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Report of the Sloan-Kettering Institute for Cancer Research t l CONTENTS $EPORT OF THE CHAIRMAN OF THE BOARD OF TRUSTEES AND THE PRESIDEXT .................. .......................... 3 t G l I C0utt: Two "bridgrs" (a rrott:s) may be sccn cs- trrtdi»g from a cancrrua.s rrvoase cell to adjacent siormal hamster celh~. The bridge growing from the rig/tt 0 tlFr maasc cell C!Mflirctg with the NltclrPts of a normal AaP)7gtfr CPll. The bridge f r<q)i iRc left of the mousc ccll does not appear to c.r- tr>rc1 A, porrd the cell mcmbrmtr of thc Anvrtsfrr cell with which it bv connected. Pine, hlame>amcs bridge,, aec»: to bc f orari>rg f rortt otlrer maftg>tattt rrmw-r crliq r rotcr:ded, brighte•r cep: I attd rx7cnd• ix,o toward neighboring normal cells. rSec de- srriptimt itt text, pages 16 and 17.) !Alag» i fieam tintr: abnut X IMMUNE REACTIONS .. ........... .............................. 7 DNA AND CANCER ............... ............................. .... 13 ELECTRON 1b1ICRUSCOPY . ..................................... 19 ADVAN CES IN SURGERY ............... .......................... 25 ADVANCES IN CHEMOTHERAPY ..................... 29 SOLVING THE PUZZLE ............................................ $3 OFFICERS ........................................................................ $5 BOARD OF TRUSTEES ... .. ........... ... ... ... . .............. 35 BOARD C!F SCIENTIFIC CONSULTANTS......... 36 PROFESSION AL STAFF ................... ......................... 3$ CERTIFICATE OF AUDIT AND FINANCIAL STATEMENT .................................... 41 STAFF PC1BLICATIONS ........... .... -.......... 47

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Thl• r•rprn•1 i!; dircctcd to those individua)s ;1np1 orrfianir.:ltic,ns whnsc suppcut makes pos- silde tilr actltitii:s of the Sloan-liettering in- s1 rtutv f4,r t•ctncvr I.csearch. Tu illu>tratc that pr t>~1 t•s• is 6cint* made rn understanding and c„nu•ollmg thc diseasc, sonir recent research dh•% clol,mcnt, will Lr dczcrihed, and an 1t- Icnll•t mtll lit maclc to furtliah a pcrspcctivr in whlch 1hi•v nta-i l,r ticwcii. Th-- imtrtnto'., 2J rrst,arch dirisimns. maclt- ul, (d almort lM' ra•t•:u•dhsrcllal~sl are wurkI )nII Iq. achivcv:ul umh•rctandinK of th•• torit:irt• nf thv c:lm ur„u: statv. and to improve mcth- od, 14 trcating c.istlnl; tiiscnsc. The number urrd Narict% 1.1' intcMlFatlce ap)tt'oaclteg cng- gi•st thr complo•xit.% of tht• prohkmts facing Thr„ut:h th, cra~~.tlr~rihhnar~ cfTorrt, t•lu•lt'hwd h.• m:rnv divcmr stuclics. sci- t•nti>i, hoq•l• cNcntu:rll~ 1o unr'avc•I 1hr m.%,. tt-riv• 1d ranc~r. llnrllig 19Gr• )u•ny;l'anl, in hasii'. nhl1fiucl. vtd cluuc-;rI r4:<c;u'ch mrr,• d1•N't•lapcd and ehul }t•,i t„ tah, :ultantapu t,f rt•lcr;ult ad• v;uu,. tn thw IthYslc;ll. m;itht•matical. and lnf,logltal .rlcncc•. f'criaun resc:u•:h nctit•itit•r woYr :1ddvd, (W t11mcWltlllnt'd. fOl11' 17P%% d1\I,Inll.• 0vl1 liwahcmi.stry. K;I/llothcl•- ;1pi l:c,c:n'c Il. Alqdlul Thrl•;rl+y• alld 1'ItYCitil)

Biology. were added during 1968. and two divisions, Experi;nenial Patholog•• and.liicro- biolop'y, +t•et•e discontinued. The Divisions of Biomathematics. Biochemistry. Endocrinol- ogr, Rinpl.csics. .llctiical Research. Biological Cnemistry. Surgicul Research, Environmen- tal ('anccrigenesis. Chemotherapy Research, Cytology. (:cnctics. \'iroloF}', Cell Biology. and Pharmacology were enlarged through additions to staff. 0114, of tht' ,re;ur's most signifi' ant events was the improvement in research facilities accomplished throuQh the reopening of thc Howard Lahttrattu:y, the original research fa- cility of the institutr. Extensive recnnMruc- tion and renovation of the 14-story building was ~tartt•d in Fcht'uary. 1467. A S1.a39.00t1 grant from tht• National lnstitules of health and n $3 million t*r;)nt from the rllfietl P. Sloan Founcl:ltlun ln•n+•itletl the iat•fiesl por- tirnl of funtl-A fortht. mndrt'nization of all laho• 1'ato)'tes a11d tltr l,t.rchacc atld in-Mnlla'inn of sut/!--tanli;el nt'n• lahnrat-',r,r equipment. The new llttn•:u•tl l.nlttu•atut•y, which has direct nccos, t., 1ht• ,tth;u•t•nt Urmr+rial llos- pital for ('t ncer and ,>,lliod 11isr:tse's. hou!~es tllt' 111~111U1~' c f'11nit;lll-v ol'it',lltyl 1't:at`al't'h groups. i:xecuti+e otlicc, of the institulc' are alsn lt,c;ttt'd in 1he llo++•tu•tl l.uluu•ntut;c. Control antl mnnnwement of Slaan-l:etter- ing lnSt1tutt•. ftttnlded in Itll:,. is in thehand> of the Iit,vvl of Trustees, elected annuall>•. Changes in Nutrd mt'm1ic1•'shil, durinF 19GS inclwled 1he resiFn;ttitm tif I tt•. Rn~t'r ,ltlants. after 1:}•e;u'~ uf set'+•tct• a• a Trurtct' of tht' instittltc. and the resignatinn of Evcrelt \ Case. a mt'mlwr for t++•o ycat•s. Tltril• ntanr cnntrihutinns tr the instttnle aue 1,*ratt•fn11Y ;erkno++lct)t:e'd. A netx tnt•ml,t'r, llr. 11c l,rit t;. honncr. wus rlrrtoi a Truste't. during 1!tf ti. Thr ('mmmlttce on Scirntttit• PrlitN of the' Itill't•n1 t4g;ltlri;t11n11. Z)t•Illn1'1711 tltKltl•h0tt•1'• mfi Ccntrl•. dcsiFnntt•d nnnuall' %. fnom :,,,'n,lw,•. of tl,t• l:o„1,•11 „f Tl•n,14•,'s of ti;t' nlaiUltr and the Ittrtr1l of .ll:utaFt'rs of the Memorial Hospital, reviews and evaluates the research programs of the various divi- sions of the institute. The committee repol'ts to the Board of Trustees on any aspects of these programs that require attention of the board. Dr. J. Englebert Dunphy. Professor and Chairman of the Department of Surgery. University of Califot'nia, San Francisco Diedi- csl Center, was elected to the Committee on Scientific Policy during 1968. An important source of guidance to the President and Director of the institute contin- ues to be the Board of Scientific Consultants. appointed by the Board of Trustees. Board membcl s, selected from among the +rorld's leading scientists, meet quarterly to evaluate particular research proiect_s chosen for pres- entatio,l. Dr. Warren H. Cole became Chair- man of the Board of Scientific Consultants for the term July 1, 196R-July 1, 1969, and Dr. Alexander G. Bearn assumed the l'ice Chait'- man:hip for the same p+riod. Three new ap- pointments ta the board were made during the year: Sir Peter Medawar, F.R.S., Direc- tor of the National Institute for Medical Rt•- search, London: Dr. George 1:. Hirst, Presi- dent and Director of the Public Health Re.,earch Institute of the City of New York. hlc.; and Dr. Frank J. Dixon. Chairman. Pc• partment of Exnerimental ?athology. Scripps Clinic and Rescarch Foundation. Each uar appointed for a three-year term. Dr. Seymour S. Cohen submitted his resignation after eight and one-hali years as a member. The cloan-l:ettcring Institute for Cancer Research functions as a teachinF ins:itutmn at hnch prednctol•al and postdoctoral le%els. The Slonn-liettering Division. Graduate Schttol of Me•tltcal Sciences, Cornell 1'ntxel•• sit y t,fTers a predoctoral program to train and tIt'yt'Inlt rcientists for original in>.'estittativc ++orl, in bittchcmistr,r, biology, biomathe• nt;ttic.s• or hit+l,h.••ics. Students may obtnin tht' I'h.Tt. or .11..S. degree through this pro- I;ratnl. Tlurt~'•tt+o ctudents. n1 canelidaleF

for the Ph.D. degree, and one candidate for the 11.S. degree, were matric+.+lated in the Sloan-Kettering Division during 1968. Three students were awarded the Ph.D. degree du:•ing 1968 and three others completed their theses and will be awardea ;hP Ph.D. degree in 1969. All of these students were supported by the institute. The postdoctnral program conducted by the institute lirovides to young investigators op- portunities to improve their competence and to enlarge their experience in laboratory and clinical research in cancer. During 1968, 92 postdoctoral Fellows received research train- ing at the institute, with an average of 57 present at anY given time. Among these 92 Fello»•s. the institute provided in full, the sti- pends of 64, and in part, the stipends of th+•ee. Of those present at the end of the year. ?4 Fellm.