sample="quota" bates="2063621826" isource="pm" decade="1990" class="ni" date="19980128" 29 01 98 11 17 FAX 41328887776 SA Neuchatel CARCHMAN R. PM 001 PHILIP MORROIS EUROPE SCIENTIFIC AFFAIRS EU/EEMA REGIONS CH-2003 NEUCHATEL / SWITZERLAND FACSIMILE TRANSMISSION CALL NO. 41- 32- 888 77 76 To: Dr. R. Carchman Date: January 28, 1998 Company: WSA, PM USA Fax No: From: A. Tricker Copies: NUMBER OF PAGES (INCL. THIS PAGE): 45 IF NOT PROPERLY RECEIVED, CALL 41-32-8887631 Re: Munich studies Dear Richard, I was in Munich visiting Richter on Monday and Tuesday this week. The following is a brief update on the current situation: Publication of result: We shall start writing a manuscript for submission to Carcinogenesis on NNK metabolism in lung tissues. A second manuscript will follow for metabolism of NNK in liver tissues. We both feel the two data sets should be published separately. Lung tissue metabolism: We now have data from five different human donors (Figs 1-3). Kinetic analysis of individual tissue samples and means of all data combined clearly shows that NNAL formation predominates and that -hydroxylation to methylating species (keto acid) is unfavorable at NNK substrate concentrations less than 30 µM. The combined data (Fig. 1) is also presented with 'curve fitting' (Fig 2). At very low substrate concentrations (0.01-1.0 µM NNK) it is clearly evident that -hydroxylation to keto acid is not a significant pathway for NNK metabolism (Fig 3). Inspection of data from individual tissue samples indicates a highly variable capacity to convert NNK to NNAL, as evident from the mean±SEM bars. We are going to extend the present data set to 8 different tissues instead of 5 as originally planned. The only published study to investigate human lung tissue metabolism used a single tissue sample with 238 µM NNK incubated for 24 h - clearly not very informative. Liver tissue metabolism: We are still having difficulties obtaining 'healthy' human tissues. The last tissue samples were clearly yellow fatty cirrhotic waste, and were not used. Extension of study: Although not originally planned, I have asked Richter to extend the program to include the SG hamster. My reasons for this are the unpublished negative NNAL bioassay by Hecht and Liginsky, and a similar negative study published by a Japanese working troup. If I have something to put on the table and into the planned Gorrod monograph, maybe I can tease the data out of Hecht. Labeled NNAL: We are waiting for delivery of the labeled compound from the US in order to complete the study. Tissue bank: Since we can obtain 20-30 different human lung tissues per week with sufficient donor data (sex, age, diagnosis etc.), I have asked Richter to establish a frozen tissue data bank. In summary, I am still very happy with the progress being made. Knowing what is currently in the published-literature,-we have made a significant contribution to understanding the science in this very controversial and speculative field of research Best regards, multipack/day Smoker intake ~1000 than 20 µM Fig 1. Keto acid derived from -hydroxylation of NNK Diol derived from -hydroxylation of NNAL but not reported to result in adduct formation HPB derived from -hydroxylation of NNK and NNN. Fig 2. Fig 3. only determined with one tissue sample. When we have more data we could blow-up to region from 10-200nM NNK (7 points on curve). ohlemeyer (5HB) Richard: use information from Walker regarding in 20 and its prevalence in lung cancer