The mechanisms of cellular sensitivity to photodynamic therapy.

摘要

Photodynamic therapy (PDT) is a cancer treatment in which a photosensitizing drug is retained by tumor cells and activated by visible light to create toxic photoproducts including singlet oxygen and other free radicals.; Although there is evidence that the p53 tumor suppressor plays a role in tumor response to the chemotherapy and radiation therapy, its role in the response of human cells to PDT is less clear. In the present study, Li-Fraumeni syndrome (LFS) skin fibroblast cells that express only mutant p53 and normal human skin fibroblasts (NHF) strains expressing wild-type p53 were used to elucidate the role of p53 in the cell response to Photofrin-mediated PDT. NHF cells were found to have a higher sensitivity to Photofrin-mediated PDT compared to LFS cells. Reintroduction of wild-type p53 reduced the viability of LFS cells following PDT. These data suggest a role for p53 in the response of human cells to PDT. Although the treatment of PDT resulted in an increased level of p53 proteins in NHF cells, no apoptosis or any alteration in the cell cycle was found. Whereas LFS cells displayed a prolonged accumulation of cells in G₂/M phase and the cells underwent apoptosis. Thus, the loss of p53 may result in a prolonged G₂/M arrest that contributes to the photoresistance of LFS cells.; In order to see the possible role of p53 in the cellular response to Nile Blue A (NBA), a secondary photosensitizer-mediated PDT, the clonogenic survival assay was used to compare the viability of LFS cells to NHF cells following NBA-mediated PDT. We found an extreme sensitivity of NHF cells compared to LFS and several tumour cells for treatment with NBA alone. In addition, Nile Blue A was found to be unable to produce a significant photo-cytotoxic effect on human cells using NBA concentrations which have relatively low toxicity for normal human fibroblasts. (Abstract shortened by UMI.)