FERMILAB THERAPY FACILITY-INITIAL BIOLOGY PROGRAM(deleted version)

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PRIVACY ACT MATERIAL REMOVED HEALTH, EDUCATION. AND WELFARE GRANT APPLICATION COUNCIL (Monrh, Yrrl DATE RECEIVED TO BE COMPLETED BY PRlNClPAL INVESTIGATOR lltwnr f t h m @ 7md 1 5 4 ) ,1. TITLE OF PROPOSAL (Do not u c w d 53 typtuitwtwcud FERMILAB THERAPY FACILITY-INITIAL BIOLOGY PROGRAM 2. PRINCIPAL INVESTIGATOR l3.DATES OF ENTIRE PROPOSED PROJECT PERIOD l n i s ooplicoiionl Argonne National Laboratory 9700 South Cass Avenue 9700 South Cass Avenue The University of Chicago 5801 South Ellis Avenue Chicago, fl lino is 60637 lb CERTIFICATION AND ACCEPTANCE. Wo, thr undw~lqwd,d f y thn tho stotomorm hdnn UW and compl.tO to tho ba Of OW

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PRIVACY ACT MATERIAL REMOVED DCIARTMLNT OF H€ALTH, EDUCATION. AND ML FARE Biological and Medical Research, Argonne National Laboratory. -- Biomedical and Environmental Research, Argonne National Laboratory. TITLE OF PROJECT Fed lab Therapy Facility - - Initial Biology Program u6c TWSSPACE TO A~STRACTYOUR PROPOSED RESEARCH. OUTLINE OBJECTIVES AND METHODS. UNDERSCORE THE KEY WORDS MOT TO EXCEED 101 IN YOUR ADSIRACT. of peak energy 67 MeV impinging on a lithium target. radio biological measurements is planned as part of the preceding application. the start of clinical studies, however, i t is essential that certain in vitro measurements be undertaken ahead of time. cie ntl y the radio biological properties of the neutron beam t o permit initial clinical studies to be started. More comprehensive radio biological measurements, in vitro and -9vivo are to follow as called for in the parent application. (V79 Chinese hamster and possibly Heta and other cells). is expected t o be quite different from those available from currently existing neutron therapy - facilities. For this reason alone, it is essential that those radio biological characteristics of the beam which relate directly to its therapeutic potential be worked out ahead of time. enhancement ratio of single and fraction a ted doses relative to survival. Other end points are t o be included i f possible. Nucleon Therapy Facility of how closely the radio biological properties of the Fermi Lab neutron beam conform to predictions based upon the properties of other neutron sources. is expected that upon the completion of this assessment, initial clinical studies can be started with an adequate measure of confidence. will not be optSmal a t the start, since the experiments are not intended t o break new ground it is expected that they can be completed in a relatively short time. A neutron therapy facility is currently being organized at the Fed National AccelerThis will involve the use of high-LET neutrons generated from protons A series of in vitro and i n vivo Therefore, the aim of this research is to characterizes uf fi - The initial radio biological experiments are t o be confined to cultured mammalian cells The neutron spectrum anticipated These will include the relative biological effectiveness and the oxygen From these studies, an assessment will be made by the therapists in charge of the Although the physical setup for the work

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I July 1,1975 I June 30,1976DETAILED BUDGET FOR FIRST 12-MONTH PERIOD TOTAL DIRECT COST (Enrcr on Page 1, ltsm 51 DATE OF DHET 0 UNDER NEGOTIATION WITH: AG REE MENT: I* I F THIS ISA SPECIAL RATE (8.9 off-sirs/, so INDICATE.

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Vacuum Dump and compressed a i r pump ( 2 ) Oxvgen meter, portable Reducing valves plus pauaes ( 3 ) SUPPLIES Plastic ware. disposable Media and tissue 'culture solutions Comoressed eas e s and minor suuulies ALTERATIONS AND RENOVATIONS

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/Include fees, travel, etc.) TOTAL DIRECT COSTS $ 4 6 , 2 5 2 DIRECT COSTS ONLY (Omit Cents) ADDITIONAL YEARS SUPPORT REQUESTED fThrs applicarron On&’) * Funds to be made available to.Argonne National SEE PAGE 4A FOR DETAIL. TOTAL FOR ENTIRE PROPOSED PROJECTPERIOD lEnrer on Page I, Item 41 - REMAAKS: Justify all cosrs for rhe fin2 year for which the need may nor be obvious For furure yea?& justify rquipmenr cosrs, as well as any

