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Annu.Rev.Pharmacol.Toxicol.1993.33:1-25.D

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P Tx -

THE QUEST FOR A CURE

Grtrd B ElionWelcome Research aboratoies, Burougs Welcome o. Reseac TanglePk rt ri 0

KE WORS: k

GG

As I loo ba o my e ad aee ad wode what wee the uees ad evets that shaped the, I eale ho little oe appeiates ha ishappeig at the tie it ous he love ad suppot o y paets, hihI oo oe o ess o gaed whe I was gowg up aowed e o tethe oad less taveled by" ad to pest the ae o osdeable obstalesWho wee these paets

y athe ho gaduaed o e o Uvesy Shoo o etstyi 94, had oe to the ited States o ithuaia as a sall boy ymothe ae o ussa 9 at the age o14 y the te she as 9she was maed to my athe who had the bee a detst o two yeas A yea ad a hal late I was bo

Although my othe eve had a ollege eduaio she was a podigouseade ad the sope o he eadig as astoudig y athe also loved to

ead ad I a eembe ay evegs duig y hldhood whe I as exposed to a vaety o lteatue pety hstoy bogaphy ad to,beig ead aloud by my athe

y mothe had moe omo sese tha ayoe I have eve ow am etai she would have bee suessul ay aee she ould haveudetake Although she eve omplaied about the at that this had otbee a optio o he those days, was appae tha she waed me to have evey oppouty to be idepedet ad to have a satisyg aeehis beae vey ipotat late whe Ias uable to d a job ad otued

o ely o y paes o a be o yeas ate gaduao om ollegeWhe I was bo we lved a apamet adjog the detal oe

what was the a mddlelass eighbohood ahatta 1th Steet ad

0242/9/04-000$02.00

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adsn vee y bhe Hebe was bo s as I was sang schShy heeae we moved o he Bnx whch was hen cnsdeed abb I oed choo I had a ea dee o e ad he mee acqo

of kowedge gae me exceme and pease I had eaed o ead webefoe I eneed he fs gade I was he csom a ha me o kp chden wh wee achevng moe han was expeced of hem By he me I hadnshed jno hgh schoo I had been skpped fo me and wa wo yeaahead of mo f my camae h peeed ome oca pobem fo medg my eenage year

y hgh scho caee was emakabe I wen o Waon Hgh Schoo an ags sch wh a gd academc ccm We wee eed o ake w fegn anages mahemacs scence Engsh hsyn

essence a cege pepaary poam The Wa See cah of 929 hadchaged o fe sye nce my fahe had o ey heay he ock makeBy he me I gadaed fm hgh scho he depessn was a s hegh and Fakn Dean Rsee had j been eeced I s qesonabewhehe my bohe o wod eve have goe o coege f we hadn beenvn n New ok whee Hne ege and he oege of he y f NewYok had fee on f yo hgh cho ade wee ood enogh o qafyyo fo admson

he mme befoe I eeed coege my maea andfahe ded ofsmach cance He had been vey cse o me dng my pescho yeasThe sffeng I wnessed dng hs as mnhs made a gea mpessn onme I decded ha a worhwhe a f my fe wod be o do smehng o hep ce hs ebe dsease I was a ga ha I neve enqhed Idecded I wod maj n chemsry n cege snce ha seemed o me be he be oad o he dcovey of dr ha cod accomph my goa I ddno kw ha years ae my mhe wd as de of cance

Hne ege was an exceen scho and we had a emakaby age

cass f chemsy majos abo 75 fo a womans coee os of he wome wee pag o each b a few of wee deermned o be aboaory scenss We wee ndbedy a e nae n eaze whawas awang s n gadaon n 193 The depesson was s wh s and he few aaabe bs o gadae sch asssanshps wee defney no f women Wha had made me hnk ha gadang smma cm ade"wod open any doos fo me o a eseach aboaoy?

Ae an ene smme f jb-hnng and of smemes beg d Wehaeee had a woma he aboaory we hk yo wod be a dacg

nfence my peseeance began o fae I decded I had bee go seceaa scho and e smehng sef e sx weeks f seceaascho I was esced by he New Yk Hspa Schoo f Nsg They

offeed me a ob a a aboaory aa hepng o each he Bochemy

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THE QUES FOR URE 3

couse o nuses was on o a mese an wou be unempoe aa a he ed o he hee mohs, bu I dd hesae secearaaee was ove

Sevea monhs ae hs epreve, I e ouae o oban a job wokn

o nohng o a oung hems exande Gaa whom had me soaHe had been gven a aboao n a sma phamaeua compan as paa pame or a daosc es he ha veed Ae sx mohs he was pemed o pa me $1 pe week B he me I e, I had oe ad a ha eas o ood aboao epeece was ea $0 pe week, ad hadsaved eouh o o o aduae schoo a ew Yok ves o m aseseee I was abe o do he eseah m hess on a pame bass, whe eachg chemsr ad phscs he New Yok C hh schoos each aee, as a so-aed permae subsue," ased wo ears Ieoed some o he me, especa whe I had ood sudes bu I wass wang o he oppoun o e no eseah

Wo Wa II na wha I ha been unabe o do on m own: opene he oos o wome o wok hems aboaoes Whe hemen wee awa, empoes ha o ake he sk" eu o he aboaowas as a qua ono hems n a oo aboaor esn he a opckes, measun he coo o maonnase a eemn he concenaoo suga n peseves was no ve gamoous bu I was eang mone and

was en o use nsumenao ha neve seen n coee e a eaad a ha, was me o move oI was oee a job n a new eseah aboao a Johnson an Johnson

New Bunswk, New Jese One he ve pesens ha ee ha he compan shoud go no he pharmaeua busess and had hed anexpeence oac chems, an Pece o hea he aboao was oeo hs wo asssans We wee soon sheszn suonames and I wasbe o ee ha I was a o m wa S mohs ae hee was achae vce pesdes ad he deso was ade o o o o he

phamaceua busness ae a I was o oud sa on, measu he ense sengh o suues ha was no ue wha had n mn o mue began jobhunn aan

TH OPPORUNIS

ntroduction to ucleic Acids

job nevew wh eoge Hchngs a Buoughs Weome o was

unusua n ha nsea o askn me a o o uesos abou mse Hchspoceee o e me wha he was o ha o hea much abou ucec acs beoe o dd I kow wha pes ad pmdes wee he dea


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that oe mit possibly iterfere with ell divisio by maki atimetabolitesof the strutural bases of ulei aids souded exiti ithis apparetly thouht my sholasti reord ad laboratory experiee were suiiet to fulll his requiremets for a hemist ad promised to all me i a week I

wet home exited at te prospet that I miht get this ob ad determied toold o eptig y oter oers o wi tere were te two) util I dheard from eore ithis A week later the ofer ame O Jue 4 44,I wet to work at the Wellome esear Laboratories at a yealy salary of$600