•s irere from the United States and 41 were from 16 other countries. The total expenditures for the institute in 1968 were $10.024.497 of which government agencies provided Rc..Op9,°i-f. The major part of the latter sum )vas provided by a single insh•iunettt grant from the National Cancer Institute of the United States I-lepartment of Health. Education and Welfare. The unre- srricted prant. representing approximately a•1.81, of the total annual operating expense of the institute, is contingent upon the re- ceipt from other sources of support equal to the remaining b3.:"( of the ,rear's budget. The remaining funds essential for support came from more than 10,000 individual and corhonrtc gifts, nraii.• prc>senterl in memor* v of friends and loved ones u•ith the hope that others will lie spared through the fruits of eemtinuing research. Among tihe agencies pro- vidink such suhpot•t for 1r.t68 Nrere the l'.S. Atomic Energy Cbmmission, the American Cancer fiuciety, The Damon Runyon Fund for Cancer Research. the New York Cancer Re- searrh Institute. and The Health Research t'ouncil of New York City. Maim• founr:atiron grants which suppert institute research in- clude those from the Alfred P. Sloan Founda- tion, the John A. 1•3artfoird Foundation, the Charles F. Kettering Foundation, the Chris- tine Sonntng Fovndation, the Elsa U. Pardee Foundation, and the T4ax C. Fleischmann Foundatioii of Nevada. D1AR1oN W. BOYER Chairm.an of the Board FRANK L. HORFFALL, JR., bi.D. Presidcnt and Director 6

IMMUNE REACTIONS .framing the questions . One Sloan-1{ettering researcher describes clinical cancer as the last stage of a process whose early phases are as yet unrecognized. Since cancer is a cellular disease, several re- search groups at the institute are attempting to understand its early phases through study of cells and Eubcellular particles. Very broad- h•, cancer research at this level is directed toward answering three general questions. (l) No%% do cancer cells differ from normal cells? (2) Is this difference pertinent to the genesis of the disease? (S) Can this differ- ence be exploited in the treatment or preven- tion of the disease? Immunologists at the institute have been prominent in the elucidation of two basic dif- ferences between normal and cancer cells. These are the only two qualitative differences that have been recognized to date. The first, now widely documented, discov- ery is the inability of certain cancer cells to make a known amino acid, asparagirie. Nor- mal cells can synthesize t.hissubstance in suffi- cient quantity for their needs, utilizing en- dogenous chemicals. Some cancer cells lack this ability and must obtain asparagilne from an external source, such as the bloodstream. An enzyme, asparaginase, destroys aspara- gine in the bloodstream, thus den•ving the can- cer cells their source ot the amino acid. As it cannot enter cells, a.cparaginase does not in- terfere with the production of asparagine in normal cells. By administering asparaginase it is possille to kill asparagine-dependenl cancer cells, leaving normal cells unaffected. This basic difference between normal and cancer cells qs being exploited clinically in the treatmem of specific types of leukemia. Suc- cess with asparaginase has led to an intensi- fird search for other enzymes with such selec- tivp potentidl. A second qualitative difference between normal and cancer cells has been ascer- tained through immunological means. Animal sludies have clearh• demonstrated that tumor I