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BUDGET ESTILIATES FOR ALL YEARS OF SUFPORT REQUESTED FROM PUBLIC HEALTH SERVICE Ilncludr fern, mvel, nc.J PATI ENT COSTS Other Expenses - To cover the automobile expenses of travelling to and from the Fermi National Lab and t h e University of Chicago; 100 miles/week a t $0.15 per mile REI MR KS : Jcanfy all costs for ;ha fimt ywr lor which th8 mdmy nor k &viwr For fururn van. junify equipment co~rs,as well LI any s & d fi unt inerysr in any other urcgory. ila raurdw annual /ne- in prronnd ern0 ir tW vr td, givr pnrrntapo. (UII Eonfinu#tion Indirect costs indicated for purposes of this proposal format only. Actual costs will be billed according t o Argonne National Laboratory costing principles

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PRIVACY ACT MATERIAL REMOVED Elkind, Mortimer M. ARGONNE NATIONAL LABORATORY Argonne's costing procedures are based on the assumption that all costs incurred will be recovered. -same basis as work for AEC program activities. the Laboratory on a consistent basis and uses standard rates. are a n average of base wages, fringe costs,divisional program direction,divisional general expenses and Laboratory indirect cost charged to the effort incurred within each scientific division. classification within the Division. revised as necessary. The cost of work for other federal agencies is charged on the The standard rates The procedure is applied throughout A standard rate is developed for each major payroll Standard rates are reviewed periodically and All labor cost is distributed within the Division using the standard rates mentioned above. The fringe costs include payroll related items such as annuities,social security, and hospital and medical payments. and Laboratory Overhead accounts include costs which cannot be charged to a specific program activity directly. Consistent with the procedure for costing work for.AEC, no depreciation or AEC added cost factor is added t o work for other federal agencies. The ANL monthly rates estimated for the year are as follows: The Division General, Program Direction Total Staff Regular $3,956

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PRIVACY ACT MATERIAL REMOVED Indhr klnd of d n and rxpimtion d d YEARINSTITUTION AND LOCATION OEGREE CONFERRED Cooper Union School of Engineering B.M.E. 1943 Polytechnic Institute of Brooklyn M.M.E. 1949 Massachusetts Institute of Technology M.S. 1951 Massachusetts Institute of Technology Ph.D. 1953 01m a t npnwnmdvr pubUat/M Da not ueod 3p l p ~for a chid vi & d I 1973 - Senior Biophysicist, Division of Biological and Medical Research, (Sept. 1971 to Aug. 1973 Guest Scientist, MRC Experimental Radiopathology Unit, 1969 - Senior Scientist, Biology Department, Brookhaven National Laboratory, 1967 - Senior Research Physicist, Laboratory of Physiology, National Cancer Institute, 1954 - Physiclet, Laboratory of Physiology, National Cancer Institute, Bethesda, Maryland. Argonne National Laboratory. Hammersmith Hospital, London, England). Upton, Long Island, New York. Donncr Laboratory, University of California, Berkeley, California. 9 - Physicist, National Cancer Institute, Bethesda, Maryland, on assignment to Massachusetts Institute of Technology. 53 - Physickf, National Cancer Institute, Bethesda, Maryland, on assignment to the 47 - Head, Instrumentation Section, Sloan-Kettering Institute for Cancer Research, Radiobiology, biophysics, cell biology ROLE IN PROPOSED PROJECT

