IN SITU MOLECULAR DOSIMETRY AND TUMOR RISK: UV-INDUCED DNA DAMAGE AND TUMOR LATENCY TIME Frank R. de Gruijl* and Rob J.W. Berg. Dermatology, University Hospital/AZU, Utrecht University, PO Box 85500, NL-3508 GA Utrecht, the Netherlands. Abstract- The quantitative relationships between the level of DNA damage, mutations and tumors can best be studied in an animal model. Such a model, e.g. with transgenic mice, can be instrumental in validating certain potential biomarkers of risk. From this perspective the mutagenic route in UV carcinogenesis is overviewed, with special focus on new experimental data on what may be considered as the 'input' to UV carcinogenesis -- i.e., the level of UV-induced DNA damage -- and the 'output'-- i.e., the ultimate formation of skin carcinomas. Hairless SKH-1 mice will develop skin tumors in the course of a regimen of daily UV exposures, and the relationship between the tumor latency time and the daily UV dose is well determined. Instead of the UV surface exposure, the in situ load of DNA damage should be a more direct measure of the carcinogenicity. To this end, cyclobutane thymine dimer loads were measured in epidermal cell suspensions by immuno-fluorescent flow cytometry; skin samples were taken after various time periods under different daily exposures. Although the average load per cell decreased in the course of time due to dilution of damage in an increasing epidermal hyperplasia, it was found that amount of thymine dimers in a 'column of epidermis' (i.e. per mm2 of skin area) became stationary, and that this amount increased with higher daily exposure. The median tumor latency time, t50, is inversely related to this stationary load, L, of thymine dimers: an empirical formula fits the data, and states that the sum of the UVB-induced DNA damage (taken to be proportional to L) and a background level (taken as a background per cell times the average number of cells) integrated over time (i.e. times t50) upto the point of tumor formation is constant. If this formula holds true, carcinoma should develop spontaneously (i.e., without UV) with a median latency time between 500 and 1400 days; with an average life span of 600-700 days for the mice, this cannot be definitely confirmed or denied with the present data. Clearly, further improvement of our understanding of the relationship between UV-induced DNA damage and subsequent tumor formation can refine our risk models.

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