Depletion of O6-methylguanine-DNA methyltransferase and potentiation of 1,3-bis(2-chloroethyl)-1-nitrosourea antitumor activity by O6-benzylguanine in vitro.
The overcoming effect of O6-benzylguanine on O6-methylguanine-DNA methyltransferase (MGMT)-mediated 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance in vitro was evaluated. Depletion of MGMT activity in Mer+ HeLa S3 cells by O6-benzylguanine was dose-dependent and a complete loss of MGMT activity was achieved at a concentration of 0.5 microM. The cytotoxic potential of BCNU on MGMT proficient HeLa S3 (1.10 pmol/mg of protein), SMMC-7721 (0.72 pmol/mg of protein) and Cc801 (0.39 pmol/mg of protein) was greatly enhanced when cells were exposed to 10 microM O6-benzylguanine for 1 h, but there was a lack of potentiation of BCNU sensitivity in Mer- HeLa MR cells due to its nearly undetectable level of MGMT. There existed a correlation between the extent of enhancement and the amount of MGMT activity. The intensity of enhancement expressed as dose modifying factor = IC50 (BCNU alone)/IC50 (10 microM O6-benzylguanine + BCNU) was 4.56, 3.89, 3.67 and 0.97 in HeLa S3, SMMC-7721, Cc801 and HeLa MR cells respectively. The results further demonstrated that O6-benzylguanine may have potential utility as an adjuvant in combination chemotherapy with chloroethylnitrosourea agents.
Chen
J M
JM
Department of Biochemistry, Institute of Radiation Medicine, People's Republic of China.
Zhang
Y P
YP
Moschel
R C
RC
Ikenaga
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002330:Carmustine / Q000494:pharmacology*; D004351:Drug Resistance; D004357:Drug Synergism; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C064976:O(6)-benzylguanine; D006147:Guanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine