d/c /nvcaiya
I/MS QI IIHWNIr a a/NnlNrlnnavc cuvcraKe d I1ereJ//ary Mca.l l'a1xYr. Inl'tlNkll are
(hnuxnt rnlhlrrrxIW% prNl rlN.rrlxvlu. ri.\ lacaw% whith in acrtam cHtunl.tantc
n/ay ayndn'aatly m11ur/N'c Ihr ruk uf Pr/nlary Kcnrlk larllw. Ikre.htary Mra.1
carxer r. tlrlrwyrrk.M/s Wlrn JLCU..inK the whtet'1. dkrcLw. am mu.l fie precl.e
Ickv:nN In /lx I/atlNulan cclarokcnctlu. Itwtu n/ alncrrn, tlaseJ.N1 Jllll't/nl; n1/1Nw
a.ww'I.NaNI. 11 r. Ix.dwhly /a11 uW.qwiale tu Ji.cuss 'hcrcJllary Mc'r.l rarxrr"
w111NNN yuallh.:NUln /d dlc .Ixti/ic hercditary cancer symhlwnr 461 ctwwcrn. I r. IIN'
S1p.A synJrtNlir, INl'asl/.W:wlan lanl'er \ynlttlNtlC antl MhCr\ 'Ihls rl'aMN11111; al.u
atq.lrcd tu ancoqll% at bn/.mR hNN1laArr. N/ hcraJNary hrraa canccr 1/rlally In
:MIIIIINw/1HNwtot.NtIF` JISCUSSNNI% Iwl lhc cardinal /w1lKlhk% tlyt asslx'lall' w11I1 INlrthlay
hwnlW ut hrca.l calw'cr. it% ttcyucrxy anJ new Jcvckh.mcn/m in hi.NnarAr r. IIN anve.tu
y:N.w.luvc PravNleJ.urve/llarne/managcmrtn Iwt/granls that emtwxc tMl.. I+tcl% tll
Illc nalural hla.wy ul Ihi. Jl.ca.e.
l.rnr h, ll 1'. r1 ul
l'~rn. rr (:. nrn... und ('yrn,rrnrnr~ 1):4 )92. IYK4.
(Pther srOp.w1: Fralernrl Order /d IiaKks.
hnwn IIk (kpattnlent /4 14evenlive MeJicine/PuMic Ikallh Il<y/artnlrnl ul Swl;cry.
IkrcJNaly Can:rr In.tilulc ('reigMan Univenily ScINr1I t/l Mcdiclrx: Omah.l Iht
Ihpartnknl 491 ('linicat Palhlltrlgy, Un/vcruty ul MeJicine anJ IkrNiaty td New
)cr%cy. New )crxy (IJkKe.d Meylicine, Newart: anlllhe (klwnnlcnl nl Mrd/c/nc
Lalrwanwy hw ('eI/ 1fNd..gy ('.1rnc1l llniversily MeJical ('tdkXe Ncw Y.wA
TUMOR INVASI()N ANt)11()ST t:X11tAC'1:1.1.111.AR MATRIX
This review Jis'ua.c. NNllc uf Ihe majlw nxYhani.lic Pathways by which tunNw
crll% arr Ihlwght 149 Invatk hn.l bsucs. Tunww mva.illn has been c.NN'erveJ tu hr lhc
rca/h ul path.d..Kla al, rGac r.nFc inletarluNls between /naliRnsnl cell% aNI IN/sl
.rnwna. lhc .ryurnre u/ evcnl% tha/ chwxKrirc inva.em can he sunnn~uir,t ar
h.th.WS' IJ) I unNw IYII llushY\ Ixellll Inwn Ihe t'.NIIIne111enN n/ I1k; primary Iu11NN 1 al..
