SKIN CANCER--IMMUNOTOXIC MECHANISMS

点击翻译按钮获取中文摘要

There is an increasing awareness that the induction of skin cancer is a multistep process requiring both initiating and promoting substances for full development of the malignant tumor. Most strategies examining immunological influences on this process have focused on immune responses to tumors. This, however, represents an investigation of such interactions at a rather late stage in the pathway. The objective of this proposal will be to examine immunological influences on skin carcinogenesis at an early stage in the pathway. This will be accomplished by inducing a contact dermatitis reaction in mice to two polyaromatic hydrocarbons, 7,12- dimethylbenz(a)anthracene (DMBA) and benzo(a)pyrene (BP). These compounds have been widely employed to investigate mechanisms of skin cancer formation. Animals will be immunized to these agents by epicutaneous application of the compound. Five days later the response will be elicited by challenging their ears with the sensitizing compound and measuring the subsequent ear swelling response. Using this model system, participation of the Ah locus in contact hypersensitivity responses both in strains of mice with high an with low affinity Ah receptors. The role of cytochrome P450 dependent enzyme metabolism in induction of contact hypersensitivity to these agents will be assessed by pre-treating animals with pharmacologic agents which induce or inhibit cytochrome P450 activity. Also, various carcinogenic and non- carcinogenic metabolites of BP and non-carcinogenic PAH analogues will be tested for their immunogenicity by determining their ability to initiate and elicit contact hypersensitivity responses. Attempts will be made to induce immunological tolerance to DMBA and BP by utilizing methods of tolerance induction which have been successfully employed for other antigens. DMBA and BP-specific T cell clones will be developed to more fully evaluate the influence of antigen specific T lymphocytes on the tumorigenic activity of these compounds. Finally, the influence of contact immunization to DMBA and BP on the induction of tumors by these agents will be examined in skin carcinogenesis experiments. Knowledge obtained from these studies may help to define the influence of cell-mediated immunity on skin carcinogenesis and may offer new immunodermatologic approaches for the prevention and therapy of this type of skin cancer.