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PRIVACY ACT MATERIAL REMOVED And, Mortimer M. Elkind, M. M. The initial shape of cell survival curves. A summary and review of the Conference, 16-20 September 1974, London, tobe published jointly by the Institute of Physics and John Wiley and Sons. Elkind, M. M. Mechanisms of DNA repair. To appear inthe Proceedings of theXI International Cancer Congress, Excerpta Medica, 20-26 October 1974, Florence, Italy. tion products i n Chinese hamster cells. International Cancer Congress, Excerpta Medica, 20-26 October 1974, Florence, Italy. Cancer Biochem. Biophys. 1,23-32 (1974). cells : relation to enhanced cell killing. the V International Congress of Radiation Research, Seattle, Wash. 14-20 July 1974. gress of Radiation Research. national Congress of Radiation Research, Seattle, Wash. 14-20 July 1974. cultured Chinese hamster cells: enhancement of lethal damage. of DNA Repair, Squaw Valley, Calif., 24 Feb.- 2 Mar. 1974. near ultraviolet light in the presence of 4,5',8-trimethyl-psoralen. EURATOM Report EUR 5122 d-e-f, 1974. To appear inthe Proceedings of theXI relation of DNA damage and repair to survival response. DNA damage and its repair in hyperthermic mammalian To b e published inthe Proceedings of To b e published inthe Proceedings of the V Inter - damage and repair of single-stranded DNA and a DNA complex. inhibition of repair of sub lethal damage and Damage-repair studies of the DNA from X-irradiated Chinese hamster To be published inthe Proceedings of the ICN-UCLA Conference on Mechanisms Ed. by P. Hanawalt and Elkind, M. M. and E. Ben-Hur. DNA damage i n mammalian cells and Its relevance t o Proceedings of t h e Fourth Symposium on Microdosimetry, Verbania-Pallanza Ben-Hur, K. and M. M. Elkind. Psoralen plus near ultraviolet light in activation of cultured hinese hamster cells and its relation to DNA cross-links. on Physical Mechanisms i n Radiation Biology, October 11-15, 1972, Airlie, Virginia. the Conference on Physical Mechanisms i n Radiation Biology, October 11-15, 1972, Elkind, M. M. Cellular radiobiology and particle radiotherapy: principles, presumplkind, M. M. Endpoints and targets in radiobiology. Proceedings of the Conference 0lkind, M. M. An introduction to the biology of the mammalian cell. Proceedings of 4 Airlie, Virginia, published by IAEA, 1972. tions, and pitfalls. Radiation Therapy, O c t . 2-4, 1972, Los Alamos, New Mexico. Lab Conference Proceedings LA-51804 issued March 1973. Proceedings of the Conference on Particle Accelerators in LOS Alamos Scientific

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Int. J. Radiat. Biol. 22, 313-324 (1972). Ben-Hur, E.; B. Bronk, and M. M. Elkind. Thermally enhanced radio een s it iv it y of complex from Chinese hameter cells. cultured Chinese hamster cells. Nature, New Biol 238, 209-210 (1972). DNA lesions and mammalian cell kill in e : cause and Repair of a DNA complex from X-irradiated Chinese labelled Chinese hamster cells exposed to fluorescent light. Elkind, M. M. Recovery, reoxygenation, and a strategy to improve radiotherapy. Proceedings of Conf. on "Biological and Clinical Basis of Tumor Sensitivity " by C. C. Thomas and presented atthe conference organized by theIst it u to Regina E l i n a , Rome, October 7-9, 1971, published by U.S. AEC Conf-721001, 1974. cules and cells. Atomic Energy, Geneva, Sept. 6-16, 1971, published 1974. cells exposed to fluorescent light following 5-bromodeoxyuridine incorporation. Proceedings, IV International Conference on the Peaceful Uses of effect of 5-bromodeoxyuridine in cultured Chinese hamster cells. Radiat. Res., ster cells: evidence fora new form of damage and its repair : =.J. Rad. Biol., Elkidd, M. M. Sedimentation of DNA released from Chinese hamster cells. Biophys. J., 5-bromodeoxyuridine i n Chinese hamster cells: a reduction i n capacity for incurring sub lethal damage. Radiat. &. , 47, 437-449 (1971). cells. a.I V Intern. Congress of Radiation Research, H. Duplan, Editor, Gordon nd Breach Science Publishers, London, 1974. ind, M. M.'. Radiobiological considerations in the applcication of Pi mesons t o 0ind, M. M. Summary of general discussion on radio biological aspects of fast 0eu tron s in radiotherapy. Europ. J. Cancer 7: 249-257 (1971). asynchronous and synchronized Chinese hamster cells. Elkind, M. M. Damage and repair processes relative t o neutron (and charged particle) irradiation.In Current Topics i n Radiation Research, 1,1-44 (1970).

