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The iInstitute for Cancer Research ELEVENTH SCIENTIFIC REPORT 1960-1962 Nox Ghade Philadelphia 11, Pa. 1.....

.a......_..~ TImOZZ-IY R. TALBOT, JR., M.D . ............................ Director SrANI" P. REIMANN, M.D . ...................... Director Emeritus H. D. PvTNEY .............................. Administrative Director R. L. HAIiRINGTON ................................... Administrator SCIENTIFIC ADVISORY COMMITTEE AlMua C. BIiAVN, Px.D. ROLLIN D. HoTCmclss, Ps.D. PxILIp P. Comv, M.D. LEON O. JACOBSON, M.D. FxANx L. HoRSFAI,I, JR., M.D. S. E. LunIA, M.D. COL.IN M. MACLEOn, M.D. k

i THE WOMEN'S AUXILIARY OF THE INSTITUTE FOR CANCER RESEARCH THE Fox CxASE CHAPTER, Fox CxASE, PA. Mrs. Israel R. Hallowell, President THE ANNA M. GRAY CHAPTER, OVF•RBROOIK, PA. Mrs. Alfred M. Gray, President THE HELEN BERGER CHAPTER, WASFIINGTON, D. C. Mrs. Leonard Hill, President THE TRAniNG PosT CxAPrER, PAOw, PA. Mrs. James A. Moody, President THE BERGEN CovNTY CI3APTER, Hn.ISnALE, N. J. Mrs. E. A. Davis, Jr., President ~ 0 0 Ln J 6 . . _.._....,.~,.~

OFFICERS ArrrxoNY H. WmrAxjm ..................................Preakient WALTER H. WEsT, JR . ............................... Vice President RoBERT MoNrcommY Scoz-r ..............................Secretary SYmexvs L. Wimn.E}r ....................................Treasurer EnwnRn GRAY ..................................... Asst. Treasurer TRUSTEES Dwvm R. ALBRicRer EnwARn B. LEZsExRUVG, JR. Jotnv W. BonrrrE HARRY R. NmsoN, jR. GEORCE M. DORRANCE, JR. ROBERT MONlY',OMEftY Scorr T1ioIvlAs HART WALTER H. WEST, JR. AxaxoxY H. WxrrAmR 3

SCIENTIFIC STAFF SENIOR MEMBERS THOMAS F. ANDESSON, PH.D. HvcH J. CaEEm, PH.D. IxENE CoxESr Duim, PH.D. ANDREW J. DONNELLY, M.D. THoMAs J. KuaG, PH.D. TmoDoRE F. LAVnaE, PH.D. A. L. PArrExsoN, PH.D. JACa Scmx-rz, PH.D. SAM SOROF, PH.D. jwxoB A. STExoz,, Sc.D. GERiuT ToENNDEs, PH.D. SmNEY WEUJHovsE, PH.D. SENIOR MEMBERS EMERITUS MARY A. BENNETT, PH.D. GxACE MEDES, PH.D. ASSOCIATE MEMBERS BEAnucm MiNZZ, PH.D. EzrzASE7H K. PATFESSON, PH.D. RicaAxD M. PE(x, PH.D. GEORGE T. RvDSm, PH.D. 7 _~~~

CONTENTS Page RFpORT OF THE DIRECfOR .................................. 11 scwTIFTC RErORTS ........................................ 13 DIVISION OF BIOGHEMISTSY ............................... 13 DIVIBION OF BIOLOGY .................................... 35 DIVISION OF CiHEMOTHERAPY ............................. 62 DIVISION OF PATHOLOGY ................................. 69 ANIMAL COLONY .......................................... 77 ScOWTIFIC PERSONNEL ..................................... 79 ADMIIVISTRATIVE PERSONNEL ................................ 85 ADMINISTRATIVE REPORT .................................... 87 LIST OF PIIBLICATIONS ...................................... 89 9

SCIENTIFIC REPORT SEPTEMSEA 1960-SEPTEMBER 1962 DIVISION OF BIOCHEMISTRY Chairman, SmNEY WEiNaovsE (until February 1961) Acting Chairman, GESarr ToENNiES (from February 1961) MAaY A. BENNETT, Px.D.,l Senior Member Emeritus (June 1962) JAoQIIEIdNE RAMSEY PIMBLE, B.A., Research Assistant (until July 1962) WII,YaW ScHEia.,2 Laboratory Helper (until June 1962) The present experimental work is an extension of a plan carried out for the past twelve years to study the relation of `7abile methyl" groups to growth. Nutritional Factors in Carcinogenesis. (In cooperation with Dr. Andrew J. Donnelly, Division of Pathology. ) It was found that vitamin Blz is the factor which, in the presence of folic acid, promotes growth of rats on a"labile methyl"-free diet and enables them to maintain normal livers. Lankenau-Wistar rats fed a homocystine diet free of both vitamin B12 and compounds containing `7abile methyl" groups have shown morphological changes in the livers, which in some cases simulate the preneoplastic changes produced by p-dimethylaminoazobenzene ( DAB ). Vitamin B12 delayed for two years, and partially inhibited, these liver lesions. Long-term experiments involving approximately the life span of the rat were undertaken in an attempt to produce tumors and to evaluate the influence of vitamin B12 and riboflavin on liver lesions. This type ' Present address: 240 W. Walnut Lane, Philadelphia 44, Pa. ' Transferred to Animal Colony. 13

