Therefore, repeated exposure of tumour cells to photodynamic therapy does not seem to result in loss of DNA mismatch Verdinexor (KPT-335)? repair, and loss of mismatch repair, in turn, does not seem to contribute to resistance to photodynamic therapy. Our results suggest recommending photodynamic therapy as a strategy for circumventing resistance due to loss of DNA mismatch repair. British Journal of Cancer (2002) 86, 1130�C1135. DOI: 10.1038/sj/bjc/6600218 www.bjcancer.com ? 2002 Cancer Research UK Keywords: photodynamic therapy, DNA mismatch repair, drug resistance, m-THPC DNA mismatch repair (MMR) proteins repair mispaired DNA bases and have an important role in maintaining the integrity of the genome (Modrich, 1997). Loss of MMR is the genetic basis for the hereditary nonpolyposis colon cancer syndrome and is a common finding in a variety of sporadic human tumours.
Recent studies have documented that loss of MMR is an important mechanism of resistance to a variety of clinically important drugs, including cisplatin (Aebi et al, 1996; Fink et al, 1996) and the topoisomerase II poisons (Fedier et al, 2001). This is due, in part, to the fact that the MMR system can recognise and bind to various types of adducts in DNA. In addition, the genomic instability that accompanies loss of MMR can increase the rate of mutation in coding or regulatory sequences of other genes whose products may play central roles in determining tumour cell sensitivity to drugs. Loss of MMR has been reported in tumour cell lines selected by repeated treatments for resistance to cisplatin, methylating agents and doxorubicin (Aebi et al, 1996; Brown et al, 1997).
Although the reports are controversial there is some evidence that MMR-deficient cells are also resistant to ionising radiation (Fritzell et al, 1997; Xu et al, 2001). The development of drug resistance during chemotherapy of initially chemosensitive tumours is a frequent problem in clinical oncology, since it may lead to tumour progression and finally to the death of the patient. Thus, finding new treatment modalities effective against MMR-deficient tumour cells is of the utmost clinical importance. Photodynamic therapy (PDT) is being evaluated as an alternative treatment option for chemotherapy-resistant tumours (Canti et al, 1995). PDT uses laser light of appropriate wavelength and energy to activate a systemically applied photosensitiser that concentrates preferentially in malignant tissues. A photochemical reaction ensues, leading Anacetrapib to selective tumour necrosis (Dougherty et al, 1975). 5,10,15,20-meta-tetra(hydroxyphenyl)chlorin (m-THPC) is a neutral lipophilic second-generation photosensitiser with an absorption maximum at 652nm.