University of California Laboratory of Nuclear Medicine and Radiation Biology Atomic Energy Commission Contract at (04-1) Gen-12 (Partial)

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UNIVERSITY OF CALIFORNIA LABORATORY OF NUCLEAR MEDICINE AND RADIATION BIOLOGY Los Angeles, California 90024 ATOMIC ENERGY COMMISSION CONTRACT AT (04-1) GIN-12 ANNUAL PROGRESS REPGRT For the period ending l ted in the United States of America. mt if ic and Technical Information,National Bureau of Standards, U.S. Department Available from Clearinghouse for Federal 1 Commerce, Springfield, Va. 22151. Price : Printed Copy $3.00; Microfiche $0.65

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TABLE OF CONTENTS REPORT OF THE DIRECTOR ! ADMINISTRATIVE STAFF AND ADVISORS STAFF MEMBERS AND SCIENTIFIC REPORTS DIVISION OF BIOCHEMISTRY Lipid Metabolism in Brain and Membranes in Development Transport and Turnover of Lipids in the Brain Control of Lipid Desaturation in Bacilli Lipid Composition, Function and Metabolism in Marine Radiation Chemistry of Lipids DIVISION OF DEVELOPMENTAL BIOLOGY Enzyme Induction and Controi by Hormonal and Serum Factor Organ Specific Protein Synthesis Membrane Function and Specific Receptors DIVISION OF ENVIRONMENTAL BIOLOGY Nutrient and Radionuclide Cycling

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DIVISIQN OF NUCLEAR MEDICINE Total Body Counter Activities DIVISION OF RMXOB TOLOGP Radiation Chemistry of Nucleic Acid Constituents Radiation Biochemistry of Nucleic Acids and Radiation Biochemistry of Proteins and Amino Acids Cellular and Mammalian Studies in Radiation Biology Reviews QII Radiation Induced Chemical Changes in Nucleic Acids Leading to Biological Damage PUBLICATIONS AND REPORTS HONORS AND AWARDS

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The 2nd Dept. of Internal Medicine Faculty of Medicine University of Tokyo ke as of Interest Development of new radiopharmaceutical agents and diagnostic procedures in nuclear medicine Cardiac and tumor studies Clinical applications of nuclear Mechanisms of viral induction of Development and production of nuclides and their metabolic Experiment a1 ph y sio logic studies of t h e cardiopulmonary system & myocardial imaging with cyclotron Clinical applications in short - Pulmonary studies in man and lung Ken Lyons, M. D. Radio aerosol inhalation studies

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r placed on hosts previously infected with MuLV. graft regeneration or the ability of thymic grafts to function in producing normal immune responses in thymectomized animals. The inhibition of lymphoma in these experiments is a result of act in o my c in D preventing the establishment of viral infect im in thymi c cells and not to a functional alteration of the thymus produced by a direct cytotoxic action of the ACT also did not affect Reference: her. SOC. Hematol. Program Book p . 65 (1971) (Abstract). Granulocvte-Monocvte Colony Forming Capacity of Human Bone Marrow An in vitro culture technique of marrow cells in soft agar has been developed and applied to studies with human marrow. The source of colony stimulating factor (CSF) has been serum from C57BL mice removed 4 hours after administration of ' endo toxin.Thirty - six patients with no obvious disturbance in gran u log poi es is have been studied with two concentrations of the serum containing CSF. With this system reproducible increment i n colony formation was observed. Marrow from patients with my elo pro lifer a - ti ve disorders showed impairment of this response of ratio.Patients with acute my el oblast ic leuk en fa showed poor colony growth, and when in remission with normal appearing marrows, showed an Fmpairnent ofthe response ratio. An increase in the response ratio was found in1patient with pH1 positive, chronic gran u loc y tic leukemia, and 2patients recovering from drug-induced neu trope nia. It has also been found that the presence of minor percentages of sarcoma cells, carcinoma cells, and leukemic lymphoblasts do not impede --i n vitro colony formation or impair the response ratio. Granulocyte-Monocyte Colonv Forming Capacity of Mouse Bone Marrow Studies with mouse bone marrow have been carried out using the same system of soft agar and serum from mice previously given endo toxin, as i n studies of human marrow. Again, two concentrations of serum have been used and a constant response ratio has been found for normal marrow. Preliminary studies have shown that AKR mice given Gross murine leukemia virus (GMuLV) have increased colony forming capacity. Such mice characteristically develop lymphoma between the second and third month of life. When their marrow becomes infiltrated with lymphoma cells,the number o f colony forming cells decrease but the ratio of response remains the same. Studies of the marrow of C3H mice after neonatal thymectomy have shown no difference in colony forming capacity when compared with normal marrow. The admin is tra - tion of hydro cortisone to animals for2 days prior to removal of marrow for study of colony forming capacity produces a striking decrease in the