My irst assigmet ws to mke -tioprxtie -merapto-6-ydoxy, 7 dimetylpurie), wi someoe wted to test or its tityoidativity Tis ivolved followi te metods o Emil Fiser desribed i teold erma literature Fortuately, my kowlede of erma was adequate, but te reatios ivolved were diiut I partiuar, te fist step, whiivolved etig teobromie with pospous oxyloride or six ours i a sealed glass tube at 160 ad roki te tube every our to filitatesolutio of te solid, was a bit frihteig. Te lass tubes were eased i metal pipes ad eated i a gaslit ove It was a ot summer ad our labortoy ws ot iroditioed Moreover, tere were dryers or dextomaltose podut diretly below our lboratoy d te temperture ote oor was geerally over 00 F. Te work-up o te reto mixture ws

also diiult ad tere were multiple steps thereaer. Nevertheless by teed o July, I ad suessfully sytesized 1.5 rams of 2-thioparaxathie Duri tat first summer I eed as mu as there was to le about

puries from te sparse literature o te subet. he syteti papers weremaily i erma, te works o raube, Fiser, Isay, d iltz publised ite ery 00s ad few Egs ppers by Boge d Davidso. I devoured te book o N Ad by Levee & Bss ad relized ow little was really kow about te strutue or biosytesis of te ulei aids Thearragemet of te uleotides i ulei aid was still bei debated i the

early 140s Were they liked trouh the sugars or through te posphatemoieties? Ws te seuee te sme i ll ulei ids, wit tetruleotideuit simply beig repeted over d over gi It ws kow tt Notaied ribouleotides of adeie uaie, urail, ad ytosie, ad DNwas omposed of deoxybouleotides of the same bases, exept tat thymie repaed urai t was i te late 40s that te work of Caraff ad his oworkers, Zmeo, Viser, d Magsik, led to te olusio thatte ompositio o DNA w ratersti of te speies rom wi it wsderved, tat dieret tissues o te sme speies yielded te sme DNA, ad

that the tetrauleotide ypothesis was iorret. Te fat that DNA otaiedgeeti iformatio was also idiated by the work o Avery wo had sow

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TE UEST FOR A URE 5

in 9 tat N ppd fom on stain of pnumoous oud ansfomanoth.

in so i was nown at that tim about th nzyms and mtaboli

pathways by whih th nli aid bass w biosynthsizd o nopoatditwas almost an act of faith that on miht b abl to synthsi antimtabolitsof ths bass that wold atally b tld by lls, o that old pntth tilization of ssntial mtabolits. Nthlss it was nown that ctainlati aidfomin batia ould ow and mltiply on dfnd mdia if onofth fo natal" pins adnin anin xanthin hypoxanthin) wassppld toth with tymin. Ths, ths batria obiosly had thpathways fo th intonsion of adnin and anin and fo th aminatonof hydroxypuns. Th nzyms sponsbl fo ths ntonsons w

not isoatd o namd until th 90s tativy on oud supply anaton powd of liv th soalld "L fato" and th miooanismwouldma its own puns and thymin. Th stut of this owth fato,fol ad, was not known ntl 1946 y th tim I d n h laboatoy,itchins, with th aid of a youn woman, lvia Falo, whom h had ntidawayfom th actioloy laboatory had st p an assay with Lobllu in which on ould tst a ompound fo its ability to substitut fo otoantaoniz a pun thymin, o foli acd. Ths tst systm was alabl, not only fo th idntfiation of nhibitos of ll diision bt fo th

aumulaton of a body of knowld fom whih on old dd thxistn and stctual imnts of nzyms not yt nown and pathwaysnot yt ludatd.

ft a fw months in th laboatoy I was main oth pns bsidsthopaxanthn as wll as pymdns and ptdns. Som of ths w ataly omponds that had n bn dsibd bfo and I flt thxitmnt of th invnto who ats a nw omposition of matt Th ptidins psntd a a challn o a yon hmist Thy w not

rystalin w hihly nsolubl, cold not b cystalizd from wat ooani solnts and had no mltin points Thy cod b synthsid fom 4,5damnopymidns by clos of th pyazn in wth dkto ompounds Th 4,5diaminopymidins w aso ntmdats o h synsisof uns

n of th instmnts that w soly lad in thos days was a photolti spophotomt W did hav an old aus and Lombspcomwhich had a bon c as a liht so Th lati absopton of a soton at aios walnths was odd on a photoaphi plat,

wth th solnt as ontrol On had to math th dnsity of sl anssualy to dtmin th d of absorpton. My fist pap publishd fomithins laboatoy was on dalin with Th Ultaiolt bsotion

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Spera of hiourails" I sill look a ha paper wih some amusemen whenI see he peuliar irregulariies in he urves resuling from he mehodology we had used ur firs Bekman DU Sperophoomeer obained in 46,

ws ause fr grea elebraionLukmia

fer a lile more han a yea in he laboraory he biohemis of nulei aids beame more hallenging o me han he mere synhesis of newompounds he ompound ha was o eah me muh abou purine uilizaion and ineronversions as well as o exie me by is aiviy agains humanleukemia was 6diaminopuine whih I synhesized in 48 he synhesishad been desribed in he erman lieraure in he ealy 00s I seemed like

suh a simple analog a possible anagonis of eiher adenine or guanineordng o L damnopune was an adenne anagonis sne he only purine ha ould reverse he inhibiory aiviy of high onenraions of diaminoprne was adenine Somewha suprsingly diaminopurine also had he haraerisis of a foli aid anagonis sine is ees ould bereversedby foli aid his fa ogeher wih daa on a number of pyrimidinesand perdines led us o he onlusion ha he 24diaminopyrimidine moiey ould onfer anifolae properies no maer wha else was aahed o hemoleule his finding was o prove an exellen lead ino he developmen

of he animalarial and anibaerial diaminopyrimidines by ohers in ourlaboraor (l)

In 147 ihings had esablished a link wih he loanKeeing Insiue hen headed by Coelius hoads his onneion enabled us o send ompounds here for aniumor esing in mie and was he basis of manyollaboraive effors in he following dade Joseph Burhenal soon found ha 6-diaminopuine had aiviy agains a mouse leukemia and ouldprodue inreases in survival similar o hose wih mehorexae alhough aa

higher dose. Diaminopurine also showed aiviy agains vainia virus aN virus in andall hompson's hands a he Universiy of IndianaAer Fred Philips had sudied he oxiology of diaminopurine in animals

and Burhenal had ound ha produed remissons n wo adus one wh aue myeloyi and one wih hroni myeloyi leukemia ineres in he ompound inensified ne of he remissions lased over wo years duringwhih ime he young woman gave bih o a hild nforunaely she hen relapsed and was resisan o furher herapy wo oher paiens failed o respond a all lhough mos paiens ould no olerae diaminopurne

beause of nausea and vomiing i seemed as hough we were on he hresholdof a breakhroughIn he nex few years we spen a grea deal of ime sudying he uilizaion

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H US FOR A UR

ad itovsio o puis ulosids ad ulotids i L. e, i ollaboatio wit M. Eal alis ad Gog ow usig adioativpusos. gat lp was t ivstigatio o t diamiopuisistatstai oL. e tat w ad isolatd. Fom ts studis (2) w oludd

tat biomial atu o t mutatio ivolvd i diamiopuisista would appa to ivolv t altatio o a zym systm widals omlly wit t iopoatio o adi" ad tat t assumptiois tat diamiopui is iopoatd ito a aalogu o t mtabolit viat dit patway by wi adi is iopoatd ad tat it is t diamiopuiotaii aalou tat is t ativ iibito" wo yas lat u Kob dsibd t isolatio ad poptis o adipospoibosyltasas ad ou zym ad b idtiid.

T piod o t 10s was a gold ag i uli aid biomisty. It was t tim w Jo uaa G. Rob Gbg ad ti oups uavld t multipl stps o pu biosytsis ad oud tat iosiiaid ypoxati iboulotid) was t ist pui ompoud omd itbiosytti patway. doubl lial stutu o DN was poposd by Watso ad Cik. Kob dsibd t zymati sytsis o DN by DN polymas. Evy Spig mti o t Fdatio o miaSoitis o Expimtal iology vald w ad astoisi iomatioabout uli aid sytsis

Exitd by t wodul kowld tat was uoldig I didd to otiu my omal duatio ad obai a PD dg. Ndlss to say Iad o tougt o givig up my ob. oly solutio was to attd aduatsool o a patim basis. ookly Polyti Istitut was t oly sool

oig gaduat lasss i Cmisty at it. Fo two yas I wt toookly sval igts a wk wi ivolvd a lo ommutatio omukao duig us ou ad a o ou subway id bak om to tox at lass lat i t vi. Suddly tis am to a d. Da iomd m tat i I was ally sious" about my aduat wok I

would av to giv up my ob ad go to sool ull tim I told im tis was ot possib My attmpt to obtai a PD was ov Fo yas I woddwt I ad mad t igt disio. Now I kow I did.

Wil t biomial studis opid som o my tim I otiud tosytsiz a vaty o puis pymidis ad ptdis. O o tsyti podus a was to pa a impota pa i m wok was

tiatio t dit xag o sulu o oxyg i toyli systms 143 Cato ad dsbd t tiatio o ydatos wit pospous

ptasulid i a i igboilig solvt ttali. I usd t mtodsussully o a umb o pymiis ad quiazolis but ad mu

mo dilty applyi it to t puis. Pa o t poblm lay i t


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EON

insolubility of uanin, xanthin, and hypoxanthin in an oanic solvnt likttalin Whn th action took plac, th poduct coatd th stain matial and no futh action occud h was also th poblm of spaatin

thiouanin fom uanin o 6mcaptopuin fom hypoxanthin nlikpyimidins, puins w difficult to chloinat, and that out to th mcaptoompounds was unsatisfactoy at that tim

With psistnc and som chans in solvnt and action conditions, I finally succdd in isolatin and pufyin thiouanin and 6mcaptopu in oth compounds bhavd lik puin antaonists in L case. Ouattntion cntd on 6-mcaptopuin (6-MP) at fist, sinc it was th asion to synthsi Whn it was tstd at Sloanttin in aly 95 aainstSacoma 180, Donald Clak potd that th tumo was not only inhbitd

but, in many of th mic, it compltly ssd o povd to b nonviabl on tanspanaton Th compound was aso actv on sva mous uk mias uchnal was xtmly anxious to tst 6-MP in childn with acutlukmia

n thos days childn with acut lukmia had a man lif xpctancy of3months if untatd With th us of cotison and th antifolat mthotxatin 949 that ava suvival tim was incasd to 6 mons y 953uchnal and his oup had xtndd th man suvival tim of lukmicchildn to on ya by th addition of 6-MP to thi tatmnt y th nd

of 953 th du had bn appovd by th FDA fo th tatmnt of acutchildhood lukmia At a th-day symposium sponsod by th Nw YokAcadmy of Scincs in 954 much of th data on 6-mcaptopuin was

potd (3)t took yas bfo th wok of a numb of dint oups vald all

of th loci of action of 6MP On of ou aly insihts was basd on studiswith a 6MPsistant sain ofL casei In 953 w dducd that, sinc th6-MPsistant mutant was unabl to ow with hypoxanthin as th punsouc, 6MP and hypoxanthin must ui th sam nzym fo utilizationn addition w sustd that a hypoxanthincontainin mtabolit may ban intmdiat in th convsion of adnin to uanin in L. ase, and thtansfomation to a uanincontainin substanc is viwd as a possib sitof action of 6-mcaptopuin" (4). Th idntification of inosinic acid as thfst puin nuclotid fomd by d novo biosynthsis had not y bn madh many loci of action of 6-MP bonuclotid its convsion to thiouanylicacid, and th subsunt incopoation of thiodoxyuanosin into DNA havbn viwd many tims (S fs in 6 As nw chmothaputic dus

oind th amamntaium fo fihtin lukmia, 6MP maind on of thmainstays in th multi-d imns, passin fom bin a mission-inducin ant to on still usd in maintnanc thapy hiouanin 6-G), which

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H US OR U

was dvlopd svaly s lat od ts at o au mylocyc lukma aduls patcully combao ih cyosarabosd.

Wth a ya o h tm 6M bcam a accptd tratm o ac

chldhood lukma bcam appar ha hs dug as o gog to b w had all opd o lapss oud ad pas ot o logspodd o 6M ad mthoxa Ths r hatbak ms Wsmd to b so clos to th soluto ad yt th ulmat goal ludd us Wsll had much o l abo lukma ts prssc prild stssuch as th ctal rous systm about th d to cotu rat log

a msso had occrd ad th mpotac o mlpl drg gsto prt o orcom rsstac

Ou appoach to mpog upo 6M as hdsgh somhatsmplst W ould mak a ay o dats o 6MP ad xplo tsuavy laosps sdy as o ssta o 6MP ad attmp somhg tha as qut usal a ta m sgato oh pharmacokcs ad mtabolc at o 6MP.

I 0 th sparao o uclc acd bass uclosds ad uclodsby oxchag ad papr chomatogaphy had b rpod by Waldo Cohad C Ca adoact sl had bom avalab ad I wa abl tosytsz _6_M o 6loop. T adoav sapls w

otd w a Gg ow o ssag dyg ah sapl oplachs o mak ly lms T oxcha colms w blkyad h o ras arabl; h sparaos rquly ook days hlssa som mabolsm suds o 6M mc by Samul br ad myslth raoact rug was studd sal lukmc patts collaboatowt Load amlto o th loaKttg Isut .

Ou modology dd o p us o do paoks t way a b do ow wh pss ld oaogapy ad assspcomtry. owv aoatos o th sapls o Dowx ad

Dowx50 oxchag olms ld to solato ad dtcao o aumbo abolc podcts W bga o dsad t vaous catabol actos to wc 6MP was subct g mthylao ad oxdao o tsl, oal o t sulu to om oac slat ad oxdato o

pr rg o th ad 8 postosh mthodology mprod th h adt o sllato ots bu

w dd ot g ou st hh pssu lqud hoatogaph l 6. Th mabol sds w o play a poat ol ou dstadg osps ds t dsposo o t ops ad cosqut

ds apu css ar umb o srucuralmodcatos o 6MP ad 6T that w mad ad tstd our laboatoy

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0 ON

i the 90s were mde lrely o empiricl bsis. We did ot yet hvethe kid of kowlede of the substrte d ihibitor specificities of the puried pyrimide metbolizi ezymes tht ws cquired lter

Two derivtives mde with the specific itetio of providig msked foms

of MP TG were heir (metyl4iroimidzolyl) deivtiveszthioprie (Imur) d thimiprie (Guer) These compouds were expected to be vulerble to ucleophilic ttck betwee the sulfur o thepurie d te methylitroimidzole rig becuse of the orhoitro substit uet opefuy tis migt ppe preferetilly iside leukemic cellsrelesi MP d TG. Tese derivtives were s ctive s MP d TG ist Adeocaciom 755 i mice but ppeaed to be less toxic dtherefore to hve better therpeutic idex We elisted the collbortio of

R. Wye Rudles t Duke iversity to study teir metbolism d tileukemic ctivities i m ( ) Altoug our lbortories were some 500 miles pa te blood d uie smples were ow bck d o betwee LGuadi Aipo d RleiDurm wit reulrty usullypcked i Rudles little blck lether doctor's b. These studies showed tht these produgs were ideed covered to MP d TG d were s ctive s tese tiopuies i coic myelocytic leuemi. Altou somequtittive differeces were disceed betwee te metbolism of MP dzthioprie i m there ws o idictio of improved chemotherpeutic

idex i leukemiWith Rudles we were ble to test the cliicl eficcy of umber of other

substituted erivtives of MP d TG tht hd show ood titumorctivity i mice I ptiets with choic myelocytic leukemi who were otvery ill efficcy could be evluted withi few weeks while the metbolicstudies were i proress. Ptiets who did ot respod to the ew derivtive s mesured by the ulocyte cout wee ive MP o TG to test whether the leukemi ws resposive to these eective thopuries. helkylthiopuries whih hd show good ctivity i the mice were ictive

i m ltoug te ptiets respoded well to MP or TG Te resofor tis discrepcy soo becme evidet I mice te lkyltiopuries werebei delkylted to te free tiopuries I m te lkyltio groups werebei oxidized to fom lkylsulfiyl roups or were removed fom the pure i completely (. Thus with studies i reltively few ptiets weelimited te eed for extesive cliicl trils of ictive compouds

mmunosupprssion and ransplantation

I 158 we were uexpectedly precipitted ito the field of immuoloyRobert chwrtz worki with Willim Dmeshek i osto d obtiedsome MP from us d hd tested it for its bility to suppress he tibody

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T UST FOR A UR 11

response n rabbs o bovne seru albumen her raonale was hammunobass w were omed wen mpoes responded o he allene o a oren roen, losel resembled leukem lmoblasshereore, a dru ha worked aan aue leukema ave an eeon e mmunoloall smulaed lmhoes. And ndeed dd Shwarzworked ou e ondons o mng and dose a ould rodue unolog al olerane n rabbs In 98, an undersandng o e mmune responsewas n s nan ere were large lmphoes and small lmhoes, bu was no a all lear wh were more mporan n he mmunologal

resonse Plasma ells and marohages were known bu no one ad edsovered B ells and ells le alone deren knds o ells Swarzmbued us w s own enusasm and onvned us o our obaon o se

uan munoloal sreen o es some o our oher anmeaboles or sneresng roer In he meanme he oered o es omounds n s rabb ssem under ode numbers wou knowlede o he hemalsrures Beber our n house" bologs se up a sreen or

munosupresson wh onssed o njeng sheep red ell no he alven o me and examnng e me or er anbod resonse a week laer

Havng a es or mmunosuressve av ued ou o be exremeluseul, no onl or wa au us abou e mmune resonse, bu beause revealed some neresng derenes beween rabbs and me w rese

o aahorne n e, aahone was more ae han 6-MP nsuppressng he mmune resonse whereas n rabbs azaoprne wasnave Ts sursng dsrean was explaned laer wen we ound ha azaorne was meabolzed derenl n e rabb an n e mouse or man Beause o hgh onenraons o aldehde odase n he rabb, eensve odaon ourred on e purine rng a poson8, beore heomound ould be sl o 6MP us e rodu released aer odaon and reaon wh gluahone was 6-merapo8dropurne whh sbologall ner Forunael, mouse and man are smlar n er meabolsm

o azaoprnehe sor o how Shwar's reor on e munosuppressve av o

6MP nsred a oun sureon, Ro Cne, n ngland, o r 6MP o prevenkdne ranslan rejeon n dos as been old beore (, 8) Cane vsed us on s wa o send a ear wh e ransplan sureon, Joseh Mura,a e Peer Ben Briam Hosal n Boson and we gave m azaorneo ry on dog kdne ranslans I oen wonder weer we would have gven h ha oound we had no alread done e meabol eermensw azaorne n ouse and man or suded s mmunosuresse an me Was Fae e use o azorne o preven kdne ransplan

reeon n man beame a real n 12 Te res s so was ears


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12 ELION

before e nex suessful mmunosuppressve agen for use n kdney tansplans ylosporn beame avalable Over 200000 kdney ransplans have now been performed worldwde and heart lver lng panreas and

bone maow ansplans ae also ommon zaopne s also a reognzedeamen fo hemaod asI as ofen been asked wee aaoprne as any real superory over

6-MP as an mmunosuppressan. ha queson really anno be answered by n vro ess sne n e absene of red blood ells e onverson of azaoprne o 6MP s very slow In a vaey o n vvo es syems he derene beween he wo drugs s no large bu s always n favor of azahoprne .e. mmunosuppressve avy ours a a lower dose and emaxmum oleraed dose s hgher s derene may be due o pharmao

logalfaors su as he slow release of 6-MP from he red blood ells afere reaon of azaoprne wh gluaone oweve moe lkely haazahoprne reas wh oer sulydryl and amno groups on ell membranesorenzymes hereby blokng some reepors n addon o releasng 6-MP.