aul iMercellular rynclNwa /Jl'snMhOrlle{, gap )I/M1NNB). aherNNwn{ in Ihe l'I/fnllCat
l.Nn1N/sNNw1 a11d (lhyslcal Iwn11er11Ct nl /h[ cell Sltrlale Clyt (km of tltwnrlee, tin a1N1
hcparan.ultalen excm anx/unls u( hyalunlmle). IuW loa>senitllt 44 cell sul.clrale inler
allinns (krss tll hemaksnNl.,wnes, filx/nu:.lin anl/ he(laran sulfate). are atrN/nK 1he
ttwlst tteyunNly In1eJ cau.es nl tunNw cell sheJJmR (h) IrureaseJ Ilnltet11y1K attlvl
I/es at dle mvaswwl frurN l.uve /utal ahera/Nlm in 1he sum.wrhn6 eslracetlular nlahr.
12 1 13
J
ln
rJ
an
Ilw rchy 1 h.nlyinE t1% l.hy.i(al pn.(r'ncw. ( UII,Iren:mC% a1NI l]Iht'INIm J% wl'II J% cIJ\
1.14 a/Ml .dlN-r nl'ul1al (NINI'/niNl'% arc the in/yllla'% IIM/%1 IH'lI1N'tNly a.t/:dcd with
I/L/Ir1\ .k'~IIIN IUNl:11NI Inva~1/N1 /n uNnc u..IN.Ihi. paNc.. i. alca Ilv.ly rcguLucJ by
Inlnhn..l..d m,Mnl .kFr.Nhng, ptlaculytK cn/ynw.. I.I funNNCC1I.ImFIJlc mlotlk
Jhcrad mJtnl" Ir..ahly oN+vlnF a. a~~rcyalc. akmK gu1.IJntc 1r,N k. pnwnkd hy Ml.t
.u1N Iwc.IhUrrl vc.4L, Iymph,nit., rK rvc.I.N malr/t 111N tININ.h't"I/k'~ (l ull.F. n arNl
11M.NN-a hn u.N {..1 Mlgr/n.m 4'cma ho hc prccc.kJ Ly uN tca%cJ vwclba) ul Flya..
.Jnluwq'lya.ln /l c. II).r1unN1a1c/ u11hc nulrit. ahcall u1 1hr m/1:r,dmg 1cI11.yNdJhnu
V:uNN/. IN../ ac11 lylt. Inut tcll., Iltxuhla+l., en.kMlN-IrJI ac11., m.N ny.hJFc. cl. 1
nlay r.vu. qIJlc ul dN.c cvcnl%
I'.nrh. /i I/ , S. hw.utv, 1) li . 11aNtjf. 1: I M., anJ Ru.nn.r K I
<'nn.cr Al.hr~r.r.r. R.-.rcN'l 2 11'/1`62, 14K1
t)thcr aMpp.n7: Nah..nJl ('anclt (nNF11dc
I1..nt tIN IAparlnNn1..ut I'.ItMlh.yy, IlNNh.nlm%lry, atNl /MINyr'1I/l %urltcty Ru.h
Mcd/. al ('.d1i1c ku.h 1'rc.hylctlan SI I_ukc'. Mcdltal ('crMcr, ('IhN':I4u
SIMt It I ANl :f Il IS 1'1'.lll (ll'.N I)I.N`IT/ )MIa RY AN11 AUTI IRAI)N K iNAI'lll('
(:RAIN (1)IINIIN(: W1111 1111-/jl1AN11M1:1 7?INi IM'AGI:-ANAI.Y11%
tiYSll M 111 IMI'Rl1Vl.MI-NIS IN 111I1.(;Y.N 1)I NS11OMIIRY
A nnthlwl ha. Mcn IkvclnttYl LN C%IIIIIa1/1N1 t1I the I e11IgCn atJInC.I I)NA t.N11Cnl