Y, cells possess antigens not shared by normal cells.' Two categories of tumor antigens have been defir.ed in animal cancers: (1) those that form part of the cell surface, called "trans- plantation antigens," because they invoke re- jection phenomena when tumor cells are transplanted from one animal to another: and (2) antigens that do not form part of the cell surface and play no part in transplant re,iect ion. Transplantation antigens have been found in tumors induced by oncogenic (i.e., cancer inducing) chemicals. It appears that each such tumor elicits an immune response peculiar to itself. Two tumors induced in the same arrmal by the same chemical will generally possess diflerent antigens. Transplantatyon antigens are a!so found in animal leukemias and sonie tumors induced by viruses. Such antigens appear to be specific for a particular virus: that is, cr.c virus will always induce the same tn an ,plantation antigen. Antigens that do not occur on :he cell sur- face, or play a part in transplant re,iection, are exemplified by the "T antigeilis" of DNA viruses.' These antigens ve products of viral genes. but ere not incorporated into the virus particles. Sonte oncogenic RNA viruses also povsess il.trarellular antigens not involved in transplant rejection. The de.tection of tumor antigens is impor- tmlt in that it provides ttew approac•hws to determining the cause of various cancers le.g., presence of an antigen specific for an oncoFenie virus %rould sugFest tlie causativc roke of that virtl:•). Of mrn•e immediate inr portancl• tti, thosl. ctricken with 1he clisease, knMelvdt;,• of 1umt,r antifiens providcs thc first ra;irnlal leads to cancer immimotherapy. This is perhah.s the most encouraging indira- 'Ar :,n.:4, r t, t l.l 1., .1, /Int ,! :u n n,.i,inf,•, lmus ,,, tnfr, l:.•u• !orrtgt: ,al wh„s,• rh:•nitr,:l strurhtt, dtRor+ Qunirnrntly fr,.m t6, 1 r:gt;, r:m nnni.uu t.. t,..m. . tion to date that one day it may be possible to harness the body's immujle responses for the treatment, and ultimate prevention, of certain forms of cancer. A particularly exciting area of immunology in which Sloan-Kettering investigators are deeply interested inv'olves the search for anti- gellic similarities among tumors occurring in different animal species. The discovery of such similarities may provide a key to the eti- ology of whole groups of cancers, a sort of "comparative oncogenesis." Techniques of virology and immunology are incorporated in these studies. Since the turn of the century scientists have speculated that one or more viruses might be responsible for causing some cancers. In 1908 Olaf Rang and Wilhelm Ellerman demon- strated that a cell-free filtrate (presumably containing a virus) could produce a leukemia- like disease in chickens. and in 1911 Peyton Rous proved a virus could induce solid tumors in such animals. It was 20-odd years before any further relationships between viruses and tumors were discovered. By now, man~ viruses have proved capable of inducing tu- mors. in laborator,v animals. Two very intriguir,g observations made at the institute recently relate to viruses asso- ciated with specific types of cancer in widely disnal•ate animal species. Indications are that researchers may be on the track of two viruses likely to be implicated in human cancer.-,. Dlurine lettkemia virus ("A1uLV"), an R\ avirus, has been recognized as a causa- tive agent in spontaneous leukemias in mice. A similar R\ A virus, avian leukemia virus or "ALA'," is responsible for leukemia in chick• ens. During the past few years investigators have discovered a morphologically similar ln uru~ ciassifirattnn, thr initial diatinctioe is madv br1N•t•efl h\A vtrus•>s. w•hnse genetic mtiterml is dr• e\yrilinnUrlCif arl(l, and R1A virusrs, u•hose genrtn m:drt.al tt rtLnrnulrir nctd. F

