The skin is a major interface between the body and the environment and as a consequence of its direct exposure to exogenous chemical and physical oncogenic agents is at considerable risk for the development of cancer. In fact of all the cancers diagnosed annually in the United States 1/3 originate in the skin. Among the clearly defined oncogens in the environment are solar UV radiation and polyaromatic hydrocarbons (PAH). The PAH are generated whenever organic substances, among them fossil fuels, are combusted. Despite the knowledge that both UV and the PAH are carcinogenic in skin the combination of these modalities have been used by dermatologists in the management of psoriasis, a human skin disease, since the early part of the twentieth century. Known as the Goeckerman regimen, this modality encompasses UV radiation and crude coal tar and remains one of the most widely used methods for managing psoriasis. In general it has been thought that patients receiving intermittent courses of Goeckerman therapy have little or no enhanced risk of devloping skin cancer. However, recent epidemiologic studies clearly indicate that individuals who receive multiple courses of Goeckerman therapy are at increased risk for skin cancer as compared to age- and sex-matched control populations. The studies to be conducted in this proposal are designed to obtain new knowledge regarding the mechanism whereby UV radiation and crude coal tar interact in inducing malignant changes. It is planned to utilize artificial light sources and coal tar preparations identical to those used in the Goeckerman regimen for these studies. In vitro assay procedures that are currently considered to be markers for events that occur in the in vivo induction of cancer will be correlated with classical tumor induction studies using UV radiation and coal tar. The in vitro procedures include measurement of enzymes such as aryl hydrocarbon hydroxylase, 7-ethoxy coumarin deethylase, epoxide hydrolase, glutathione S-transferase and ornithine decarboxylase, analysis of the patterns of PAH metabolism using HPLC and dtection of the enzyme-mediated binding of isotopically labelled PAH to DNA. Finally in collaboration with Dr. I.B. Weinstein it is planned to probe for carcinogen-DNA adducts using an ELISA assay and monoclonal antibodies to the adducts in the skin and circulating mononuclear cells of experimental animals and in selected patients undergoing Goeckerman therapy for psoriasis. The long range goal of these studies is to more precisely define the oncogenic risk of exposure to UV radiation and coal tar products by analyzing the mechanism of interaction of these two distinct cutaneous carcinogens.
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