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, MAJOR RESEARCH INTEREST Responses i n mammalian cell cultures ROLE IN PROPOSED PROJECT Supervisor and guidance Indican klnd of vin and oxplmtlon Atel Associate laboratory Director for Biomedical & Environmental Research, Argonne National Laboratory Director, Division of Biological b Medical Research, Argonne National Senior Biophysicist, Division of Biological & Medical Research, Argonne Prof. of Radiology, University of Chicago c+'* Prof. of Physics, The Univ. of Texas Postgrad. School of Med., . Houston &mistant Physicist, Royal Cancer Hospital, London Lecturer, Radiological Physics L Biophysics, Univ. of London Lecturer i n Physics, University of Otago, New Zealand Demonstrator i n Physics, University of New Zealand Assistant Physicist, D.S.I.R., New Zealand, Government 1945 t o 1947 Physicist, Dunedin Hospital,h ned in, New Zealand

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PRIVACY ACT MATER1AL REMOVED Sinclair, W. It. 1969. Radiobiological Dosimetry. Radiation Dosimetzy, Academic Press, The combined effect of hydroxyurea and X-rays on Chinese hamster X-ray survival and DNA synthesis in Chinese hamster cells. I. cells i n vitro. Cancer Research, Vol 28, pp. 190-206. Proc. Nat. Acad. Sci., 58, pp.115-122 hms ter cells during the cell cycle. synchronizing concentrations of hydroxyurea. Cellular and Species Radiosensitivity i n Animals. malignant cell growth. Sinclair, W. K. 1969. X-ray survival of cultured mammalian cells. Conf. on Comparative Differential X-ray protective effect on Chinese X-ray sensitivity of synchronized cells irradiated Cytological effects oh Chinese hamster cells of Methods and criteria of mammalian cell synchrony i n normal and The tadiobiology of cultured mammalian cells. Pi otec tion by cysteamine against lethal X-ray damage during the Springer Verlag, New Pork. pp.90-103. cell cycle of oll nes e hamster cells. Modes of growth i n mammalian cells. Biophys. Sensitivity of synchronized Chinese hamster cells t o ultraviolet light. Biophys. J. 3, pp. 1171-1192. Chinese hamster cells during t h e cell cycle. Taylor and Francis, London, pp. 201-210. chromosomal aberrations inducad by X-rays i n synchronized Chinese hamster cells. Sinclair, W. K: 1969. Dependence of radio sensitivity upon cell age. Conf. on Time Sensitization by hydroxyurea and protection by cysteamine of and Ibse Relationships i n Radiation Biology a s Applied t o Radiotherapy. Camel, Calif. S inc lak, W. K. 1970. Synchronous tissue culture. Laboratory Management, Oct. 1970, The relation of protein synthesis to radiationinduced division delay in Chinese hamster cells. cycle response of mamnalian cells t o X-rays. synchronized Chinese hamster cells. Biophys. J. ll, pp. 540-549. I Ross, D. W. asrd W. K. Sinclair 1972. Cell cycle compartment analysis of Chinese hamster ceJ& i n ' stationary phase cultures. Sinclair, W. E. 1972. Cell cycle dependence of the let hd radiation response i n mammalian cells. ar rent Topics i n Rad. Res. Quarterly z, pp. 264-285. Sl nrl air, W. K. 1972. Sensitivity to. mitotic delay and stage in the cell cycle. Current Topics i n Rad. Res. Quarterly 1,pp. 323-327. of Chinese hamster cells in vitro. Chinese hamster cells. Rad. Res. 55, pp. 41-57. Sinclair, W. K. 1972. Mechanisms of sensitization in cells and cellula r, I models. Review Physical Mechanisms i n Radiation Biol, USAEC Conf.-721001, pp. 288-295, (1974). Sinclair, W. K. 1974. Modification of cell cycle response of. synchronous mammalian call ! to ionizing radiation by inhibition of repair. Proc. Cold Spring Harbor Symp.,pp.985-9' 5th ,Int. Cong. Rad. Res. In press. Advances i n Rad. Res., Biology and Introductory remarks and the role of sylfhydryls inthe cell Han, Antun and W. K. Sinclair 1971. Ultraviolet light induced division delay in.. C e l l and Tissue Kinetics 2,No. 1, pp. 1-1

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PRIVACY ACT MATERIAL REMOVED E-..ind, Mortimer M. t The aim of this research is to initiate an assessment of the radioc ter is tics of the high-LET neutron beam expected t o be generated a i a1 Laboratory using protons a t a peak energy of 67 MeV impinging on a will be the relative biological effectiveness (RBE) and the oxygen enhancement ratio (OER) of single and fraction a ted doses relative to cell survival. permit,the RBE and OER …