The influence of a number of chemotherapeutic agents on the development of UV-induced squamous cell carcinomas and malignant melanomas and the possible mechanisms of these effects will be evaluated in the hairless mouse model. The squamous cell carcinoma was chosen because its etiology, structure and development closely simulate human skin cancer formation. The malignant melanoma was selected because circumstantial evidence suggests that the progressively increasing incidence of this cancer in humans is associated with sun exposure. The primary carcinogenic stimuli will be UVB energy and 8-methoxypsoralen (8-MOP) plus UVA radiation. A hot quartz contact lamp will be the radiation source associated with sun exposure. Specifically, the cancer will be induced by Uv radiation from a hot quartz contact source. The chemicals to be studied will include anticancer drugs, modulators, antiinflammatory medications, depigmenting chemicals and photoactive and photoprotective agents which are used topically and/or systemically for prolonged periods in chronic human diseases. The formation and growth of the experimental tumors will be monitored. In addition, acute and chronic effects of these chemicals with and without Uv irradiation on DNA synthesis, UV- damaged DNA, and mitosis formation, will be evaluated using autoradiographic and colcemid mitoses arrest techniques. Their influence on melanocyte function in normal, UV-stimulated, chemical carcinogen-stimulated and melanoma tissue in vivo will be examined by microscopic and dopa staining procedures. Plasminogen activator and proteinase inhibitor activities will also be studied in the tissues by immunochemical and biochemical procedures. In addition to defining the above noted experimental parameters, analysis of DNA damage and repair events during early stages of skin exposure and modifications of certain cellular proto-oncogenes in developed tumors will permit further understanding of the processes of skin carcinogenesis and the potential for intervention in the process. Certain chemicals such as the nitrosoureas and nitrogen mustard and 8-MOP plus ultraviolet A radiation which accelerate UV-induced squamous cell carcnoma formation are also potent stimulators of melanogenesis and melanocyte proliferation. Antioxidants such as 4-tertiary butyl catechol, which can inhibit UV-induced squamous cell carcinoma formation, can transform eumelanogenesis to pheomelanogenesis in melanocytes in vivo. The influence of these chemicals on UV-- induced melanoma formation will be evaluated.
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