Standardized protocols for photocarcinogenesis safety testing

Abstract

Solar ultraviolet radiation (UVR) is recognized as a major cause of non-melanoma skin cancer in man. Skin cancer occurs most frequently in the most heavily exposed areas and correlates with degree of outdoor exposure. The incidence of skin cancer is also increased by contact with photosensitizing drugs and chemicals such as psoralens, coal tars and petroleum stocks. Other substances which do not act as photosensitizers, such as immunosuppressants taken by organ transplant recipients, also increase the risk of skin cancer. The U.S. Food and Drug Administration requests, on a case-by-case basis, that risk of enhanced photocarcinogenesis is assessed for many classes of drugs. Health Canada's Therapeutic Products Programme has issued a Notice of Intent to regulate pharmaceutical products which may enhance carcinogenicity of the skin induced by ultraviolet radiation. Other national regulatory agencies review such data when they exist, but their own requirements emphasize batteries of short-term in vitro and in vivo tests. While they may support drug development strategies, short-term tests have yet to be validated as predictors of the ability of drugs or chemicals to enhance photocarcinogenesis. Published protocols now describe study designs and procedures capable of determining whether test agents enhance the rate of formation of UVR-induced skin tumors.

UV-induced photochemistry of methyl coumalate (methyl 2-pyrone-5-carboxylate) isolated in low-temperature inert matrices

“…a-Pyrone is an important sub-unit of psoralen. Psoralen has a potential to increase skin pigmentation [5,6], moreover, in combination with UV irradiation it has been used over decades in the treatment of psoriasis and other dermatoses [7][8][9][10][11]. Thus, the knowledge of the UV-induced photochemistry of a-pyrone and substituted a-pyrones may shed some light on the mechanisms of their biological activity.…”

Neonatal mice do not have increased sensitivity to induction of squamous cell carcinomas

“…Human tan is limited to epidermis, but in mice, the melanocytes reside dermally and in follicles so the tan is dermal, or at least starts in the dermis. Rodent response to UVR is similar to human response . The predominant type of UVB‐mediated deoxyribonucleic acid damage includes cyclobutane pyrimidine dimers and 6‐4 photoproducts, which occur in both human and rodent cells .…”

Topical nutlin‐3a does not decrease photocarcinogenesis induced by simulated solar radiation in hairless mice

“…Hairless mice constitute an internationally accepted model for the investigation of the photocarcinogenicity of topical drugs (20) and thereby also the possible photoprotective effects of topical drugs. Mice and humans have a similar response to UVR (21)(22)(23).…”