ul 'It IllynnduN l.lltIrsl cclh,n J1d.N.NhuF/J1.11. in canInltum wllh Jtn.anJtc.l yr.un
l.Nnll nNa.NrcnN'nl u.u1F aOu..UhnN1 tclcvl.uM unJ/'ml'.y.tcol Rc1uNI.N'nt. In /hc
aNtlNrkdnfy .uc /c/rNNd whl.h /Mlu.lf (II IM' 11N.NIMNJINNI nl :In 1111.11s. 1.a1n.N
Mlrlolr ult.. IIM' V11:In1111N't 11N4IIItP lIN/I/1urJuno. 1.'/ dN .yNUnvJlum ../ Inauknl
IUI/II///LttNNI h.14'11 tl(MM t'YJIIIJh.NI ..I Y1/nN1% I/Fhl ..NU. a. 1 II a hangc m IIN'
.qlNa1
avNdlKu1:/1NN1 whn h rlJuac I;larc ,NNI nnnuru/c IIN- Icvcl nl nN.nINN .h.NhnF ca/tcalNm;
p1/1hc IyMnnvJn.m ul 4anrkr .cn.ulvny JnJ ISI tM cv,duaU.Nl nl t cll 11.111cnmg anti
.tannnK wltll rr.lti-.1 la Ikrnvt.mNIry 1C4.III1NN1 aNI .cn.nlvdy. IIN%c rcInNnlcnts
rcadlyd m a a.w 111aanl ol vanalu.m 1CV /111 k+% than 6 J'X lu 11N- ( i 1 atNl ( i-2 I1NA
pt'ak% u/ r:U kNhky aell% in auuNaJil.Krallhs cINn1l:/rcJ lu the prcvilw. ('Ir nl NI.S4,
and a G 2 N. (: I ralilr ld 2 025 PIN a/i.ed IicAi p..i1Nrl the ('V wa. 5 19i and the
rcplwalNN1 crnN k.% than I 11') Thi% tct hn14/qty i% ut Inlclts/ Ixcaua 14 d. (+INcnllal
al>f/1ra':/tNN1 In t1N tcll ayck: snaly.l. Id tni.cll pdyplual uwNN ulqrywl:dnNr..
SAlrnrn, R I
/hc l.wnwl r./ l/r u.N hrreiqct nnJ ('1I.r AcnriVry 111111) 12 24-12 12, 14111
fr/NN New Y.NA I tniver.ily Rc~earrh ticrvNc. New YINk (Inivcr.ily MeJnril ('cntcr,
(NCl.lwalcr McnNNlal llu.(Nlal KlrnavtIt LIanJ. Ncw Y.Nk.
('YTI IKINI:.11('%t11-111:TIiRltt'I (111) TIIM(1R Sl1NIY)I'lI1.Al1ONS ITY
('I)MIIINI 1) AtI1tIRAt)IIK:RAI'lll(' IMA(i1N(i AN1111a11.(il.N
111 N\IIt1A(1 Ik1'
In hu..un 1..,,... whtn (.Ivpl....lv arNl a.N'upl.N.l v.an.N11. //l.1ui.d1V ..N'tm~l the
n aL.... 1 .u.r..1.../. qau. nr 11...1. /w ..n.dt....d IIN . 111 . y. 1/' kl//.'/l. \.I
IIIIINN\,
1.L.r,../...11 I IIN ./n 1.11.Li 11 J11.11 IIIIKI ,/n11111f 11 .Il~lr'1 ~LNI
1i
I/l lht INIINII:11111n a% J wh..h' thr nIN felalC ttl the l'yt1111,rN'tN hChavNN t1t the lhmln.t
PhNJy IlntaKc. In II11% %tu11y, an a(111fty(II 1~ 1/CK/IIICaI I.N M hll Y/nF a tla'I.NIVl1t111NN1
