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An unexpected spectrum of p53 mutations from squamous cell carcinomas in psoriasis patients treated with PUVA.

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.

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