GENETIC ALTERATIONS IN PUVA INDUCED SKIN CANCERS

本发明公开了一种补骨脂素和紫外线-A（320-400 nm）（UVA）辐射的组合， 通常被称为“PUVA”，被广泛用于治疗 银屑病随着PUVA疗法的广泛使用， 人们的注意力集中在 PUVA。许多研究表明，PUVA治疗诱发皮肤癌 对小鼠此外，一些报告表明PUVA治疗存在风险 人类皮肤癌发展的因素。然而，分子 参与PUVA诱导的皮肤病发病机制的机制 对癌症知之甚少。该提案的长期目标是 确定与起源相关的遗传改变， PUVA治疗的患者中皮肤癌的发展。由于病因 接受PUVA治疗的银屑病患者中出现的人类皮肤癌 治疗是有争议的，它可能会使用p53肿瘤 抑制基因作为分子标记，并确定这些皮肤 癌症由UV辐射或PUVA诱发。由于紫外线和PUVA诱导 不同类型的DNA损伤，我们假设， 这两种致癌物质也是不同的，因此可能会留下他们的 独特的“签名”。我们的具体目标是：（1）鉴定ras和p53 与PUVA诱导的小鼠皮肤癌相关的突变，（2） 确定PUVA诱导的ras和p53突变是早期的还是晚期的。 PUVA致癌过程中的晚期事件，以及（3）为了确定人类是否 接受PUVA治疗的银屑病患者的皮肤癌 携带ras和p53突变，与PUVA中检测到的突变相似， 诱发小鼠皮肤癌。ras和p53基因的突变将是 通过单链构象多态性分析鉴定， 核苷酸测序对患者既往的 暴露于化疗或放疗、数量、持续时间和强度 暴露于PUVA，皮肤类型等，将使ras与 p53突变数据与临床数据。ras和p53突变研究 PUVA、4，4 '，6-三甲基当归素+UVA和当归素+UVA诱导的小鼠皮肤 肿瘤应该提供重要的信息的作用， PUVA致癌作用中的加合物和DNA交联。获得的信息 来自PUVA治疗患者的人类皮肤癌的p53研究可能 为这些皮肤癌的病因学提供线索， 为将来制定干预方案提供参考。

A combination of psoralen and ultraviolet-A (320-400 nm) (UVA) radiation, commonly referred to as "PUVA", is being widely used in the treatment of psoriasis. With the wide-spread use of PUVA therapy, considerable attention has been focused on the mutagenic and carcinogenic effects of PUVA. Numerous studies have shown that PUVA treatment induces skin cancer in mice. In addition, several reports indicate that PUVA therapy is a risk factor for skin cancer development in humans. However, the molecular mechanisms that are involved in the pathogenesis of PUVA-induced skin cancers are poorly understood. The long-term goal of this proposal is to identify the genetic alterations that are associated with the origin and development of skin cancer in PUVA treated patients. Since the etiology of human skin cancers arising in psoriasis patients who have undergone PUVA therapy is controversial, it may be possible to use the p53 tumor suppressor gene as a molecular marker and determine whether these skin cancers are induced by UV radiation or by PUVA. Since UV and PUVA induces different types of DNA damage, we hypothesize that mutations induced by these two carcinogenic agents are also different, and thus may leave their unique "signature". Our specific aims are: (1) To identify ras and p53 mutations associated with PUVA-induced mouse skin cancers, (2) To determine whether PUVA-induced ras and p53 mutations are an early or a late event during PUVA carcinogenesis, and (3) To determine whether human skin cancers from psoriasis patients who have undergone PUVA therapy harbor ras and p53 mutations that are similar to those detected in PUVA- induced murine skin cancers. Mutations in ras and p53 genes will be identified by single strand conformation polymorphism analysis and nucleotide sequencing. A thorough clinical evaluation of patient's prior exposure to chemotherapy or radiotherapy, number, duration, and intensity of exposure to PUVA, skin type, etc., will be made to correlate ras and p53 mutation data with clinical data. ras and p53 mutation studies in PUVA, 4,4',6-trimethylangelicin+UVA and angelicin+UVA induced mouse skin tumors should provide important information on the role of monofunctional adducts and DNA cross-links in PUVA carcinogenesis. Information obtained from p53 studies in human skin cancers from PUVA-treated patients may provide clues to the etiology of these skin cancers, which may be useful for the future formulation of intervention protocols.