Id IIM tcll cyrk I+ha%C III%Ir111u1NN1 /n n11tC11 hckYnlfkNll Iu11NN phrulalNmm d/mn4
c><t..Nrvui.d gruwlh llM .thcnN (NUviJc. (II the pKN1Ia1Nln Ircyucnay alNl I.h.l.c
JLInhu1NN1 ut J/4lctc .ulqw.llulatNN1. J/.hnguiJlcd by Ihclr 1)NA pluldy level. 1?1
IIMn Ir:ul.n tullt' AuNtR% ay rCveakJ by aCrlJl C>Ii1N:NC. UI lIN/y1:/1U/N'rlt.J (u/twrvt1
ul
S, G2. (:1 :IINI in the Uvftall fyl k'; and I I) IhC/t cell (ll/t CrNNr11N11NN/1 at thc S/l i2,
(i./Mttu.l% atNl (il/\ I>fu.e hurNlarie.. Thr analy.i% i.I:Ni1qNeJ by an auhNU.ncd
o1c11Nrkr/.ryy.k'vrLqN.1 wltb a VuanUuk9 71/N) bna~r analy.i. ayda m LN .inndl:uN
uu. dilcrnnnali.Nr u1 I1N I1NA aNqcM alNl grain aauNl ul 11-TJR I:d1.kJ tcll. /o
1-cldycn .l,n/wJ auta.yrJph., 'fhc tkagu% invlrlve 91 and INILc Iats'I//Ir,
IkNlhlc hltt hng JINI a INIIIIItN/u% IaIlChnr, in flNllunl'INN/ w/lll ('I.IIY'n1/1I I IIC ININ
l'.Iltlf
ha. INl'n t7N1/1Nlh'1/~e/I Ir.Nll at11u1v11NN1/1/ 1111Jg/n1,' al.lla, IIN.NIrh Ihc a'alcul:rtum ol
rclavJnt paranKtcr. .ml their Kra14rN Jlyday. 111a aady.i. i% dlu.ua/cJ in J IN'lino
pkad, u1wkNNJ M('1' 7 a/dnuc wbhnc Ihr.:yMNnatfi clrau/nvcnl. [1w 1n11:N1J1.k
IN..Idcnl ..1 re.ulvlnK I/I/RCaI hctan.pkNa) and anlIq.kN.l .uh/+/NNdau..u, l/.lol dN1.
l/NtqNr.nc 1)NA d1./1i1NrtNN1 what (il, \ anJ (i2 aNlqrNlenl. W varNN/. Irvcl.l.vcrLNk etttcN.rvcly
in Ilx'Ir I1NA canknl range. In the lulwe, /1 .arul./ta4.nahla dl,d IIN o4
.d pkddy nr,n{.cr.lu a1cMlly ekNUl hm alet. huh(N.IN/Ia1NN1~) /Ilay Ilhtlll.lta'Iy IMUVnk J
h.1.r./1N Ila,crnnlning Itlrir 4nNItvlly aol/ rC.i.l.Nwe ttl a varlcly Ut al!aNI. In
/.Idtl.wt tU
Uku cyck pha4: d1.p11w1NN1 and ltvcrall /rcaluCna'y.
SllurcN, N J.
1
In' (41M'l'rJ/np t/I Ihc IIMh IDICrnatNNN1I ('cll Cycle ('INlltfl'Ml, Ha11II ('anuc, AI
hcna. ('analla. Apr11 24-211, 14114. 1lle 1luNlana IYe.. Inc., (lillun, NJ
1-nNU New YINk Univcnily Sa'hnld /11 MeJNele, (iuklwaltr Mcnwuial ILNpllal.
R/N..cvch LIa1N1, New YINt<.
