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## C26 From: Dianne E. Godar, DEG@CDRH.FDA.GOV Date: 11/25/97 Time: 9:58:00 PM Remote Name: 150.148.47.70 ### Comments This is an interesting paper that shows UVA radiation induces immediate apoptosis (<6 h) and that PUVA induces delayed apoptosis (>6 h) of human epidermoid cells. These findings add yet another cell type to the list of cells already reported to undergo immediate preprogrammed apoptosis by UVA1 radiaiton. Godar et al, demonstrated that two different mechanisms of apoptosis are induced by different irraditions procedures, i.e., UVA1 induces prepprogrammed immediate apoptosis while UVB and UVC (and PUVA; unpublished findings) irradiation procedures induce programmed cell death or delayed apoptosis in L5178Y-R mouse lymphoma cells. Tyrrell's group demonstrated UVA1 radiation induces immediate apoptosis of Rat fibroblasts. These findings are important in helping to demonstrate that these two mechanisms apply to a variety of different cell types, including those in the skin, and so are probably universal (except for p53 -/- and other mutated cell types). However, I have two problems with the paper. First, there is no survival data presented, which is very important for determining which mechansim of apoptosis is induced by reasonable dose levels (physiologically or therapeutically relevant). This is critical because very high doses of UVC or UVB and even PUVA treatment can result in immediate apoptosis. We see this at very high doses in our cell line as well (and others). Second, the authors state that there is a biphasic response demonstrated in figures 2 and 3, but I do not see two peaks or anything that resembles another peak. There are no error bars to determine whether or not a rise is significant and the later rise after some treatments appears to be due to background apoptosis, i.e., if the sham-exposed values are subtracted from the exposed then there would only be one peak. I believe the authors mean biphasic in the kinetic sense, but they may be reffering to biphaisc in the mechanistic sense. Could the authors please clear this point up for the readers, and if a biphasic response is present show error bars to support this statement or make a statemnt about the error present in their system. This could be a very important finding, because it may support a dual mechanism for UVA, i.e., immediate and delayed apoptosis, which may have relevance in the induction of certain types of cancers, such as SCC. Thank you. Back to the list of comments