Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy.
Improving the efficacy of standard chemotherapy by targeting DNA repair mechanisms remains an important area of research. O6-methylguanine-DNA-methyltransferase (MGMT), which repairs alkylating agent damage, is one such target. Downregulation of the gene through epigenetic silencing has been shown to predict response to alkylating agent therapy in selected malignancies. Platinums have also been found to downregulate MGMT expression and this approach is currently under exploration. Another way to deplete O6-alkylguanine DNA alkyltransferase (AGT) levels is to modify methylating agent scheduling. Extended dosing has met with early favourable results. However, pseudosubstrates used to inhibit AGT activity have had limited success because of dose-limiting myelotoxicity. Topoisomerase I is 'trapped' on DNA by alteration of ligation kinetics following alkylating agent damage, leading to interest in combining AGT inhibitors or O6-alkylating agents with topoisomerase I inhibitors. DNA repair by AGT is an interesting target for cancer therapy that remains to be fully evaluated. The best results are likely to be achieved where its inhibition is part of treatment targeting multiple DNA damage processing pathways.
Sabharwal
Ami
A
Cancer Research UK, Medical Oncology Unit, Churchill Hospital, Oxford OX3 7LJ, UK.
Middleton
Mark R
MR
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D018736:DNA Adducts / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000187:drug effects; D000077204:Temozolomide; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D018736:DNA Adducts; D004791:Enzyme Inhibitors; C403290:O(6)-(4-bromothenyl)guanine; D009944:Organoplatinum Compounds; D059004:Topoisomerase I Inhibitors; C064976:O(6)-benzylguanine; D006147:Guanine; D000077146:Irinotecan; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin; D000077204:Temozolomide