Similarly, it

Similarly, it selleck chemicals Regorafenib has been reported that low levels of MLH1 and MSH2 in malignant gliomas correlate with resistance to temozolomide, a methylating agent (Friedman et al, 1998). PDT is a relatively new treatment modality for malignant tumours. Selective tumour cell necrosis is induced by a distinct photochemical mechanism. While chemoresistance in MMR-deficient tumours seems to force physicians to surrender an efficient anticancer treatment, the present study suggests that PDT might offer a future treatment option for these patients. So far, it has been reported that PDT does not induce resistance to chemo- or radiotherapy, and that this treatment can be repeated without increasing toxicity and with low probability of inducing resistance to PDT (Sharkey et al, 1993; Luna et al, 1995; Hornung et al, 1998; Singh et al, 2001).

Our study extends the theoretical advantages to conventional treatment modalities for cancer by demonstrating that loss of MMR does not result in resistance to PDT. Loss of MMR has been reported in tumour cells selected by repeated treatments with cisplatin, methylating agents or doxorubicin (Aebi et al, 1996; Brown et al, 1997). Therefore, we analysed by immunoblot the presence of the MMR proteins in MCF-7 cells that survived five subsequent cycles of PDT. As shown in Figure 2, the PDT-treated MCF-7 cells expressed parental levels of MLH1, MSH2, MSH6 and PMS2. Thus, PDT is not only effective against MMR-deficient cells but – unlike some chemotherapeutic agents �C it does not result in loss of MMR, allowing standard chemo- or radiotherapy following PDT-mediated tumour treatment.

PDT-induced cell killing is not fully understood and may depend on the photosensitiser and the treatment protocol used. 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. As demonstrated in Figure 4, the cationic and lipophilic photosensitiser m-THPC localises in cellular membranes, mainly in the mitochondria with highly negative electrochemical potential of the inner membrane, and to a lower extent in the nuclear membrane. Singlet oxygen, the major mediator of the PDT-induced photochemical reaction (Henderson and Dougherty, 1992), has a very short diffusion GSK-3 distance of 0.01��m and a very short lifetime of 0.01��s (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).

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