Gout and yeucema

One of e prnpal aabol produs of 6-MP s s oxdaon produ thour ad. We ad shown n e early meabol studes n 954 a hs ompound was formed by e enzyme xanhne oxdase Dos Loz adsuded s enzyme n deph from 950 o 956 examnng fo bohsubsrae and nbor spefy he me now seemed pe o deemne

weher nbors of hs enzyme ould funon n vvo and ould ange he aabol fae of 6MP We hose 4-hydroxypyrazolo4d pymdneallopunol) a ompound syneszed by Falo n e md50s for our frsn vvo trals n me hs ompond was a poen nhbor of xanhneoxdase ad no yoox avy on baera o umors and was well oleraedby he me ad we esed a number of he oher avalable nhbors as we

dd subseqenly) we would have onluded a s appoah was no vablen me and n dogs he oxdaon of 6MP o our ad was markedlynbed by onoman ue of allopurnol s nreased he anumor and mmunosppessve aves of 6-MP ee o fouold. oxy was also nreased b n me ere was an mpovemen n he heapeu ndex.n man he efe o allopurnol on e meabolsm of 6-MP was smlar oa n he mose and e anlekem effay of 6MP was also neasedhree o fourfold bu ere appeared o be no ange n e erapeu ndexOr nal dsapponmen gave way o exemen a he hough tha a

nonox n vvo nbor of xanthne oxdase mg be useful for nhbngur ad formaon ndeed n one of undles leukem paens n whome ombnaon of 6-MP and allopurnol was suded he levels of serum andurnary u ad dd deease

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H US OR UR 3

Te sease w exess ur a s a majr rem s Te ex n sues ooe quk n oboron unes n JesWynen Duke (5, 9). e nn ey ee unequvo r sove uner reen, eu n urnr ur erese,

a se ees were ma ug au as a s ae e seum, s xa ru, xur, as a a-e, au 1824r Mrever, oxur s as a e xae xase r s aenzye nn s rone n e u nee o be ven ny ne y Vnen Msey oun xurno bn very y o e reueo o xe oxase a s reease o aer reoxaon o e enzeW Are Guma a saFa u we swe ur s reasre e rxma e uue a maer sma ur aT au or o ama ae Hyxane a xe, eoxurne neree n une eron, re exree b e kney ose o gomeru ra rae, r are reuze or riueoe sess.I 19, e ear a aur was arve e FDA a smosume Lo uer e auses e Heere Se ou geer an e vesgrs r varus s e r rese erexerees aourno (10). A e eeve ree or ou abee aue

xpnding the orizonAug b s e our boror been resosbe or uber omra emereu ages eze ue aeos een ue n n e: xnne oxse n rooe reuase e 2,4amrmnes sesze vra Fa, Peeruse, rbara o e o e mra rmeme oe e-ser nbaer reorm ). We Jmes ura joe e eren n 9, e be e soon n rerzon o e

rooe reuae rom m ere see e eree eee ese ue, e aua sesves e ezme mere sres ere amrmes, w a revusy ee eeae emra ea e uers Mreover, a eouao r e sear or ew seeve ooe euse nbor

I 9 e re os rensk, ou boes ose oo or ork been vove une oore Our ogr ovege ea e emes ue a me measm wasw aue ees. s vesga was gve us e ears a

we, uers e susrae a r sees e sraserases, srsraserases, kases, oxases a ense, s e o e enzyes o ueoe neronverson s ou

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14 EON

hep us to uderstd d ptze o some of the etg seetve tvtestht we ter eoutered wth protozo d vrses.

967 Hthgs ws promoted to Ve Presdet hrge of Reserh.he Bohemstry eprtmet ws dvded to the eprtmet of per

met herpy of whh eme the hed d the Deprtmet ofMrooogy heded y Burh.

A yer ter the ouemet ws mde tht Buroughs Weome Co.woud e vtg the premses t ukhoe, New ork, d movg 190to ew reserh fty to be ostruted eserh rge Prk, NorthCro. The ftory woud so move to North Cro. Both fteswoud e muh ger d thus we oud eg to reut ddto stffwhh hd ot ee posse our dequte ortory spe. Whe we

were e to squeeze few ew peope to the ukhoe orores durgthe st yer before our move m joed us North Cro. he ewudg ws ot redy whe we rrved d wtg for few ew ortoresto e ve eh week requred good de of ptee d stm.Fortutey the uverstes the re, uke Uversty, the Uversty ofNorth Cro t Chpe H, d North Cro Stte Uversty, were eto e some spe ve for our hests for tht frst yer. The rest ofthe reserh st oped s we s t oud.

A sd feture of the move for me ws the oss of most of group of

youg, dedted, teted wome who hd worked treessy wth me to studythe metosm of 6merptopure, thogue thopre d opuo. They were ue to move to oth Cro euse of fmyogtos. so ost sever of my youg hem ssstts, some of whomwet o to rdute shoo some to other jos the New ork re.

Wth yer or two f the ove y deprtmet hd grety epdedKretsky's seto of Eyoogy hd dded three PhD's Rhrd MerJmes Fyfe, d homs Spetor. A seto of Meto Studes hd eeformed, wth Dod Neso d Puo de Mrd s seor vestgtors,

wth Thoms Zmmerm soo to foow. here ws uoogy Seto,wth Gerd Woerg d Rhrd u, d Chemstry Seto wth etRdeout d Lowre Beh. We so estshed tssue uture ortoy,heded y om Coh he kowedge epertse, d dedto of thstem d those who joed them the 1970s, ws respose for the workwhh foowed

ddto to rge rese stff, there ws upgrdg of ourstrumetto d ftes. We ought our frst hgh pressure qudhromtogrph 969 wth fve yers we hd four of them. Reordgfrred d utrvoet spetrophotometers, uer mget reoe, dmss spetrometry were tke for grted d omputerzto of strmets

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THE QUEST FOR A CURE 5

eme ommople. The evoluio i mehodology hd mde some of ouely expemes seem h d eme lmos emss o pulishhe d oied y hose old mehods

