Wang X M, McNiff J M, Klump V, Asgari M, Gasparro F P
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107-5541, USA.
Photochem Photobiol. 1997 Aug;66(2):294-9. doi: 10.1111/j.1751-1097.1997.tb08658.x.
Photochemotherapy employing 8-methoxypsoralen and long-wavelength ultraviolet radiation (UVA, 320-400 nm) is widely used in the treatment of psoriasis. The photoactivation of psoralens in skin cells leads to formation of DNA photoadducts which may be responsible, at least in part, for the efficacy of these photochemotherapies. However, mutations arising from these adducts may also lead to the well-characterized increased incidence of squamous cell carcinoma. Mutations in the p53 tumor suppressor gene have been detected in many human cancers. To determine whether p53 mutations occur in squamous cell carcinomas in PUVA patients, PCR was used to amplify the exons (5-9) in which other studies have found a high frequency of point mutations. Gel electrophoresis was used to detect single-strand conformational polymorphisms. Aberrantly migrating bands were excised, reamplified and sequenced. Thirty-four specimens from 10 patients were examined. Specimens from one patient who had received no phototherapy as well as from normal controls were also analyzed. Five of the 10 patients showed at least one p53 mutation. In contrast to previously reported psoralen-induced p53 mutations in mice, the expected psoralen type mutations at alternating AT sites were not detected. All but two of the altered sequences occurred at dipyrimidine sites which is typical of solar type mutations. Two C-->T mutations and two dipyrimidine mutations (CC-->TT) were found. Other mutations included: C-->G, G-->T, C-->A and an 18 bp deletion. A review of therapeutic history of these patients showed that some had also received UVB phototherapy. Furthermore, because sunlight is thought to be beneficial for psoriasis, nontherapeutic, casual UVB exposure cannot be excluded. Our observations suggest that the SCC may have arisen from the solar mutations and that PUVA may enhance tumor progression or immune suppression.
采用8-甲氧基补骨脂素和长波紫外线辐射（UVA，320 - 400纳米）的光化学疗法被广泛应用于银屑病的治疗。补骨脂素在皮肤细胞中的光活化作用会导致DNA光加合物的形成，这些光加合物可能至少部分地解释了这些光化学疗法的疗效。然而，由这些加合物引发的突变也可能导致鳞状细胞癌的发病率显著增加，这一点已得到充分证实。在许多人类癌症中都检测到了p53肿瘤抑制基因的突变。为了确定接受光化学疗法（PUVA）的患者的鳞状细胞癌中是否发生p53突变，采用聚合酶链反应（PCR）扩增外显子（5 - 9），其他研究已发现这些外显子中存在高频点突变。利用凝胶电泳检测单链构象多态性。切除迁移异常的条带，重新扩增并测序。对10例患者的34个标本进行了检查。还分析了1例未接受光疗患者的标本以及正常对照标本。10例患者中有5例至少出现1个p53突变。与先前报道的补骨脂素诱导的小鼠p53突变不同，未检测到预期的在交替AT位点的补骨脂素类型突变。除2个外，所有改变的序列均发生在二嘧啶位点，这是典型的阳光型突变。发现了2个C→T突变和2个二嘧啶突变（CC→TT）。其他突变包括：C→G、G→T、C→A和1个18 bp的缺失。对这些患者治疗史的回顾表明，一些患者还接受过中波紫外线（UVB）光疗。此外，由于阳光被认为对银屑病有益，不能排除非治疗性的偶然UVB暴露。我们的观察结果表明，鳞状细胞癌可能源于阳光诱导的突变，而PUVA可能会促进肿瘤进展或免疫抑制。
