Genomic instability and tolerance to alkylating agents.
Experimental models clearly indicate that the cytotoxic effects of the chemotherapeutic methylating agents are mediated by incomplete processing of one of the common DNA methylation products, O6-meGua. These attempts at processing persistent O6-meGua are by DNA mismatch repair, and resistance to methylating agents frequently arises through loss of this pathway. It is to be expected that mismatch repair defects will be found among cells that have developed clinical resistance to agents such as temozolomide and the methyltriazines. The selective sensitivity of mismatch repair defective cells to chloroethylating agents may have a direct applicability to clinical practice and offers real promise of effective chemotherapy for the substantial number of human tumours that show microsatellite instability. As for the mechanisms of human mismatch repair, the complexity of the early steps of the pathway(s) is underlined by the likely participation of multiple heterodimers in the mismatch recognition steps. just as different types of mismatch may be processed by distinct branches of the same pathway, the same may be true for different types of DNA damage.
Karran
P
P
Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Hertfordshire.
Hampson
R
R
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism*; D018895:Microsatellite Repeats / Q000235:genetics*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010641:Phenotype; D010984:Platinum / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D010984:Platinum; D006147:Guanine; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase