MODULATION OF O-6-METHYLGUANINE-DNA METHYLTRANSFERASE-MEDIATED 1-(4-AMINO-2-METHYL-5-PYRIMIDINYL) METHYL-3-(2-CHLOROETHYL)-3-NITROSOUREA RESISTANCE BY O-6-BENZYLGUANINE IN-VITRO AND IN-VIVO

Our previous studies have indicated that O6-methylguanine-DNA methyltr ansferase (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-mediat ed ACNU resistance by O6-benzylguanine pretreatment. The ACNU sensitiv ity of MGMT proficient human tumor HeLa S3, SMMC-7721, anti Cc801 cell s in tissue culture was markly enhanced by 10 mm O6 -benzylguanine, an d a correlation between the extent of enhancement and the level of MGM T acitivities was observed. A single i.p. injection of 100 mg/kg of O6 -benzylguanine caused a complete inhibition of MGMT acitivities in HeL a S3 tumor xenografts and combination of O6-benzylguanine with ACNU (7 .5 mg/kg) significantly inhibited HeLa S3 tumor growth. The results de monstrated that O6-benzylguanine could be used as a potential adjuvant in combination chemotherapy with ACNU to treat MGMT proficient tumors .