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number o f colony forming cells without remarkably changing thedi ' ffe rc nti al count ofthe bone marrow. Characterization of Various Transplanted Mouse Lymphonia Cell Populations Donna L. Vredevoe and Esther F. Hays Single Gross virus - induced mouse lymphoma cells or low doses of such cells have been isolated and transplanted to syngeneic recipients. Three mouse strains have been studied : AKR, C3H/HeJ, and CBA / 9 (CBA/TbTs donor lymphoma). Single cells were isolated and transplanted in a semisolid gelatin medium which minimized trauma to the cell and chances that the cell might adhere to glassware or instruments used for isolation and Cells of the following types are being analyzed: 1) AKR: sponaddition lines derived from the isolation and transplantation of single cells from any of these sources are be lng characterized. Work this year has shown that single mouse lymphoma cells can transplant lymphoma i n syn gene ic recipients,but that success of such transplantation 16 dependent upon the cell source. In the C3H/HeJ system long - transplanted cell lines transfer lymphoma with single cells whereas i n C3H/lieJ virus -induced lymphomas the LD 100 dose i s as high as1x lo8 cells. Lymphoma donor cell populations are being sorted as t o 1) virus content (XC cell and newborn as says), 2) LD 100, 3) incidence and latent period of lymphoma upon syngeneic transfer of standard cell doses,4) histology of lymphomas, and 5) theta antigen content. It is the purpose of this project to eventually compare success of immunotherapy, applied with transplantation of syngeneic lymphoma cells, o f mouse lymphomas of these characterized types. The objective will be t o determine those tumor cell characteristics which are correlated with Comparative' Uptake of Potassium and Cesium After Intravenous and Direct Coronary Arterial Injection Following intravenous administration of K-42 and Cs-131 approximately 5% of the injected dose concentrates in the myocardium, but there are rate

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differences. Potassium reaches a peak between 5-20 minutes post in j ec - tion and clears with aT1 / 2 of about 6hours ; Cesium peaks between 1 - 2 hours and clears with a half - time in excess of 16 hours. These findings are i n agreement with published data. With intra coronary injection approximately 70% o f potassium is extracted on the first passage versus only 22X for cesium. ' Half - times are approximately 1 and 6 hours re spec - t iv ely. Were it not for the higher radiation dose and less optimal gamma emissions,K43 would appear t o be preferable to Cs-129 for myocardial scanning,particularly following intra coronary injection. Four classes of parti clc s were investigated : albumin macroaggregates (MA-I) 10-100 diameter and under 35 p diameter ; anion resin microspheres 10-100 i~ and ultra fine microspheres under 35 p. All were labeled with technetium-99m. Batches o f each of these preparations were injected simultaneously with Cs-131 in three experimental models: left atrial injections in normal animals,left atrial injections in anililals with liga - ttion of the anterior descending coronary artery, and arterial injections directly into thc anterior descending coronary artery.lt w n ty - eight dogs inall were studied. The hearts were removed and multiple full - depth sections taken for tissue counting, The cesium was distributed equally (within 10% range) throughout the normal left ventricle. The best particle / cesium correlation was found with the ultra fine micro sp herc s.These, likewise, had the best internal correlation.After liga tion of the anterior descending coronary artery,the perfusion defects obtained by scanning were qualitatively similar but quantitatively significantly different. With the particles,the defects were larger. Presumably, the cesium enter cd the ischemic area by anastarnoses and re circulation. These observations were confirmed by in vitro tissue analyses. An analogous situation was found by direct intra coronary injection. The particles were restricted to a clearly defined region corr csp on ding to the injected vascular bed. Although a substantial portion of the cesium was similarly localized,this material was found throughout the myocardium. The local distribution of the particles often was more erratic than the solution of cesium probably because of streaming and other mechnnical effects of blood flou on the particles. It was concluded from this study that the ultra fine microspheres provide the most accurate and reproducible estimate of regional flow providing adequate mixing takes place prior to entering the coronary circulation.

