Inflammatory mediators and UV-induced carcinogenesis

炎症介质和紫外线诱发的致癌作用

基本信息

批准号：
6965357
负责人：
Stephen E ULLRICH
金额：
$ 23.7万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2010-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：皮肤癌是人类肿瘤最常见的形式。据估计，五分之一的美国人在其一生中将被诊断出患有非黑色素瘤皮肤癌；据估计，一生中患侵袭性黑色素瘤的风险为六十七分之一。美国每年用于皮肤癌护理和治疗的费用估计超过 290 亿美元。诱发皮肤癌的最主要环境因素是阳光中的紫外线 (UV) 辐射。除了完全致癌外，紫外线辐射还具有免疫抑制作用，大量使用实验动物和活检证实的皮肤癌患者的研究表明，紫外线辐射引起的免疫抑制是非黑色素瘤皮肤癌的主要危险因素就职。最近对紫外线诱导免疫抑制机制的研究发现了两个重要事实。首先，是角质形成细胞衍生的炎症脂质介质血小板激活因子（PAF）在紫外线诱导的免疫抑制中的作用。其次，认识到顺式尿刊酸 (c/s-UCA) 通过与血清素 (5HT2A) 受体结合来介导免疫抑制。支持 PAF 和血清素受体结合作用的数据主要来自使用选择性受体拮抗剂来阻断紫外线诱导的免疫抑制的研究。由于紫外线诱发的致癌作用与紫外线诱发的免疫抑制之间的密切联系，我们建议血清素和 PAF 受体拮抗剂可作为阻止阳光诱发的皮肤癌形成的理想药物。该提案的重点是检验该假设。将检查两个具体目标来支持该假设。首先，将详细研究 PAF 和血清素受体结合激活免疫抑制的机制。其次，我们将使用光致癌动物模型来测试 PAF 和血清素受体拮抗剂（单独或组合）阻止紫外线诱导的皮肤癌诱导的能力。我实验室进行的研究的长期目标是确定紫外线引起的免疫抑制的机制，希望设计合理的治疗方法来改善免疫抑制，从而减少阳光引起的皮肤癌的主要危险因素。小分子量 PAF 和血清素受体拮抗剂可能被证明是实现这一目标的理想药物。 PAF受体拮抗剂已在临床上用于治疗脓毒症，血清素受体(5HT2A)拮抗剂已用作抗精神病药和抗抑郁药。两者的耐受性都相对较好。此外，两者都能阻止紫外线引起的免疫抑制和炎症，这是皮肤癌发展所必需的过程。这里提出的研究的重点是提供证据来支持这些药物可以作为预防皮肤癌形成的新药的假设。