ASSISTANT MEMBERS JEROME J. FREED, PH.D. DAVIn A. HUNGERFoRD, Px.D. IRwIN I. OsTER, PH.D. ROBERT P. PERRY, PH.D. ROBERT K. PRESTON, PH.D. STEPHEN S. SUBTELNY, PH.D. EBERHARDT WEILER, DR.RER.NAT. RESEARCH ASSOCIATES BoHDAN BAKAY MANFRED BAYER, DR.MED. MARIE A. Di BERARnINO, PH.D. MURRAY COHEN, PH.D. ADnIE B. CRISSMAN DAVIn L. DiP11;rIeo, PH.D. NORMAN F. FLOYD, B.S. JENNY PIQCWORTH GLUSKER, D.PHII.. GEORGE L. HAGEN, PH.D. H. FRANcis HAVAS, PH.D. SHU-HsI HsIAo, PH.D. ICAzuo IwAI, PH.D. PHILIP KIMBEL, M.D. JoSErH J. KoLB, B.S. ZBIGNIEW T. MANKOWSKI, M.D. ROBERT G. McKINNELL, PH.D. THoMAs MoNTIE, PH.D. MARTIN J. NEMER, PH.D. GEORGE A. REICHABD, JR., PH.D. HELEN REDFIELD SCHIILTZ, PH.D. G. LEnYARn STEBBINS, PH.D. MURRAY STRASSMAN, PH.D. DIcK vAN nER HELM, D.Sc. IVAN JEANNE WEILER, PH.D. GEORGE L. WOLFF, PH.D. NOBUTO YAMAMOTO, PH.D. ~ 0 0 Lm -A 8 .

In every case the dispersion effect was in agreement with that calculated from the lactone of n,T, isocitric acid which in the Fischer convention COOH o H-C-OH :; HOOC-C-H -A a Hz w ~ ~ COOH This isomer may also be described as (1R:2S)-1-hydroxy-1,2,3-propanetri- carboxylic acid in the Cahn-Ingold-Prelog notation. Our result is in agreement with the synthetic work of Kaneko and his co-workers (Chem. Ind., 1187, 1188, 1960; J. Chem. Soc., Japan, 82(1) :91, 92, 98, 1961) and in disagreement with the physico-chemical predictions of Greenstein and his co-workers ( J. Am. Chem. Soc., 77:707, 716, 1955). When the investigations of the salts of isocitric lactone were under- taken, no suitable crystalline isocitrates were available. Since that time Dr. H. B. Vickery (Connecticut Agricultural Experiment Station ) has prepared crystals of both potassium and rubidium dihydrogen isocitrate, which form an isomorphous pair on the space group P212121. The potas- sium salt is being studied in detail (van der Helm, Glusker, Minkin, Burow, and Johnson, 23). It has cell dimensions a-12.03 A b-13.16 A c-5.17 A and four molecules in the unit cell. Anomalous dispersion effects from 535 sets of reflections were measured with the diffractometer using chromium radiation. Data are being collected both by photographic and counter methods with molybdenum and copper radiation. Using the chromium data, three-dimensional P,(u) and P,(u) maps (Okaya, Saito and Pepinsky, Phys. Rev., 98:1857, 1955) were calculated and a three-dimen- sional IF1z-map was calculated from partial molybdenum and copper data. The structure was solved from these three maps. Although the refinement is not complete (R = 0.14), it is established that the absolute configura- tion agrees with that found from the lactone. The Crystal Structure of Trimagnesium Dicitrate Decahydrate. (John- son, 40.) Divalent cations are essential for the activation of several enzymes which modify citric acid. It is often postulated that chelation is the mode of activation. Mg8(CeH607)2 • 10Hz0 was chosen for structural has the formula: 18 t

of experiment should show effects of these substances not observed under more drastic short-term procedures. The studies have now been termi- nated owing to the retirement of the principal investigator. Some interest- ing results have been obtained and a report is being prepared for publication. Tm;onoRE F. LAviNE, PH.D., Senior Member NoRMeN F. FLOYn, B.S., Research Associate MARY S. CAMMAROTI, B.S., Research Assistant Biochemistry o f Sul f ur-Contain4ng Compounds. (Lavine, Floyd, Cam- maroti. ) This program is devoted to the study of the basic chemistry of sulfur-containing cellular constituents. We had found previously that methionine may be distinguished from its sulfonium derivatives by differences in the rate of methyl iodide for- mation on heating in hydriodic acid solution. The conditions for this reaction were further investigated and a procedure developed for differ- entiating between compounds containing O-methyl, S-methyl and sul- fonium-methyl groups (42). Controlling factors for differentiation are acidity, iodide concentration and the use of a non-volatile alkylating agent. The procedure appears to offer advantages over other methods both as to manipulation and scope of application. We are currently engaged in utilizing this procedure for the examination of the sulfur components of proteins and enzymes with particular emphasis on the possible occurrence of sulfoxide or sulfonium derivatives of inethionine. The existence of such structural variations of methionine residues in proteins is of current interest to biochemistry in connection with the study of enzyme structure and function. u7 0 0 MARTIN J. NEMER, PH.D., Research Associate (from October 1960) ~ SANnRA G. BARn, B.A., Research Assistant (from February 1962) A Oxr,Ent ALExANVat, Technician (October 1960-June 1962) ~ Ci.ARA B. RucuR, Laboratory Helper (August 1961-August 1962) `O The embryonic system that we use, the echinoderm egg, is especially susceptible to specific chemical probing and control. The reservoir of 14