('YT(1KINIaI('S 01: S118P( WUI.ATI(NVS IN MIXI:1) III lliRU1M .l>11)
1l/M()RS IIY 11:I.I:VIti1(NJ IMA(iING. 1. IN:(1)NV(N.ll'II()N tll lllls
S-IMIASI:1)NA 1'1.(/11)Y (Y/M1'l)SITN)N. II. ANALYSIS ()1: TIII: S 1'l1A\I:
I:MI'fYIN('.1'I(()hILI: (/FF IM.(NI)Y SIINIY)M/LATI()NS
The /Nlrhkm /d evaluating the a'tll cycle t<irkNias nt Jw.ntt .uh1.yN/1au/N1. i/l
n1iReJ 1unwN cell Iu.IN/lalNma hav heen nw.a inrrac/ahk:. Ilowever, a.a'Iw'Nw /cl% ln.n
Ik veksilcal hN Jecil.MrlnR the cell cycle linle parallKler% nl ecll .I/h~1111yI J111N1~ 111.41
1I1/1Cr in their I)NA 11hIMIy level and that cYR nIN in III/RCII hCICrl111kN1/ tu11NN III tln,
p:qur, the S-ptla.e an:lly.ic i. prese/NrJ. lllc ayTlawa'h 1% cuupk'J lo an auhNwurJ
i/nalanl,' rnellNNklkrl!y LN \I/tN1Ua/1eaNN IlPll'ItINnWlu/1 n/ the IYuI)!en %/a//N'.I IINA
c/NNC/N anll Rratn t'uunl l./ 11 thynlN/ine IahckJ tellr in auar'r1u.toraph./SAlarcw R I
)I/LhNhcru('yhrhanl M11`, N14Y,1V112/ IlleetpcrolNnlalakaxminvulva '11 Jud
"('-t:lymNllne J.Nrhk IahchnK anll ('/Ik'Cr11NI tnl'u1WNN1 I he t/fl'aNIvnIWNNI 11( IIN' 1
(.ha.t (IlniJy tlNNpritNNl i% i11u.IrMeJ in ral wclNm auNure% cnnl(N/ang LNN marN
p11NJy .uhpqN/1Niuns with ( i 2.nd n1iNNic 1)NA aNNents u( aWUrlnr.acly 4('. N(',
Ih(', anJ 12(' Thc t'.NnIrNNnl% were iJrMibt/I by theu 1)NA IIkN.Iy k'vl'I, anMl IM'l/ S
treyutnt-/c" anJ Ia1NIInK uNhce% wett IIM.IneJ A 4'henN i% al.u .kvcl.qrd ,uNl
va1NlaiCt1 //N uhlain/nr. IIN' \ rha.e cn1111y/nK INldlk /.1 ..NIqNNacnl Id.NJy .u(ywhN.1
IhNN11, \MI Ihe/r cel/ Ilu at Ihe SHi-2 arNl 1i2//nnua. pha.c INNIrNlal/c lu dN
15 '
.rrl..ma ( ulturr. \ trn.hilily was f/wnJ lo Ikctrt:lcc wuh Inl'rer.mg 1)NA pUnJy Irvrl
uvcr IIN cnufc pLudy ranKe
,1lLur.r, R l
t hr l..ranrd n/ llt.t.a hrnultrv nnJ (yr.h hrrrrzltrr 3214) 411 42/1, 1'/N1.
I n.nl rtlr, lkprrtnwnl n( rrlhldnpy, New Ylxk llnivcr.uy Rr.rrrlh Scrvltt. New
Y.NA llnwrt.uy SIIN.d /d McJ.une, (N./dwatcr MlnNN1.1I IhNIf11:1I. NINIMVrlt (.
