Involvement of the DNA mismatch repair system in antineoplastic drug resistance

Different types of antineoplastic drugs, such as the alkylating agents busu lfan, N-methyl-N'-nitro-nitrosoguanidine, N-methyl-N-nitrosourea, procarbaz ine and temozolomide, the antimetabolites, mercaptopurine and 6-thioguanine , the platinum compounds carboplatin and cisplatin, the anthracycline doxor ubicin and the epipodophyllotoxine etoposide act by damaging DNA directly o r indirectly. Increasing evidence has shown that tumours could acquire resi stance to these drugs by loss of DNA-mismatch repair (MMR) activity. This p henomenon is caused by a decreased MMR-dependent stimulation of signal-tran sduction pathways causing programmed cell death. Simultaneously, the mutati on rate in MMR-deficient tumours is increasing, which could lead to additio nal secondary drug/resistance phenotypes to other antineoplastic agents. In addition to this, an enhanced mutation rate may contribute to increased ph enotypic variation and therefore the clinical aggressiveness of primary tum ours and their metastases.