Modulation of O6-methylguanine-DNA methyltransferase-mediated 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea resistance by O6-benzylguanine in vitro and in vivo.
Our previous studies have indicated that O6-methyl-guanine-DNA methyltransferase (MGMT) is a key factor determining tumor cellular resistance to 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU). This study describes the modulation of MGMT-mediated ACNU resistance by O6-benzylguanine pretreatment. The ACNU sensitivity of MGMT proficient human tumor HeLa S3, SMMC-7721, and Cc801 cells in tissue culture was markly enhanced by 10 mm O6-benzylguanine, and a correlation between the extent of enhancement and the level of MGMT activities was observed. A single i.p. injection of 100 mg/kg of O6-benzylguanine caused a complete inhibition of MGMT activities in HeLa S3 tumor xenografts and combination of O6-benzylguanine with ACNU (7.5 mg/kg) significantly inhibited HeLa S3 tumor growth. The results demonstrated that O6-benzylguanine could be used as a potential adjuvant in combination chemotherapy with ACNU to treat MGMT proficient tumors.
Chen
J M
JM
Department of Biochemistry, Institute of Radiation Medicine, Beijing, People's Republic of China.
Zhang
Y P
YP
Sui
J L
JL
Moschel
R C
RC
Ikenaga
M
M
D000818:Animals; D004351:Drug Resistance; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006367:HeLa Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015376:Nimustine / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
C064976:O(6)-benzylguanine; D015376:Nimustine; D006147:Guanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase