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：
7090739
负责人：
Stephen E ULLRICH
金额：
$ 23.14万
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）：皮肤癌是人类肿瘤的最普遍形式。据估计，五分之一的美国人一生将被诊断出患有非黑色素瘤皮肤癌。侵入性黑色素瘤的终生风险估计为67分之一。在美国，皮肤癌的护理和治疗费用估计超过29亿美元。阳光中最负责皮肤癌诱导的环境剂是紫外线（UV）辐射。除了完全致癌物外，紫外线辐射也是免疫抑制性的，并且使用实验性动物和证实活检的皮肤癌患者的大量研究表明，紫外线辐射诱导的免疫抑制是非黑色素瘤皮肤癌的主要危险因素就职。最近关于紫外线诱导的免疫抑制的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，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，意识到顺式尿酸（C/S-UCA）通过与5-羟色胺（5HT2A）受体结合来介导免疫抑制。支持PAF和5-羟色胺受体结合作用的数据主要来自研究，其中选择性受体拮抗剂用于阻断紫外线诱导的免疫抑制。由于紫外线诱导的致癌作用与紫外线诱导的免疫抑制之间存在密切的联系，因此我们提出5-羟色胺和PAF受体拮抗剂将作为阻止阳光诱发的皮肤癌形成的理想药物。该提议的重点是检验该假设。将检查两个具体目标以支持该假设。首先，将详细研究通过PAF和5-羟色胺受体结合激活免疫抑制的机制。其次，我们将使用光碳纤维生成的动物模型，单独或组合使用PAF和5-羟色胺受体拮抗剂的能力来阻止紫外线诱导的皮肤癌诱导。在我的实验室进行的研究的长期目标是确定紫外线诱导的免疫抑制的机制，以期设计合理的治疗方法以改善免疫抑制，从而降低了阳光诱发的皮肤癌变的主要危险因素。小分子量PAF和5-羟色胺受体拮抗剂可能被证明是实现这一目标的理想药物。 PAF受体拮抗剂已在诊所中用于治疗败血症，5-羟色胺受体（5HT2A）拮抗剂已被用作ANLI-PESSHICTS和抗抑郁药。两者的耐受性相对较好。此外，两者都阻止了紫外线诱导的免疫抑制和炎症，这是对皮肤癌发展至关重要的过程。这里提出的研究的重点是提供证据，以支持这些药物可以作为防止皮肤癌形成的新药物的假设。