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15 dogs at3,6 and 24 hours. microspheres were injected into the left atrium. -Scans.of the hearts were made followed by sacrifice. spec tro metrically for relative radio nuclide content : the Tc-99m gives sue of known degree and duration of ischemia; and similarly the Cs-129 shows cesiunr uptake in this tissue.Preliminary analysis of the data shows that very little (approximately 20% or less) cesium is lost from ischemic or in farc ted myocardium in the first 3-6 hours but by 24 hours a definite loss is evident,the degree of which approximates the attained decrease in flow. Sur pris in sly,the Cs-129 values at all times correlated well with the Tc-99m microspheres.Differences were anticipated because .- - cesium uptake is a function of both flow and cellular function while the spheres depend solely on flow. This question is being further invest i - gated in acute infarction with restored flow. A series of chronically After liga tion, Cs-129 and Tc-99m labeled Sections of the myocardium were analyzed 1in farc ted animals is being studied at intervals up to6 months. Clinical Myocardial Investigations with Cs-129 and K-43 The administration of Cs-129 t o human volunteers com cn ced 9/24/71. To date16patients have received Cs-129 by the intravenous or intra cor - onary route or both.Of these,5patients had intra coronary and intra - venous Cs-129 injection on separate days. Nine patients have had intra - venous Cs-129 administration only and 4patients have had the Cs injected directly into a coronary artery at the time of cardiac catheter iz ation. Five patients had ang io graphically - normal coronary arteries. the intra coronary injections were made into the left coronary system as this was most commonly involved in aneurysm production. Heart scans obtained 1-2 hours following intra coronary Cs-129 admin is - t ration were clinically useful in localizing under per fused areas of myocardium which corresponded to regions of abnormal ventricular contraction visualized by vent ric u lo graph y.Inthe absence o f computer image-enhancing systems,only grossly a kinetic or paradoxing areas even correlated with filling defects on the scans. Areas o f minor motion disturbances,such as localized hypo kin es is, were not identifiable on the scans.

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The images obtained after intravenous administration of CS -129 were Becauseg ene rally not of sufficient quality as t o be clinically useful. of the poor target to background ratio, areas o f myocardium known t o be aneurysmic could not be identified on the scans. As our present equip - ment has no capacity for elimination of background, we plan to limit further intravenous studies with Cs-129 until we obtain an on - line comput er modification (probably around Sept. 1, 1972). Preliminary obserlrations withK43suffer similar limitations to those noted above with Cs-129. However, as anticipated from the animal investigations,intra coronary injections of K-43 give superior results to Carbon-11 Labeled Carboxylic Acids In an attempt to evaluate fatty acids as pQ tent i al myocardial scan agents,several compounds have been prepared and tested in animals. Rel ht ive myocardial uptake of acetate was evaluated in2 dogs. n if i cant myocardial retention was not demonstrated.Distribution of oct a no ate was studied in3 dogs and 2rabbits.This material cleared more slowly from the blood than did the acetate but showed no definite myocardial concentration distinguishable from blood content. Palm it ate likewise failed to demonstrate substantial myocardial uptake as wousd have been anticipated from reports ' using C - 14,but the precise composition of the material used was not determined.Further work inthe area is in progress. with Radio nucl iac Labeled Proteins and the Total Body Counter N.S. MacDonald, 1. Ban, and Anna Mae Fles her A total of 74 studies of the metabolic turnover rates o f serum immune proteins (immune globulin s,G and M) were made inpatients suffering from rheumatic disorders.This work was conducted in collaboration with Dr.Joshua Levy and others of the Department of Medicine. is aimed at elucidating some of the factors in rheumatic diseases and providing methods for objective evaluation of the efficacy of therapeutic *measures. Our contribution consisted in measuring the turnover rates