In7: Very interesting paper on CTD and SCC.

From: Dianne E. Godar  DEG@CDRH.FDA.GOV
Date: 12/5/97
Time: 11:16:33 PM
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This is a very interesting paper on CTD (cyclobutane pyrimidine dimers) and SCC (squamous cell carcinoma). This was a well planned and executed research endeavor on the part of the authors. It represents quite a lot of work - congradualtions on a very nice piece of work, Frank and Rob! Of course, I have some comments and questions. First, I noticed you stated that p53 is also responsible for the G2 arrest. Are you refering to p53as (alternately spliced form)? Also, although CTD do not lead to mutations (could you please provide a citation for us all here?) it still is a very good indicator of the extent of DNA damage from UVB exposure. Although UVA can also produce CTD, the yiled is low compared to UVB and almost non-existent in the UVA1 waveband region. What do you think would be a good indicator for tumor formation in the UVA1 range? (i.e., for SCC) Since DNA damage correlates with tumor formation and hyperplasia, and since the formation of "sunburn" or apoptotic cells occurs prior to hyperplasia, according to the data of Ley and Applegate, 1985 (JID), do you think the formation of apoptotic cells would be the best indicator in the UVA1 waveband region? And, if so, do you think it may be a good indicator throughout the enitre UV spectrum? (Of course, since UVB induces delayed apoptosis the measurments would have to be made around 36-48 h but at 2-4 h in the UVA1 region, since UVA1 induces immediate apoptosis). I ask this because apoptotic cells are good indicators that DNA damage occurred, and some surviving cells may repair the damage in a sloppy way, leading to mutations, while others may override the apoptotic mechanism and go on to divide, replicating their faulty DNA. Has your group, or any other, ever tried to correlate sunburn cell formation with tumor latency time? I wonder if the equations would be rendered more predictive? If you still have skin samples left from these and other experments they could be analyzed for sunburn cells and we could find out if a correlation exists, and if it is a better predictor for SCC, or just as good so people would then have a choice of endpoints (I guess I'm offering to collaborate, if you like, though I know your group is capable of doing this on their own, i.e., if you think it is a reasonable idea. (Actually, I would just like to know this answer, but if you don't have the time then I could do it) Concerning the FACS analysis, if you have LYSYS II software, there is a double discrimination module hidden away in that program which can be used for cell cycle analysis, but Cell Fit software is better because it has statistical analysis capabilities that are superior. If you do have LYSIS II software, contact me by e-mail and I will direct you to where it is hidden. Concerning risk assessment issues, have you seen the series of papers about human exposures through glass? I believe they are C17, C19 and C23, but I'm not sure that I remeber them all correctly. (Parisi and Wong) These additional exposures were not taken into account in past risk assessments according to the authors (see discussion comments). I just thought you might be interested in their findings and the implications for future risk assessments. Again, congradualtions, and may I request a reprint when they are available. Thank you.

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