In situ molecular dosimetry and tumor risk: UV-induced DNA damage and tumor latency time.
In UV carcinogenesis there is a fundamental chain of causal events from UV-induced DNA damage through mutations up to tumor formation: each of the early events should be predictive of the ultimate tumor risk. Instead of the UV surface exposure, the in situ load of DNA damage should be a more direct measure of the carcinogenicity. To explore this further we measured cyclobutane thymine dimer loads of epidermal cell suspensions from chronically UV-exposed hairless SKH-1 mice; 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, the amount of thymine dimers in a column of epidermis (i.e. per mm2 of skin area) became stationary, and this amount increased with higher daily exposure. The median tumor latency time, t50, is inversely related to this stationary load. Extrapolation of a fitted relationship would imply a t50 between 450 and 1430 days for spontaneous skin carcinomas. The present data suggest that the skin strives to maintain a maximum level of tolerable DNA damage by lowering the average genotoxic load in vital cells in a hyperplastic reaction: pseudo-repair by dilution. This would also explain the strong hyperplastic reactions in DNA repair-deficient mouse strains. An understanding of these short-term adaptive reactions can refine our assessments of skin cancer risks in humans.
de Gruijl
F R
FR
Dermatology, University Hospital/AZU, Utrecht University, The Netherlands. F.deGruijl@DIGD.AZU.NL
Berg
R J
RJ
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects; D002478:Cells, Cultured; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D004817:Epidermis / Q000473:pathology / Q000528:radiation effects*; D005260:Female; D006965:Hyperplasia; D051379:Mice; D008812:Mice, Hairless; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000473:pathology; D011740:Pyrimidine Dimers / Q000032:analysis; D012867:Skin / Q000473:pathology / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000209:etiology* / Q000473:pathology; D013997:Time Factors; D014466:Ultraviolet Rays / Q000009:adverse effects*
D011740:Pyrimidine Dimers; D004247:DNA