Ia1Nl Nrw Y.NL
t'Y r( )KINI '11('S l)1 Slll(I'( )Nq.ATII )NS IN MIXI 1) P! )1 YPI.011) 11 /Mt INS
ItY 11'I 1VI%It/N IMA(:IN(i III '11 IIIYMII)INI.IN('t/N1Y/RA1//1N IIY
I'11)t1)Y S11H1V)1'l/l ATI/1N\ (YININ(N.(/1 '11 AllSl)RI'11tIN ANII
I MIII.SIt/N 1.111( 11 N('Y IN Al11URA1N(R:RAI'l/Y
1111111% t tII t ultufr.thNly, an af%w.%alfi 1% prr.cnlctl l.N .ktr nninlnF rrlrtlvc l,dr. ol
'II Ihy1tINI11N Inl.M1\nr/NNl in % f.hrV' f.N JIK'rNe (.h.Nly \OhLywl.NnN1. thrt./ra1.1
In hrlrl.q4.NJ IIIIINn. I hc analy.r. h Irt Ihlrtt'J by rn r1/Nw/lrllJ IIIIal.'Ing IIN'Ih14htl
..py .L.rh.lvJ wuh rOuanl/nNt 7!11 tiy.lrra I.n suuol6mruul Iklrrlnmrn.Nl 1.1
I.ulrln.t.mNJ I)NA a.wMCnl rlNl yrrm l.wmt. ut 'II IIIymNhnrl.lltkJ trll. /n
I rulyrn .1.,u/Nd r11/.N:NIN.letrph. I IN r.fr't/nwnlr) .k..Fn Invulvr. '11 a1NI '(' Ihy
II/NIIIM.I.M/L1.~ Irlwlm~ m Ilh /aa vfN r.d l.dll/IINI I/rlritlNlllM'tlt1111hnJ rrt.ru.aor
lnlllnr. JIu.Ifrly dN pruhN/nd udlucnlc .d dJlrrcnllrl '11 ah.+NINNM anJ trlrtlvr
r/nul.NmllhtNINy IhesCIJl4M.rrl'hNdt/dlrJ.repr.hvcly.thaNfkhnNr.urrnNnl.
ul nKan ou. trrr .ywN :J .knIty r/Nl Krr/n.kn.ny l lu.l. r.antt:d l.w a wlhJ t.unprl /
..Nt o) grarn t.Nlnl% httwttrl cPll.Ih.lt Jlt/ct in Iheu au1.N:NIN.F'ra(dhlr Kr.NIN'Ify 1
hlt..
rrl.dlvr (/NA .(rt I/N :N rlvlly nuy he r..a.aJ In fnr/1vNlurl crll. lhr I+na.a.d r/NI
:Inrlya..aly.nt a.Inlullrnr.rl. cv.durn.m u/ Ihc S ph.l.c ph/Nly t'.Nn1...nNn1 rfNl S
rlnlMylng INUIdc. a. I.rl'.l'nted in r l'INIII.afINNt anlCli ah.tlactrJ hcle.
UlnrrN. R l
t'br l.-r.n.d .4 l1r.nn brwu.rr), ra.t ('WIw Grrmdry 12141:421 -4)1 19N4.
hr/ml dlr 11`parnnrnl o( hrllNdupy Nrw Yfuk Ilnivcr.ity Rc.carch Scrvice, New
Ylwk Univtt.ily tia'hIN/11d Mcdllmc, GuWwalcr McnNN/al Ihlpital. R.Nt.cvrh 1.-
laml, Ncw Ynrk
1'LASMII). 1't1A(:I:, ANI)(iliNOMI(' 11NA-MI?I)IATIiI)TRANSI FR ANI)
I.XPRI.SSION /)1 1'R(N(ARYU11(' ANI) I:.IIKARYO'f1('(31:.NI_S IN
('lI1:Il1R1:U 1111MAN ('1:1.1 S
lr.n.i/ttnln nf nWInnlUhan IeII% with gfMNnN' I)NA aM) lhN1l'.I prnl. 1. M1w
re1r1/vcly ruutirle 1lawevcr. the va.l ntarwi/y 14 slulhe\ havc uKd nNknl lcllk a%
rn: ifnent. I llrY 111e aulhlNt dl'M'rlhe efhl'Ienl Iran.ItcINM nf Iw.111111nan t'CII IIINN. IIh
hylNf.a/ahinc guanine pM/lphllrilNr+yllran.lerax 1111'N Il-/kficicnt 1(rla hrw, IY)Nr
All-2. anJ the aJrnine pIN1y+MNilNnyUran.lcrase /AI'RT)lk/il/cnt II11(u11) bnc,
1110114 1 wN t AI I 2 ccll% were tran.fn tcd with the pS V 2 Kp p1a.mNl u/ Mu1liKan anJ
Itrrg, whNh ..w.l.nn. the F.nt. ..nlhinlRuanine rtx..{+INy/1Nl.yhtrn/rra.r /Kpt)
/. ..r Mb1 I q.. njnJr...ro. wr.r v'/r./rJ in I IA I nNJruln 11111114 t rll. wlte
.. ...Jr, .. ,t - .h . I . r.......n, 1...... I. . I -N A a...l .«../1.r.n tr.l.Iro1 1PNn.l ..