The exploio of ew fields o oque wih ou imeoles oiued ogehe wih bsi sudies of mehism of io esisephwys of meolism, spo, d emps o egule immuologileios

eshmanass

would like o digess somewh his po fom he hoologil sequeeo ele ou expeiees wih llopuiol i e io whih w wee hus

uexpeedly i he mid-970s Joseph M, who ws he i he Depmeof Mediie i S ouis, lled oe dy o ifom me h he hd foudllopuol o e oxi o leishmi poo hh uss diseseleishmisis h is widesped i opil ouies ws skepil fisOu pevious sudies wih llopuiol hd show i o e mzigly iivewh espe o y of he ol phwys of ule d syhess.Keisky hd foud i o e suse fo puie uleoside phosphoylse,u he llopuiol iouleoside fomed oued fo oly 0% of llopuiol dose i hums, ws ie, d ws exeed he uie

Allopuiol ws vey poo suse fo hum hypoxhie phosphoiosylsfese (HPRT) d he mou of llopuiol iouleoidefomed i issues ws so low h i ould oly e deeed e usile iveous doses ofC-llopuiol of hih speifi vy. Eve udehe le odios opuo ws o iopoed io he ule dsM's fdis wih leshmi wee, heefoe, iui d hlleThey equied explio We se up poduive olloio wih Mduig whih we leed ge del ou he dieee ewee poozod mmmli ezymes (See efs i ou oup he piipl plyeswee elso Keisky d Speo

The s supise ws h he leishmi ould ove llopuiol veyeffiiely o iouleoide. f, he mou of llopuio ouleoide fomed o uio of llopuol wh he pomsgoe foms of Ldoovi o L. rzilii fo 2 h i ulue ws moe h hee imes heoeio of ATP i hese poozo. This ws due o vey hih levels of eishmi PRT wih lowe K d hihe Vmx h fo he mmmlieyme Eve moe uexpeed ws he fidi h he leihmi hd

oveed lopuiol iouleoide o he oespodi mio logue,d fomed -miopyzolo (,-d)pyimidie moo, di- d iphosphesThse le ompouds (APP-P, APPDP, d APP-TP e o fomed

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6

mmml el Stude o the mtg ezyme, uodeylteSAMP) ythete howed tht the lehml ezyme oud deed overtllopuol rbouleotde to the uylmo devtve, whh the

overed by SAMP ye to the mo ompoud he mmml SAMPythete doe ot t upo lopuol bouleotde. he to ompoud ppetly the A e t t ubtte fo the lehmlA polymee d be orpoted the A.

Aothe uuul fdg wth the ehm w t blty to utlzelopuro bouleode d overt t detly to the ueotde etoot foud m heefoe, t eemed pobe tht lopurol boueodeoud be ued tetmet fo ehm ple of lopuol. hubttuto mght be dvtge e lopuro rboueode ute

ouble d eeted the uie eety uhged m, wheelopuol oveted ute pdy to oypuro whh tve olehm fortutely we wee uble to tet lopuol rboueode the vbe odet model fo lehm e odet, uke m,odze llopurol rboueode to oypurol bouleode whh tve

Aothe potozo tht epobe fo wdeped topl dee Tpanosoma rui the etolog get of Chg' dee Le theehm, T. ru lo overt llopuo to APPP, whh to

to the pte he ll effy of llopuol the tetmet of Chgdee ) d uteou lehm h eetly bee demotted) Ou euo to the bohemty of protozo w gug dueful.

rpsvrs nftons

Aothe feld, whh we hd o touhed upo 4, tht of tvlhemothepy, w vtg. he urret dogm w tht oe ould ot hope

to terfee wth the epto of v DA wthout toty to the DA ofthe hot el. dourde (odou deoybode) hd foud utty tretmet fo herpet kett by top pplto to the eye he ompoudw, howeve, too to d too metbollly utbe to be gve petelly 8 thee w epor tht dee rbode, oed fom thefemetto frte of t of teptomye, hd tvty gt DAvrue h g be. Se 2,6dmopue hd how tv tvtygt v vu DA vr d ll ou tude o dmopurehd how t to be loe og of dee pehp 6dmopue

bode would o hve tv tvty Although we dd ot t thttme hve tv ee opetg houe, ou ollegue Joh Bue, the Weome Reeh Lbotoe the U hd kept umbe of

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TH UST FOR CUR

trl srees gog, o d o We sytheszed 26dmopre rosde d 1969 set t of to Ber to test he swer me tlrm Th ompod ws te st hps smpl rs dst rs m ew fld ws ope to s!

he sythess d trl stdes of mer of pre rosds wrepded. he sythet work ws performed y Jet Rdeot, Ber dete Coll oted the trl sreeg he Of plterest ws the fd y de rd tht 26dmopre rosdews demed o to e rosde, whh ws s potet trl s the dmo dert (). hs ws ood ws se thedemto of dee rosde rested lge derese trpotey Or moe to North Crol dsupted the work emporrly,

lthogh the dely ted ot to e less dsgse. Better ompodswere jst eyod the horzo w mvd pv ad ofa Cmy d d w

qred ew hed Howrd Sheer who me from the Uersty ofBfflo Sheffer hd for yers ee stdyg the sstrte d htorspeftes of the ezyme deose demse. He hd fod good htor,erythro9(2hydroyoyl)dee (HNA d hd lso fod tht porto of the rosde moety of deose old e ltered to yl sdeh wthot elmto of sstrte tty He oted to epd the

seres of yl leosdes whe he me to Brroghs Wellome heompods were set to the UK for trl sre he ttes ofoth HNA d 9(2hydroyethoymethyl)dee st the hees smple rs (HV) were terestg d wrrted frher sythet efforts.Shefer d l Behmp eteded the seres oth wth respet to theheteroyl se d the sde h he 26dmo9(2hyroyethoymethyl)pre ws more te th the dee derte oreoer, s hdhppeed the rosde seres, the dmopr ompod ws demted o to th dete. o oe old he tptd thtths e derte (ylor) wold e tms more e th thedmo ompod. deed, the dmo derte ws te se of tsoerso to the ge log y deose demse. the presee of deose demse htor t ws te.

From the tme we frst w tht we hd et ew trl et hd, l rop of dlet d deoted setsts wored s tm toot oth he s d prtl foto edd to mk th ompod sessfl tretmet for herpesrus fetos he frst hlee ws to

dsoer the reso for the hgh degree of seletty of ylor (orgllylled yloose) ts lty to ht replto of herpes smplerses types d 2 (HSVl HSV2) d rell oster s (VZV) t

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ON

concnaion bwn 01 whil h 50% inhibioy valu foh c in hich h i w own 300 3000 pod animpoan challn. h anw would undoubdly yild imporan infomaion abou h biochmical difnc bwn hrp viru and mammalian cll.

o do h kind of mchaniic and mabolim udi ha w had in mindw ablihd a viu laboaoy in ou buildin in 9 and id PhillipFuman and a Kan Biron a wl a val junio cini o undah vial udi Th wokd clo wih h oh mmb of hDpamn Ou collau in h .K coninud o xplo h acivi ofacclovi in a vari of animal modl and wih a vai of viu

