O6-alkylguanine-DNA alkyltransferase inactivation in cancer chemotherapy.
The protein O(6)-alkylguanine-DNA alkyltransferase is the basis of an important process for repairing damage to cellular DNA, which renders cells resistant to drugs that alkylate at the O(6)-position of guanine residues. The development of various pseudosubstrates which inactivate this protein is reviewed, from a chemical standpoint. Study of the influence of pseudosubstrate molecular structure on their interaction with the active site cysteine has progressed together with direct investigation of protein structure. Combination therapy using a powerful inactivator with a suitable alkylating agent shows great clinical promise in the treatment of cancer, particularly when some degree of selectivity is possible.
McElhinney
R S
RS
University Chemical Laboratory, Trinity College, Dublin 2, Ireland. chemdept@tcd.ie
McMurry
T B H
TB
Margison
G P
GP
D000478:Alkylation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D009705:Nucleosides / Q000494:pharmacology; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D009705:Nucleosides; D019853:O(6)-Methylguanine-DNA Methyltransferase; D009713:Nucleotidyltransferases; C020658:glutamine-synthetase adenylyltransferase