O6-alkylguanine-DNA alkyltransferase. A target for the modulation of drug resistance.
The DNA repair protein, O6-alkylguanine DNA alkyltransferase, is a major contributor to the resistance to the nitrosourea, triazine, and tetrazine class of alkylating agents. Many tumor cells and primary tumor samples contain high levels of this protein, although a great deal of heterogeneity exists between and within tumors. Inhibition of the alkyl-transferase by O6-benzylguanine results in significant potentiation of the cytotoxic effects of these chemotherapeutic agents, generating responses in human tumor xenografts that are completely resistant to nitrosoureas alone. These studies may rekindle the interest in the nitrosourea class of alkylating agents and stimulate the search for inhibitors of other mechanisms of chemotherapy resistance.
Gerson
S L
SL
Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Willson
J K
JK
D000477:Alkylating Agents / Q000145:classification / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport; D002330:Carmustine / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D004351:Drug Resistance; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008658:Inactivation, Metabolic; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D019853:O(6)-Methylguanine-DNA Methyltransferase
D000477:Alkylating Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; C064976:O(6)-benzylguanine; D006147:Guanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine