Skin cancer is the most prevalent form of human neoplasia. It is estimated that that 1 in 5 Americans will be diagnosed with non-melanoma skin cancer during their lifetime; the lifetime risk for invasive melanoma is estimated to be 1 in 67. The annual cost for care and treatment of skin cancer in the United States is estimated to be in excess of 29 billion dollars. The environmental agent most responsible for skin cancer induction is the ultraviolet (UV) radiation found in sunlight. In addition to being a complete carcinogen, UV radiation is also immune suppressive, and numerous studies using both experimental animals and biopsy-proven skin cancer patients have demonstrated that the immune suppression induced by UV radiation is a major risk factor for non-melanoma skin cancer induction. Recent studies on the mechanisms underlying UV-induced immune suppression have uncovered two important facts. First, is the role of the keratinocyte-derived lipid mediator of inflammation, platelet-activating factor (PAF) in UV induced immune suppression. Second, is the realization that cis-urocanic acid (c/s-UCA) mediates immune suppression by binding to the serotonin (5HT2A) receptor. Data to support the role of PAF and serotonin receptor binding comes primarily from studies in which selective receptor antagonists were used to block UV-induced immune suppression. Because of the close link between UV-induced carcinogenesis and UV-induced immune suppression, we propose that serotonin and PAF receptor antagonists would serve as ideal agents to block sunlight-induced skin cancer formation. The focus of this proposal is to test that hypothesis.
Two specific aims will be examined to support the hypothesis. First, the mechanism(s) through which PAF and serotonin receptor binding activates immune suppression will be studied in detail. Second, we will test, using an animal model of photocarcinogenesis, the ability of PAF and serotonin receptor antagonists, either alone or in combination, to block UV-induced skin cancer induction. The long-term goal of research performed in my laboratory is to determine the mechanism(s) underlying UV induced immune suppression in the hope of designing rational treatments to ameliorate immune suppression, thus reducing a major risk factor for sunlight-induced skin carcinogenesis. Small molecular weight PAF and serotonin receptor antagonists may prove to be ideal agents to accomplish this goal. PAF receptor antagonists have been used in the clinic to treat sepsis, and serotonin receptor (5HT2A) antagonists have been used as anli-psychotics and antidepressants. Both are relatively well tolerated. Moreover, both block UV-induced immune suppression and inflammation, a process essential for the development of skin cancer. The focus of the studies presented here is to provide evidence to support the hypothesis that these drugs can act as novel agents to prevent skin cancer formation. ? ?
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