Th fi dfiniiv xpimn on mchanim of acion w ho which

howd ha

Cacyclovi wa convd in HVinfcd cll o h nwadioaciv maboli h appad in a hih pu liquid chomaoam of h cll xa in h ion of h nucloid mono di andriphopha h compound w no formd o any noicabl d inuninfcd cll Th idniy of h nw compound wa lavly ay oablih inc h w covib nmaica o h oiina accovi(ACV)

om lan biochmiy b f idnifid h fi nm in hconvion of ACV o i phopha a a hrp virupcifid hymidin

kina. Ahough hi nym wa nown o x uba pcifcihad nv bn inviad o an xn Th ida ha an accic ncloidanalo of uanoin cod a a ba fo hi nm ould cainlyno hav md likl o any knowldabl chmi Y i a unqionabl ru Whn h vial nzym wa iolad and puifid i ability ophophoryla ACV wa confirmd Th cllular hymidin ina ioladfom uninfcd Vo cll wa inaciv o ACV. Thu h fi majo baifo h lcivi of h compound a ablihd

h ubra pcifici of h hp viupcifid hymidin kina waxamind in dail by Paul Kll. A cain laiud in h i and nauof h acyclic id chain wa prmiibl bu a rminal hdoxl goup wanial Th nzym did no ola chan in h puin ba o any xn. xanhin adnin o diaminopuin ih a 9(hdoxyhoxymhl id chain w no uba Howv -mhylhio6aminopuinwih h am id chain wa a uba fo h hp hymidin kinaninly i did not hav anivial acivi Thi findin mindd u haphophoylaion o a monophopha wa a ncay bu no a ufficin

quii fo anivial aciviy.Th maining p in h acivaion of ACV o a riphopha winvigad by Richad and Wayn ill Thy found ha h cllula

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Q A 1

uanylae inase ansfomed ACV monopospae o e dipospae anda seveal ellula enymes ould onve e di- o ipospae.

Te nex seleive sep in e aiviy of ACV was e effe of is

ipospa on vial an llula DA polymeass Fuman Bion anS. Clai conduce is invesiaion e vial DA polmeases of HSV ,HV, and VZV poved o be muc moe sensiive o inibiion b ACVipospae an wee e ellula a and DA polymeases oeove,e vial polymeases wee able o inopoae ACV ino e owin vialDA moleule, eeby ausin ain eminaion, sine ACV laed a3 -ydoxyl oup Tee was also an inaivaion of e vial DA polymease by ACV ipospae a was no seen wi e cellula enmes

Wile e synei and meanisi sudies wee poessin, ee was

muc o be leed abou e eapeui poenial of aylovi in animalmodel sysems and is absopion issue disbuion eabolism pamaoinics, and oxioloy. Wn we publised e fis wo paps inPrceeding f the Ntinl Acdemy f Science and Nture in lae 177(14 and eay 178 (1, e sudies ad been oin on fo ove e yeasWile fis wo paps did no appea o aa a ea deal of aenion,e ien poses pesened a e Inesiene Confeene on AnimiobialAens an Cemoeapy in obe 19 eaed a majo si I emembe occasion well fo psonal as well as pofessional easons I was in e

pocess of ecovein fom bac suey, wic ad been pefome a ebeinnin of epembe Te sueon ou i inadvisable fo me o y oAlana fo e meein on Oobe s. I assued im a noin ould eepm awa even if as did appen I ad o be aied ono e plane on a palleand aen off in a weel ai. W ad waid oo lon fo is momen andI was no oin o miss all e fun. y bac evenually ealed anyway.

ne eason fo e exiemen a e 78 meein was a we ad finallysown a anivial dus could be sleive and a one ould apialie one diffeenes bween e via and cellula enymes. Wiin mons, alle lae paaeuial ompanies ad nae anval poams an eompeiion beame fiee Peaps i was a ood in fo, wen e AIDpidemi bo sveal yeas lae, sieniss wee aleady eaed up o ina anivial emoeapy was no impossible.

Te pamacoloical popeies of ACV wee bee an we ould fullyave expeed: i was meabolially sable and was exeed in e uineessniall uncaned in man was isibued in all issues incluin ebain and ad a plasma alf-life of abou 3 Is oal absopion vad

ealy fom species o species, bein vey ood in e mouse and do, pooin e a and inediae (abou 0 in man Te money absobedalmos none of d oally and e plasma alflif was vey so T

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20 EON

data on hamacontc and mtabolm n dnt anmal c wa vyhlful n undtandn wh th d had to b vn at much hh don om anmal modl tm fo h viu infcton than n oth (5

)A w had hod and antcatd, ACV wa nontoxc at do that faxcdd tho ndd fo antval actvty h thoouh toxcoloy wo-uby Walt uc and h tam wa vy aun and wa motant toconvnc th tc that an ffctv anthtc ant all culd b af

Duin th nxt fw a w had man collaboato who w outtandnn th clncal and clncal valuaton of th antval actvt Bau andCollin ttd acyclov n a numb of h vu nfcton n mc andabbit; Eal K amind it actiity in Vinfctd uina i; Kn

oi ttd it ffct on th mian aclla ot iu in mony hntanou hamacontc n man wa nvtatd by d Manda, HavyKan, and tvn Good n collaboaton wth Rchad Whtl, aultman, and Jam Conno h aly clincal tial aant ntal hinfction w conductd by Lawnc Coy

n tm 9, uouh Wllcom Co hld a thday ntatonalmoum on acclov n Wahnton DC und ont onoh wthth atonal nttut of All and nfctou Da h ocdn ofthat ymoum w ublhd a a ulmnt to th A meian Jounal ofMd in 9 h 77 a that w ntd cod chmity,mchanim of action, antiial ctm, clinical hamacoloy andtoxcolo, ffcac n anmal modl, antivial fficac n th nomal and inth mmunocomomd hot wth mucocutanou ocula and ntal hnfcton n 19, th FDA aovd th ontmnt and ntavnou fomulation of ACV (ovax) and al ya lat th oal fom h numbof indication fo th u of ACV ha continud to inca and now includmucocutanou h nfcton, ntal h, h nchalt hn

l and chcn ox ohlactc u of th du ha n of at hl nvntn th actvaton of latnt vu n immunoud atnt tho undon bon maow o oan tanlantaton o canc chmothay n atint wth nital h who ff fm funt cunc,ohylactc u of ACV ha madly ducd th numb of cunc ovntd thm ntl (7) Antval chmotha ha com of a

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n 19 had to ma a dcon whth to ti o o on won: choto do both Wth acyclov now launchd, thouht it mht b a ood tmto ti a had of th Datmnt bfo a nw d tud u that couldn 't

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TH S FOR A R

r o lv Th mmrs of h roup wr suh lln siniss ndI nw hy would ll o on o do wll wih or wihou m. For yrs I hdh plsu of in n ohs onduo of som fin musiins Thyould indd m uiful musi oh I ws foun h I oud lv

h roup in h pl hnds of Tom Knisy whil I mind Buouhs llom s Sinis Emrius nd onsuln I fl I hd hs of oh worlds.

