Mutagenicity of Photodynamic Therapy as Compared to UVC and Ionizing Radiation in Human and Murine Lymphoblast Cell Lines

Abstract

The mutagenicity of photodynamic therapy (PDT) using red light and either Photofrin (porfimer sodium) (PF) or aluminum phthalocyanine (AlPc) as the photosensitizer was determined at the thymidine kinase (TK) locus in the human lymphoblastic cell lines, TK6 and WTK1, and was compared to the mutagenicity of UVC and X-radiation in these cells as well as the mutagenicity of PDT in murine L5178Y lymphoblastic cell lines. Photodynamic therapy was found not to be mutagenic in TK6 cells, which possess an active p53 gene and which are relatively deficient in recombination and repair of DNA double-strand breaks. In contrast, PDT with either sensitizer was significantly mutagenic in WTK1 cells, which harbor an inactivating mutation in the p53 gene and are relatively efficient in recombination and double-strand break repair as compared to TK6 cells. The induced mutant frequency in WTK1 cells with PF as the photosensitizer was similar to that induced by UVC radiation but lower than that induced by X-radiation at equitoxic fluences/doses. The mutant frequency induced by PDT in WTK1 cells with either photosensitizer was much lower than that induced in murine lymphoblasts at equitoxic fluences. The TK6 and WTK1 cells did not differ in their sensitivity to the cytotoxic effects of PDT, but the level of PDT-induced apoptosis was greater in TK6 than in WTK1 cells. These results indicate that the mutagenicity of PDT varies in different types of cells and may be related to the repair capabilities as well as the p53 status of the cells.

Photodynamic therapy of DNA mismatch repair-deficient and -proficient tumour cells

“…However, the potential of PDT to induce genotoxic damage seems to be relatively low compared with ionising radiation or chemotherapy (Evans et al, 1997). This may, in part, be explained as follows.…”

“…Singlet oxygen, the major mediator of the PDTinduced photochemical reaction (Henderson and Dougherty, 1992), has a very short diffusion distance of 0.01 mm and a very short lifetime of 0.01 ms (Moan and Berg, 1991). The photochemical reaction may therefore reach only DNA that is located very close to the nuclear membrane (Evans et al, 1997). Oxidative damage leading to single-strand breaks and alkali-labile sites, DNA-protein crosslinks and DNA degradation, as well as to chromosome aberrations has been reported (Evans et al, 1997; Oleinick and Evans, 1998).…”

“…Although there is no localisation of the photosensitiser within the nucleus, a low level of potentially mutagenic DNA damage could occur, depending on the photosensitiser, the cellular repair mechanisms and the affected genes (Oleinick and Evans, 1998). Indeed, PDT has been reported to result in DNA lesions such as single-strand breaks and alkali-labile sites, DNA protein crosslink-correlation and DNA degradation as well as in chromosome aberrations (Evans et al, 1997;Oleinick and Evans, 1998). One major advantage of PDT over other treatment modalities is that it can be safely repeated several times (Hornung et al, 1998).…”

Potentiating Effect of .BETA.-Glucans on Photodynamic Therapy of Implanted Cancer Cells in Mice

“…It has been reported that PDT results in DNA lesions such as single-strand breaks and DNA degradation as well as in chromosome aberrations (Evans et al 1997;Oleinick and Evans 1998). DNA damage induces several cellular responses including DNA repair and the triggering of apoptotic pathways (Niida and Nakanishi 2006).…”

Mass spectrometry analysis of the oxidation states of the pro-oncogenic protein anterior gradient-2 reveals covalent dimerization via an intermolecular disulphide bond

“…Additionally, AGR2 is also able to mediate export of p53 from the nucleus into the cytoplasm better upon UVC irradiation [25]. UVC is a known pro-oxidizing stimulus in cells [45,46] and these data allow a model to be developed that proposes AGR2 protein activity might be stimulated by stresses present in a pro-oxidizing environment revealing a potentially physiological role for dimer assembly in AGR2-mediated oncogenesis.…”