UVR-INDUCED SYSTEMIC EFFECTS AND MELANOMA INDUCTION

皮肤和眼睛是身体唯一直接暴露的器官 太阳紫外线辐射(UVR)。阳光会导致许多不良反应 影响，包括皮肤癌和视力下降。 平流层臭氧消耗的前景及伴随而来的 人类暴露在紫外线下的增加使得我们必须了解 急性和长期暴露在紫外线照射下的有害影响。因为 包括免疫抑制在内的全身效应参与了UVR- 诱导的致癌作用，它是相当有意义的描绘 全身影响可能是致癌因素的程度 进程。家养有袋单胞虫是一种实验动物 唯一适合这些研究的模型是因为：1)这种动物不同于 啮齿动物，已被证明对紫外线诱导的黑色素瘤敏感；2)低 皮肤剂量的UVR以免疫的形式诱导全身效应 抑制和增强对UVR诱导的角膜肿瘤的敏感性； 以及，3)家蝇中活跃的光复活修复途径，但 在啮齿类动物中不存在，可用于研究嘧啶二聚体在DNA中的作用 紫外线诱导的癌症和全身效应。 最近对家蝇的研究表明，紫外线诱导的全身效应 显著加速UVR诱导的角膜肿瘤的出现。 此外，光复活研究表明，紫外线诱导的 皮肤和/或角膜的DNA损伤参与了 角膜肿瘤。这里提出的研究将：1)确定剂量- 皮肤紫外线照射能力的反应关系 加速紫外光诱导的家蝇角膜肿瘤的出现； 2)确定紫外线照射引起的局部和全身影响是否会改变 化学诱导的黑素细胞病变进展为FRANK 黑色素性肿瘤；以及，3)根据已发现的光修复途径确定 有袋类动物皮肤中嘧啶二聚体的相对重要性 和角膜DNA对UVR诱导的角膜癌出现时间的影响。 这些拟议的研究将有助于阐明 致癌过程中的DNA损伤。

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.