Th fis yr of my "irmn ws vry usy on nd md m lizh I would poly nv hv im o wond ou wh o do n. Iws prsidn of h Amrin Assoiion fo Cnr Rsh h yr ndhd jus n ppoind o h Nionl Cn Advisor Bord for si-yrrm I ws lso srvin on Sin Commi o Filrisis fo h orldHlh Oniion. Thr ws sill im o o o sinifi mins ndiv lurs round h world I ws lso in h hppy posiion of mininglos o h wor oin on Burrouhs llom whin h pnsionof h nivl prom in priul. I ws sisfyin o wh h smm h hd don so wll wih h dvlopmn of ACV now pnd ndprod o us hi sills o dvlop idohymidin AZ idovudinRovi) fo h trmn of AIS.

In midOo 988 o my ompl surpris I ws noifid h I hdn wdd h Nol Pz in Physioloy o Mdiin, oh wih

Gor Hiins nd Sir Jms Bl. Popl on s whh his wsn'wh I hd n imin fo ll my lif. Nohin ould frhr from htrh. I hd nvr ourrd o m h I mih onsidd for his wrdMy wds hd ldy om in sin hildn wih lumi suvivmn pns wh lon-m idny rnsplns nd whn ylovisv livs nd du surin. Th Nol Piz ws wondrful inionlroniion no only fo m u fo ou who m for whom i ws mol oosr

Th Nol Priz rmony islf is of ours mmorl vn nd h

w of ion h surounds i is s my fivy old ndnidsid i fiy l. I ws wondrful o l o shr h osionwih lvn mms of my fmly my ohs hildn nd ndhildn.nfounly my oh ws ill h im nd ould no om

h I dd no niip ws how muh h rip of h Nol Prizwould hn my lif Suddnly I ws ly in dmnd y h pss,lision, univsiis, ommis nd Bords Honos n o om in sdy sm I ws ld o h Nionl Admy of Sins, h NionlInvnos' Hll of m Nionl omn's Hll of m nd ivd h

Nionl Mdl of in I now h mny honory ds, u I sillmmr h flin of prid whn I rivd h firs wo in 16 from

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22 EON

Gorg Wshigo d Brow Uivrsiis. Thy rpresd h Ph hdvr rived d he vidiio of my pres fih i m. Uforly,ihr of hem livd log eogh o see i

PA

Shorly my rirm, ws skd o Rsrh Profssor ofPhooy d Mde he uk Uversy Med Cer. grdo work wih hirdyer mdil sd h yr o rsrh projThe sds re llowd his opiol yer of rsrh i pl of orswork The suds hve worked i h lorory of Hry Fridm i heprm of Pediris, whil hv ed s mor, hlpig o dli

he prolm dsig he xprims, ly h rsuls, d pl h xsps. We hve worked o ri mor iohmisry, phrmoloy dhemohrpy oh i viro d i hm xogrfs i d mi. hs eehlegig for m d hik for he sudes Thy r l so righ somoivd d so ergi h fid myslf eedig o rd d sudy logwih hem. hv hd sv suds o de, hr wom d four m,d ll hv doe eedigly well i hir fil yr d i hir mdirsideis. is h kid of ehi horoghly joy d hope o oiei s log s m le.

As look o m d s youg popl shyi wy from sie, feel lmos missiory el o do somhi o h h red. My hop ish o oly help sds lredy ommied o si, h sprd h ews mo h yogr grio h si is f I woldlike o se hem experiee he sme exieme d flfillme h I hvehd y reer. Howvr I ry o o mme h dffulies hey myor or he prsvr i my reqir. f h gol is wohwhil dis pursui oyl, h rwrd will ivil.

Lttu Ctd

1 Hitchings H 1989 obl Leturen Physiology o Medcne-1988, Selective inhbiors of dhydrofoate educase In Vitro Cell Dev. Bio. 25:3030

2 Elon, B. VandeWeff H., Hitchngs H . , Bais M. E Lene,D H Bown B 95 unemetabolm of a damnopune-esstant

san o Lactobacillus casei. J Bio.he. 20076

Rhoads ed 1 954 6Mcaptopune Ann. NY Acad Sci. 608507

4 on B, inger , Hitng H. 19 The pune meabosmof a 6mercaptopuneresstan Lac bacills casei. J Bio Ce. 20:3541

5. Eion B 989 Nobe Lecue nPhysiology o Medicine 988 , he pune pah to chemotheapy n ioell ev Bio. 220

6. Eon G. B 96. The bohemstand phamacology of pune anaogs.Fed Prc 6898904

7. Elon B Calahan . RundesR. W. hngs 963 Rela

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ionhp beween meabolc ate andantiumor acivite ofthopurne. Can cer Res. 2:1207-7

8. Hching, G H . , Elon, G. B . 985.Laye on laye. anr R 4525

209 . Runde, R. W , Wyngaarden, J. B .

Htchng G . H . Eon G . B . Sibeman, H R. 9 63 . Eect of a xanhineoxidae nhbio on hopuine meabom, hypercemia nd gou. TransAsso. Am. Physiians 76:20

O Scott, T. ed. 966. Sympoium onaopurinol. nn Rhum i 25599-78 (6 Supp)

. Galeano R. H , M, Soa,R. R 990 Theapeuc ecacy oalopuno n paen wh Chaga'dieae. Am 1 Tp Md Hyg 435966

2. Manez, S. , Ma, 992. Alopurl th rt f uneou lehmn. N Engl JMd 2674

THE QUES FOR A CURE 23

. Elion, G. B . , ideout, de Mranda, P. , olin, P. Baue, D 975 Bioogica acivii of omepurine aabnoide. Ann NY AadSi 2556880

1 . Eion, G B . , Fuan . A., Fyfe, A . de Miranda P , Beachmp,L Schaee H 9. Seecivyo acon o an anherpeic agen,9(2hydoxyehoxymehylguaninePro NaIL Aad S USA 745720

5 Schaee H Beauchamp deanda, P Elon, G. B . , Baue, J., Colns P 978. 9(2hydxyehoymehyl)guanne acvyagan vre of he herpe gup.Natu 27258385

6. Kng, H, Galao, G. d. 982.Pceedng o a ympoum onacyclov. A J d 7(IA) -92

7 eman, P. S , ddian, P. hapman,. S K ds 988 Th Wlcome eatonal Anva Sympoum, Am.1 d 82A) 4

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