Tobacco Documents Online

Till'; COU~'CIL FoR TOBACCO RI-~SE,%RCll-U.~¢"~.,[., INc. June 28, 19'73 MEMORANDUM TO: DrS. Andervont, Hockett, Nordsiek and Sommers FROM: W.O. Gardner SUBJECT: Application 915. Edward Bresnick, Medical College of Georgia, Augusta. "Synthesis, Interaction With 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 ] Know the Drs. Liebelts. This applications seems to be essentially a meahs of using the talents of Dr. Stoming, a recent Ph.D. (]972 Purdue - Synthetic Medicinal Ch%mistry) and the inbred mice maintained by Dr. Liebelt to work on the AHH system of enzymes. They have 17 i~bred strains that differ greatly in susceptibility to methylcholanthrene (MCA) induced cancers. The idea will be to select strains susceptible to MCA iBalb, NH, A, CBA) and those resistant to McA (C57BI and AKR), and those moderately susceptible (BA, C3H, FB, Is and YBR) and determining in the lung microsomal fractions the levels of 3MC epoxide hydrase. The epoxide hydrase assay depends on the separation of trimethylsilyl (TMS) derivative of the trans-diol. This is a new method in press at writing. Gas chromatography is required. Three derivatives of the TMS treated. MCA epoxide have been identified and expressed in terms of "methylene units." This work was apparently done on liver ~crosomes. The liver microsoma] reaction was linear for i0 minutes. Liver was most active, kidney about I/4 as activ~ and lung 1/20 as active. A compound (TCP0) inhibited the formation of the diol. 3MC epoxide synthetase activity will also be determined. Again the ~ final products will be determinted.by gas chromatography. Both synthetase and - hydrase activity will be determined. (How many m~ce 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 - ~ -n~phthoflavone, phenobarbetol and pregnenolone'16 ~ carbonitrile wil~ a~so be studied. Th~ work of Cleaver on endonucleases will also be studied. This is Bresnick"s major area of interest. This will be used to study strain differences in endonuclease activity. Repair mechanisms wi:l be determihed Jn lung tissue by determining DNA repair synthesis by thymidin uptaken in fetal lung explants exposed to MCA in th~ presence Of hydroxyurea (which prevents all hey n[~A synthesis but not repair of broken chromatin strands. They wi~l also use the same on human fJbroblasts in culture. This would be classed as a "predzsposition to cancer" study. It has nothing to dO with smoke or a cigarette-derived c~rcinogen. It combines people with three different talents in an area of ~n~erest. It compliments and s~]ements the MAI study. ::or6. ~ doubt the report on pagc ~ ef ~pT~tion form. it important enough for a s~te visit. would think WUG:ek W.U.G.