The hypotheses to be experimentally explored In this project state that immunoenhancers which decrease UVB-induced immunosuppression, or agents which induce excision repair of precancerous DNA photoproducts, can prevent photocarcinogenesis.
The specific aims to approach these hypotheses include: 1) to evaluate the capacity of topical difluoromethylornithine (DFMO), topical alpha-tocopherol succinate, nicotinamide (vitamin b5), m-galloylgallic acid (tannic acid), epigallocatechin gallate, and vanillin to reduce tumor number, size, or incidence induced in mice by UVB irradiation; 2) to evaluate the capacity and mechanisms of these same test agents to decrease UV-induced immunosuppression in UVB irradiated mice; and 3) to evaluate the capacity of these test agents to influence the levels of UV induced mutagenic DNA lesions in epidermis of UV irradiated mice. In the first specific aim, small numbers of mice (10) will be used to determine a nontoxic dose range in UVB irradiated mice and the optimal route to achieve an estimate of prevention of photocarcinogenesis. The most promising agents will be tested in a larger sample size (45 mice/group) to obtain an accurate measure of cancer prevention.
in specific aim 2, UV induced immunosuppression will be assessed by the ability of splenocytes from UV irradiated mice to transfer the suppressor phenotype to naive mice. Resistance of UV irradiated mice to a syngeneic, antigenic, UV induced tumor will also be assessed. To study mechanisms of prevention of UV induced immunosuppression, the leukocyte phenotypes in, and lymphokine secretion by, tumor-draining lymph node cells and tumors will be evaluated in UV irradiated mice exposed to the test agents. Leukocyte phenotypes will be determined by flow cytometry, using antibodies reactive with leukocyte differentiation or activation antigens: Lyt-2 (CD8), L3T4 (CD4), Mac-1, IL-2R, mouse Ig kappa and lambda chains (B cells) and, MHC II (Ia). Lymphokines to be measured by enzyme-linked immunosorbent assays (ELISA) include Interleukins-4, -10, -2, and interferon-gamma.
In specific aim 3, the levels of cyclobutane dimers and of 6-4 photoproducts In dorsal epidermal DNA after UVB irradiation In chemopreventive treated and untreated mice will be measured by radioimmunoassay. By assessing the relative contributions of different host defense mechanisms new strategies for Intervention by chemoprevention can be designed.
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