(r.n% wrtr
. 6 .., .1 ,.. . .. k/ .v./..,n . 1,. ..... .,../ ... n.~ 1. n..oN I INA e.Ml /1tn1
u11,
were .rktlcJ in AAA nNJlum; ( l) p1a.mNls coMaininK either thr ch.nrJ hrnlarr .N
nNrl.r AI'N 1 Kcnr., atNl Allrt' cclI% were v hckJ. am//4/ p11aKe parlaic, clNNr/nmy r
cWNNJ uN.ua AI'N f grntr, and Aprt' crllk wcre .ckrteJ 7 ran.Icl tNtn aUN IcIN lc%
ranrcJ Itlwo 11 25 lu 1.5 l 111' Iranslrclanls prr µE ONA, arNl in ccrt.nn l'a.c\ .cI.NNIrf y
/ran.IrctNMn wrre lMak lvwriFn 1)NA in rallplcnl% was lklclIrJ by hh.t hyht/Jvr
tuNl, a1Nl t11r eslxr..Nm nl LNCiKn Kcnes wa. tklc/ krl hy tcll Kruwlh /n .rktl/vc uNJlr
a111I Ihr t'4(NrNNM III tniynw% ah:uackriair llt the .prclc..d thr fwnN.r 1)NA 11N
nl:lpnlty u1 urn.lcltanl. aN.wlJ .tahk clpre..i.Ml f.l the trrn.prn.wlr.
Srivrl.au. 1: S Sf.mMIJAr. l:' J.. Sas/Nt, 1'. 1. SlawMlN.k, 1'- 1 lrlll, I I rINI
'l la h11rAl, ) A
('lb.rrrufN ..nrJ ( rN Mrrn n. l 1N 227-214 1'!N4
Ilthrr .ulrywrrr; N.ItuNl.d lu.lltulc. ul 1lrahh arN/ Ihc NatiaNrrl Sa /cIN c I INUNI.w..n
1 f.Nn IIN I kI.rfn/Nul ol MN ru(+1oloE.y. ('.d1trc n/ MaYIN /llr. I IItI Vr1\Il y/II (',IIIL
N lltr,
If valr. I ltpatlnwIn1 u1 Anrl.any a1N1('t11 Itn.M.9 y. ('nikkc nl MrJ1luN, I tulvlLUy
4.1
('/Ik /1111:N/ t/I I. :IINI I)t'1.:1/tl/lr/ft lll AllrtfNlly Ml'JN.'aI ('ISIIII.Y l11 (
NtN l- l.. Allr u.lr
i
1ttMONI(iliNl('I'll' OF III/MAN 11"111Nt1111alR(riAR('OMA X Nt)NMAI.
I IIIRt /H1.A\7 IIY9RIUS: ('1IN//MI1S1)MI: I)()1A(:1: hla'I:NUI.NI'Y
llu IonNNi)ynla' cap:N'/ly ul hyhriJ.lllruwJ by IusilNl //f thl Iuyhly tunlwnlrlnl.
