Relevance of Animal Models of Photocarcinogenesis to Humans

Abstract

Relevance of Animal Models of Photocarcinogenesis to Humans P. Donald ForbesArgus Research Laboratories, Inc.,* Horsham, PA, USA Ultraviolet radiation is a natural and variable component of our environment; its one unambiguous benefit is the vitamin D, production that it stimulates. Ultraviolet radiation is better known for the several types of skin damage it causes, including the production of skin tumors. Evaluating benefits and risks may thus be considered essential to the life of a cutaneous photobiologist. Like most organisms exposed to solar UV radiation, humans have an assortment of mechanisms that function to offer protection or to repair damage caused by UV radiation. Mechanisms for the production of damage, as well as for protection and repair, would be poorly understood were it not for the availability of laboratory animal models in research.This essay, along with others in the symposium proceedings, addresses the relevance of photocarcinogenesis research models to the human situation. To set the stage, we begin by considering the characteristics of the material selected for laboratory studies and the designs of such studies, whether for basic research or for purposes of regulatory submission. Mouse modelsAmong laboratory mammals, mice are particularly suitable for toxicology studies because they are prolific, and because their size facilitates their use in numbers appropriate for statistical power. Mice are thus the most used animals in experimental carcinogenesis. Their dense fur is, however, a disadvantage for photocarcinogenesis studies. The earliest laboratory studies on photocarcinogenesis depended on the exposure of repeatedly depilated skin, or of the more sparsely haired areas such as ears and extremities (1). The tumors that were produced included many that exhibited malignant $Argus Research Laboratories, Inc., is a member of the Genzyme Transgenics, Corp. family of companies.criteria but few that were morphologically similar to those found in human skin damaged by UV radiation. In addition, removing the hair in order to expose the underlying skin introduced an unmeasured stirnulatory effect on cell turnover, along with other confounding effects. The discovery of UV-induced squamous cell tumors in genetically hairless mice (23) was thus a pivotal laboratory finding.Genetically hairless mice had been known among mouse fanciers for the better part of a century, and the heritable characteristics of one recessive allele in particular (hrlhr) were described in detail in the 1920s (4). By the 1950s, breeding studies had resulted in the availability of this allele in a diversity of mouse stocks and strains, housed in universities, government laboratories, and research foundations (5). In general, the hairless stocks and strains were characterized by small litters and relatively inefficient output of the desired hairless phenotype (typically, heterozygous haired dams were used because the homozygous hairless dams successfully raised very few offspring). Exceptions to this rule were the animals repo...

Topical pimecrolimus and tacrolimus do not accelerate photocarcinogenesis in hairless mice after UVA or simulated solar radiation

“…However, there was no difference or even protective effect in the median time to onset of skin tumor formation for the 1% formulations compared with the vehicle, indicating that increased tumor formation was caused by the vehicle alone (3,24). Vehicles might reduce random ‘light scatter’ in the stratum corneum resulting in greater transmission to the deeper target tissues (11). We did not test the vehicle in our study because we were interested in testing the commerciel formulation that patients use.…”

Proliferative and Non-Proliferative Lesions of the Rat and Mouse Integument

“…Although there are in vitro test systems to determine the general reactivity of a chemical with UV light, in vivo testing in hairless mice may still be necessary. This is particularly true when testing the potential for carcinogenesis due to a chemical in association with ultraviolet light ('photocarcinogenesis') ( 36 Forbes, 1996). Histologically, ultraviolet light-induced skin lesions are not distinguishable from other toxic skin changes.…”

Inhibition of AP-1 and MAPK signaling and activation of Nrf2/ARE pathway by quercitrin

“…Ultraviolet B (UVB), as a tumor initiator, is the most frequently used photocarcinogen in animal studies (19)(20)(21). 12-O-tetradecanolyphorbol-13-acetate (TPA) is used as a promoter in skin tumor development in mice (21).…”