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TIn; Cacl.cU~. Tult Tui;ncco RiaL,u;cn-L'.S.A., INC. t June 28, 1973 MFMOFZANDUM TO: Drs. Andervont, Hockett, Nordsiek and Sommers FROM: W. U. Gardner H h+0089209~ SUBJPiCT: Application 915. Edward Bresnick, Medical College of Georgia, Augusta. "Synthesis, Interactior vith DNA, and Inactivation of the Epoxide of 3MC in Lung." I've known of Bresnick's work for some years while he was at Baylor and j know the Drs. Liebelts. This applications seems to be essentially a means of using the talents of Dr. Stoming, a recent Ph.D. (1972 Pi:rdue,- Synthetic Medicinal Chemistry) and the inbred mice mpintained by Dr. %.iebelt to work on the AHH system of enzymes. They have 17 inbred strains that differ greatly in susceptibility to methyl.cholanthrene (MCA) induced cancers. The idea will be to select strains susceptible to MCA (Balb, NH, A, CBA) and those resistant to MCA (CS7B1 and .AKR), and th ose moderately susceptible (BA, C3H, FB, Is ano Y8R) and determining in the lung microsomal fractions the levels of 3MC enoxide hydrase. The epoxide hydrase assay depends on the separation of trimethy]sily] (TMS) derivative of the trans-diol. This is a new method in uress at writing. Gas chromatography is required. Three derivatives of the TMS ti•eated. MCA epoxide have been identified and expressed in terms of "methylene utr:its." This work was apparently done on liver microsomes. The liver microsomal reaction was linear for 10 minutes. Liver was most active, kidney about 1/4 as active and lung 1/20 as active. A compound (TCPO) inhibited the formation of the diol. 3MC epoxide synthetase activity will also be determined. Again the finall product5 will be determinted by gas chromatography. Both synthetase and - hydrase activity will be determined. (How many mice may be required to be donors of lung tissue? on what data are the figures for differences in MCA susceptibility based? The applicant should supply this data.) Other AHH inducers -P -naphthoflavone, phenobarbetol and pregnenolone-16 q carbonitrile will also be studied. The work of Cleaver on endonuclea:.Fs will also be studycd. This is BreSnick"s major area of interest. This will be used to study strain d.fferences in endonuclease activity. Repair mechanisms will be determined in lung tissue by determining DNA repair synthesis by thymidin uptaken in fetal lung explants exposed to MCA in the presence of hydroxyurea (which prevents all new DNA synthesis but not repair of broken chromatin strands. They will also use the same on human fihroblasts in culture. This would be classed as a"oredisoosition to cancer" study. It has nothing to do with smoke or a cigarette-derived carcinogen. It combines people with threc different talents in an area of interest. Tt cc+mrlimentc and supplements the MAI study. Note: I doubt the report on paae 5 of application form. I:uould thin.: it important enough for a site visit. W.Y1.G. WUG:ck