I11'llNttl hullcm hM...arr.Nlcl cell llne with rNrNuolllri~enir n11r/11aI /IhtllhLl.t. wa.
r1:1/111fIr1I Ihl.' II 1111N1/ alVl t'11111a1n[ an all/va/el/ N-ra\ IwN'/1glrlr. Neat Ir11:11.LuJ
hyhrNls whlth c/1rNa/tKd an approsirna/rly rlNllplrlc clmNrNS.wna/ ruuq./rnNnt /n.nl
INMh p:lnntal ccllk wrrc twwNunNriK/nic whcn Ix NI' cell% wcrc inw.lrJ % l lulu
alhynl/t /nlnk 1 r/l/ce, wlwrc.s thc /larental tl'fNNI(I lrils pnN/uael/1unNNi in I'NI'A nl
thr animala with rN/ latrnly /lrrinJ h1llawinR initt'lilw ul 2 x NM trllt l'unNUirrnN'
vx/aul% were ulMaineJ tnlm Ihcse hyhriJ% which hxl wr.l ltnly a Icw lhuN/N../N/N%
elnlh:ltell hl cell. If/Nll the INNIIu11NK11,'enlc Ina.ll ruhurl'% In ad.111NM, .cveral rNrr-
heRaph.wl hyhri.k were uhraineJ which clln1ai11cJ a/lllrllaimatrly a tMluhk liu/NINp
vllllal t'ffnM+lenlenl Iulln Ihc 11'1NIN111wen1al line anJ a sinKk a'haatNl.,urlal r.Nlq./c-
nlcnl lnnn Ihc rNlr1u:/1lihrrlMa.1.. All lll Ihe.e near-hea aphwll hyMillk pr/ Nlutrd IunNfr%
in NNMS ul nuJc luicf: with rN/ Ia1elNy Itvild. Resulls nl th/. .Iwly /twht:rlc Ihat
lunwri"/c/ty ol dk.e partilular human malipna/N cells l/f n/csenchyu/rl faiyin aan he
.ul+prl:..nl when In.eJ with nllrnull Ji11/f1iJ IihntM,1.1.. In addililun, llle rc.ulls suFkr.t
that IuuNNlgenilily in Ihiv .y.ICm is chnlnw/xlmal /l1.wFc lkpemknt, s/nlc a JqIhNJ
ChrININWMnaI e1N111.IlYllrnl Irlttll 1Nlrmal hhrtlhla%t\ /N ra(Wl/k 44 .uplre.auK the tu-
nN.rll,`rnlrily /11 a nrar JIIIh./J hut nIM a tlCar-tetriplllNJ thrlNOIrNN/M1 l'/NIM.Ir1/N'lll
Irllm Ihc lunNlriyra/l' IlTlt/ltl/ pareM. Finally,lhr 1/.../11 lfinlnN../.nN I 111N lhr.a.N.
.unle tn whith the N ra.InN.pccne hay hren a../KnrJ/ as wrll a% aINUnN...NIN 4 wr%
el.nclatcJ wilh Ihc tlaplxatanle o( tunNlriFlnN'ily /n Ihe rara varianl pyN/1rn.Nll /runl
tnhrrwi.e INIm1ulNlriEenir near-tclr:IptlliJ hylaNl cultureu. Tl1e.e rc.u11% a/v..uK1r.l
the pu..ihilily thallunNKiFcnicily in Urcse hyhrd% nuy he a gene lh.ugr cl/n 1 mv.dv.
.
ins the number /.( activalyd N-raa Senev in the hyhriJ% cl/nlparrJ lu thr Frnl(/
clltNrldllnK the .u/ll.rc..ilm nl Ihr aaiivaleJ N ras renes.
Ncncdil l. W f, WtLVnan, (t (`. . Mar1, (' , aml Srunhrl.IKr, f. I
('on/ rr Rnr.nl h 4.1 1471 14 7'/, 1')N4.
.r. 1 17
