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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA015605-14
Application #
3164223
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1977-08-01
Project End
1993-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
14
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Epstein, J H; Cleaver, J E (1992) 3-Aminobenzamide can act as a cocarcinogen for ultraviolet light-induced carcinogenesis in mouse skin. Cancer Res 52:4053-4
Mitchell, D L; Jen, J; Cleaver, J E (1992) Sequence specificity of cyclobutane pyrimidine dimers in DNA treated with solar (ultraviolet B) radiation. Nucleic Acids Res 20:225-9
Epstein, J H (1992) Experimental models for primary melanoma. Photodermatol Photoimmunol Photomed 9:91-8
Stefanini, M; Collins, A R; Riboni, R et al. (1991) Novel Chinese hamster ultraviolet-sensitive mutants for excision repair form complementation groups 9 and 10. Cancer Res 51:3965-71
Mitchell, D L; Hartman, P S (1990) The regulation of DNA repair during development. Bioessays 12:74-9
Mitchell, D L; Nguyen, T D; Cleaver, J E (1990) Nonrandom induction of pyrimidine-pyrimidone (6-4) photoproducts in ultraviolet-irradiated human chromatin. J Biol Chem 265:5353-6
Mitchell, D L; Applegate, L A; Nairn, R S et al. (1990) Photoreactivation of cyclobutane dimers and (6-4) photoproducts in the epidermis of the marsupial, Monodelphis domestica. Photochem Photobiol 51:653-8
Mitchell, D L; Cleaver, J E; Epstein, J H (1990) Repair of pyrimidine(6-4)pyrimidone photoproducts in mouse skin. J Invest Dermatol 95:55-9
Alidina, R; Kikuchi, M; Kashima, M et al. (1988) Cysteine protease and its inhibitor in experimentally produced squamous cell carcinomas in hairless mouse skin. Exp Mol Pathol 49:118-27
Epstein, J H (1988) Photocarcinogenesis promotion studies with benzoyl peroxide (BPO) and croton oil. J Invest Dermatol 91:114-6

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