Gasparro F P, Liao B, Foley P J, Wang X M, McNiff J M
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Environ Mol Mutagen. 1998;31(2):105-12.
Photochemotherapy employing 8-methoxypsoralen and ultraviolet radiation (PUVA) is widely used in the treatment of psoriasis. The photoactivation of psoralens in skin cells leads to DNA photoadduct formation which may be responsible for the efficacy of PUVA. Subsequent mutations may lead to the increased incidence of squamous cell carcinoma (SCC). Mutations in the p53 tumor suppressor gene have been detected in many human cancers. In this review, p53 mutation spectra in murine and human SCC are compared to those obtained from murine cells and skin treated with PUVA as well as to the p53 mutation spectrum in human solar SCC. While the expected psoralen-type mutations at alternating AT sites were detected in the treated cells and murine SCC (average frequency > 40%), such mutations were not commonly detected in the human SCC (< 10%). Other common mutations in the human SCC included: CG-->TA transitions (18%) and CG-->AT and TA-->GC transversions (17 and 25%, respectively). In addition, the frequency of UVB-type mutations at dipyrimidine sites (CC-->TT) in the SCC PUVA-treated psoriasis patients was comparable to that in patients with SCC from only solar exposure. A review of therapeutic history of these patients showed that many had also received UVB phototherapy. Furthermore, because sunlight is thought to be beneficial for psoriasis, nontherapeutic, casual UVB exposure cannot be excluded. Thus, the PUVA SCC may have arisen from the solar mutations and PUVA may enhance tumor progression by other epigenetic effects.
采用8-甲氧基补骨脂素和紫外线辐射（PUVA）的光化学疗法被广泛用于治疗银屑病。补骨脂素在皮肤细胞中的光活化导致DNA光加合物的形成，这可能是PUVA疗效的原因。随后的突变可能导致鳞状细胞癌（SCC）发病率增加。在许多人类癌症中都检测到了p53肿瘤抑制基因突变。在本综述中，将小鼠和人类SCC中的p53突变谱与用PUVA处理的小鼠细胞和皮肤中获得的突变谱以及人类日光性SCC中的p53突变谱进行了比较。虽然在处理过的细胞和小鼠SCC中检测到了交替AT位点处预期的补骨脂素型突变（平均频率>40%），但在人类SCC中并不常见（<10%）。人类SCC中的其他常见突变包括：CG→TA转换（18%）以及CG→AT和TA→GC颠换（分别为17%和25%）。此外，接受PUVA治疗的银屑病患者的SCC中双嘧啶位点（CC→TT）处UVB型突变的频率与仅因日光照射而患SCC的患者相当。对这些患者治疗史的回顾表明，许多人也接受过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。因此，PUVA诱导的SCC可能源于日光性突变，而PUVA可能通过其他表观遗传效应增强肿瘤进展。