virus in cats with naturally occurring lym phosarcomas, the most common type of can- cer in cats. This rii•us has been designated feline leukemia virus, or "FeLI'." Initially FeLN' was detected by electron microscopy. Under the electron microscope FeLV appears indistinguishable from A1uLY and A)N. Its presenc~ can also ))e determined through tests of infectivity in living animals. Very recently a group of scientists at Sloan- l:ettcring conducted a series of immunologi- cal tests ml feline leukemia virus. and the re- lationship it bears to the murine and avian leukemia viruses. These researchers employed a reliahlr, and incidentalll• very dramatic, technidue in their .cork. This immunoprecipi- tation tcc)uiiqur, called "double diffusion" or "the Ouchterlony inethod," is illustrated pho- trtgt:•tphica)ly in Fig. 1. The test is designed to detect precipitation t•unctions between solultle aniigens and their antihodies. A shallow agar gel is permitted to solidifit• in aspecialh• designed dish in t+1hich a metal matrix stands. As the agar scjlidifies and thr matrix is removed. "~~•ells" are left in thv gel. An antib„iic or antigen solution is hourrd intio cach wcll. These liquids diffuse tlu•mtgh 1he gcl and meet one another. If the antibod>• and its related antigen react with eac•h other, la•ccipitation %Vill occur and ,1 light-colorr•r) haml Nvill appear between the tl+(o we)l< imok•et) in ti.e reaction. It(,)lendin€ upon the number and arrange. ment (if the a•clls. a single reaction may be tested or several may be tested simultr.nr• ouSlY. t)nr u.'cful confilan;otiun i> :r centtal wrll. Nvith n ring of wclls surrounding it. If :~itthn,)r specific for tttt antigen of mouse leu- krmia virus (Mul.\' ) is placed in thc central \\rll, and extrat ts of varions RNA .•irutes, in• cludinF .llul.l' extract. arc poured into the hrralhera) «-c)6, it is )w',~Siblc to compare the nntillod' y-antiFen rr•.rctirn occurring hctwer» the anttiUndr a+td the mouse viral antigen witL• thw.t. ricrtn•ring ltetmrtm thr antihodly and rICUat 1. The OrtrGterlonv method is eraed krrc to drmmtshntr the vridraprrad orcrrrrertcr of anti- body to Btirkftt's lpmpb0»m ontigen. Thr renter U•ril confains $r+rki't'c llpnp4omn enfigrn. Rear- tio»s arr fnr,nd trith blood Jronr patirnts with BxrAitf', lyntplirnno d'tcrll D, carcinontn oJ the pnstnasal spnri~ (n•rll 2), and ltfrnphosarrmnn ( u•rlt ;1. /1t rw» t) n,.t, a» tibodlr is rarely drfrrfrd in tbc bluod of rurrmnl indiE•idaals or in thi blorad f.f pntifnfs u'ifh breast canr,r (u•rll 5 1 or mrln- ttiamt r w4 115 J, antigens pns ses.sed by the other viral extracts. 1t'here idrntieal reactions occur, precipitation bands ioiii, showing that the viruses repre- sented share an antigen. More than one preci- pit:dion band may form between the central well and am• other well, indicating that the antibodY is a"mixture" and that more than one nntibrtrdy-antigen reaction is occurring. By placing the gel on light-sensitive paper. and lighting from above, it is possible to Ob- tain a photoFraphic record of the reaetion.,. Double diffusion tests conducted with )eu- krnti:a viruses from mice (MuLV) and cats (Fr1.1') indicate quite conclusively that the cat and mbusr• ieukemia viruses share an anti- grn, meaning in effect that the coats of the .9

B viruses are structurally related. This antigen is not shared by the avian leukemia virus. Ex- cited at finding this apparent immunological relationship between diseases in animals of widely different species, Sloan-Kettering sci- entists are conducting similar tests to dis- cover whether tissues and milk of hamsters and rats, in which a similar RNA virus occurs, have an antigen in common with cats and mice, with chickens, or with each other. At least one researcher in the group conjec- tures that as viruses of this type are studied in greater detail a related virus may be :m- plicated in acute leukemia of children. A second recent invnunological discovery is perhaps even more pertinent than the cat- mouse relationship. In this case man is in- rolved directly, rather than by implication. For the past decaele intense study has yielded a series of curious fact.c concerning a type of cancer which occurs most frequently among children in certain parts of Africa. Called "Burkitt's l.•mphoma," this disease has sev- eral characteristics of interest to investi- gators. Some African Burkitt's tumor cells grown in the laboratory are rich in herpes• type virus particles ("HTX*"). presumabh• a DNA virus of previously unknown type. Further, antibori,v to Burkitt's }1T\' is found in the blood of pat ients sufierinR from several other malignant diseases, including carcinom" of the postnasal space, l,rmphosarcoma, and chronic lymphatic leukemia. and the nonma- lignant disease'. infectious mononucleosis. Prompted by the apparenth widespread uc• ctrrence of antibodies to Burkitt's HTV, Sloan-1:ettering researchers undertook to ex- aminc the antiFenic properties of HT\' a«o- crnted with a naturally occurring malignanc.• in frogs, Lucke renat adenocarcinoma. Anal.-- sis of the frog viral antigens indicated that natural antibodies against them occur widely 'Serum frrnn an amum:d .V'rnch ha* W~rn cxpnfrl to thr ~iru.. and hu~ reaNcd intntufinln~~calh' aFtuust it. among arnphibia. Aiore surprising, the anti- serum' to Lucke HTV prodaces strong posi- tive reactionswhien it is tested with Burkitt's HTV. These tests have been repeated success- fully, and demonstrate, positively that the human agent and the frog virus possess a common antigen. Similar tests are now being conducted to Zetermine whether a relation- ship exists between either of thcse herpes- type viruses and the NTV associated with rAeurolynnphomatosis (lttarelk's disease) of chickens. The shared antigen associated with malig- nant diseases of human beings and frogs may i6rdicate that the herpes-type virus family possesEes a common group antigen which cuts across the animal kingdom. Alternatively, it may mean that those hei pes-type viruses as- sbciated 'with malignant diseases carry a com- mon antigen. In either event the implications of the discovery are of gr•eatt interest to sci- eintists involved in cancer research. 10

IQ DNA AND CANCER mec)tavism,o, of change As evidence is accu=u?ated thst. a causal ie- laXionship exists between viruses and some forms of cancer in animals, some investi- gators seek to integrate viral causation into a larger concept of the nature of the disease. One such coacFpt is that cancer, whatever the immediate triggering factor may lie, is ulti- mately a cell genekic disease.ll'hether a virus, irradiation, or an oncogenic chemical initiates the change, the cancerous cell reproduces it- self, trat•.smitting its malignant characteris- tics to its cell progeny. It is therefore postu- lated that cancer is a disease of DA'A, If this interpretation is valid, then genetic material isolated from cancer cells might differ in some regard from that of normal cells. Evidence for this conter:tion would be obtained if such I)\A were capable of inducing malignant transformation ot normal cells. To understand the relationship between DNA and cancer, a group of cell biochemists at the institute has been engaged for some years in a series of exacting, and often frus• trating. experpme~nts. One approach involves ati attempt to define chemical differences be- tween the gettctic deter.ninants of normal and malignant cells. Comparisons have been made Uetween the DNA of pormal Chinese hamster cells and Chinese hamstt>r cells transformed to the cnncerou.~ state through exposure to oncogenic chemicats such as benzp,rrene (BP) and oncofienic viruses. To date, no significant chemical differences have been found. hnvestieatnrs have looked for differences between normal and fiP-transformed ce11s in terms of their patterns of ribonucleic acid 11RNA) biosynthesis. Of the millions of gen- etic messapes thought to be encoded in the D`:A contained in the nucleus of a single mammalian cell, onh• a small fraction is ever expres,-ed. The genetic messages are trsn- sc~ribvd into a series of ribonucleic acids and the information contained therein is trans• lated into chemical activity in the cell's cytrn plasm. Investigators have sought some dis-