GENETIC ALTERATIONS IN PUVA INDUCED SKIN CANCERS

补骨脂素和紫外线-A(320-400 nm)(UVA)辐射的组合， 通常被称为“PUVA”，正被广泛用于治疗 银屑病。随着PUVA疗法的广泛使用，相当大的 人们的注意力集中在它的诱变和致癌作用上。 PUVA。大量研究表明，PUVA治疗会导致皮肤癌 在老鼠身上。此外，几份报告表明，PUVA疗法是一种风险 人类皮肤癌发生的因素。然而，分子 PUVA致皮肤损伤发病机制的研究进展 人们对癌症知之甚少。这项提议的长期目标是 确定与起源和基因改变相关的基因改变 PUVA治疗患者皮肤癌的发生。因为从病因学角度来看 接受PUVA治疗的银屑病患者发生皮肤癌 治疗方法存在争议，有可能使用P53肿瘤 以抑癌基因作为分子标志物，确定这些皮肤 癌症是由紫外线辐射或PUVA引起的。因为紫外线和PUVA会引起 不同类型的DNA损伤，我们假设由 这两种致癌物质也是不同的，因此可能会留下它们的 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)到 确定PUVA诱导的ras和p53突变是早期还是早期 PUVA致癌过程中的晚期事件，以及(3)确定人类 接受过PUVA治疗的银屑病患者的皮肤癌 港湾ras和p53突变与PUVA中检测到的相似- 诱发小鼠皮肤癌。Ras和p53基因的突变将是 经单链构象多态分析鉴定 核苷酸测序。对患者既往病史的全面临床评估 接受化疗或放射治疗的次数、持续时间和强度 暴露于PUVA、皮肤类型等，将使RAS和 P53基因突变资料与临床资料。乳腺癌RAS和P53基因突变的研究 PUVA、4，4‘，6-三甲基当归素合UVA和当归素合UVA致小鼠皮肤损伤 肿瘤应提供有关单功能蛋白作用的重要信息 PUVA致癌中的加合物和DNA交联物。获取的信息 来自PUVA治疗患者皮肤癌的P53研究可能 提供这些皮肤癌的病因学线索，这可能是有用的 为今后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.