UVR-INDUCED SYSTEMIC EFFECTS AND MELANOMA INDUCTION

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Skin and eyes are the only organs of the body that are exposed directly to solar ultraviolet radiation (UVR). Sunlight causes many adverse effects which include cancers of the skin and a reduced visual acuity. The prospect of stratospheric ozone depletion and the accompanying increase in human exposure to UVR makes it imperative that we understand the detrimental effects of acute and chronic exposure to UVR. Because systemic effects which include immune suppression are involved in UVR- induced carcinogenesis, it is of considerable interest to delineate the extent to which systemic effects may be a factor in the carcinogenic process. The marsupial Monodelphis domestica is an experimental animal model uniquely suited for these studies because: 1) this animal, unlike rodents, has been shown to be susceptible to UVR-induced melanoma; 2) low cutaneous doses of UVR induce systemic effects in the form of immune suppression and enhanced susceptibility to UVR-induced corneal tumors; and, 3) the photoreactivation repair pathway active in M domestica, but not in rodents, can be used to study the role of pyrimidine dimers in DNA in UVR-induced cancer and systemic effects. Recent studies with M domestica showed that UVR-induced systemic effects significantly accelerated the appearance of UVR-induced corneal tumors. Furthermore, photoreactivation studies have shown that UVR-induced cutaneous and/or corneal DNA damage are involved in the induction of corneal tumors. The studies proposed herein will: 1) determine dose- response relationships for the capacity of cutaneous UVR exposures to accelerate the appearance of UVR-induced corneal tumors in M domestica; 2) determine whether UVR-induced local and systemic effects will alter the progression of chemically-induced melanocytic lesions to frank melanotic tumors; and, 3) determine with the photorepair pathway found in marsupials the relative importance of pyrimidine dimers in cutaneous and corneal DNA on the time to appearance of UVR-induced corneal cancers. These proposed studies will aid in elucidating a multi-faceted role for DNA damage in the carcinogenic process.