The genotoxicity of the chloroethylating agent mitozolomide is enhanced in CHO mex+ cells by the administration of antimessenger oligonucleotide targeted against methylguanine-DNA methyltransferase gene (MGMT).

The alkylating drug resistance is frequently related to the DNA repair activity 0(6)-alkylguanine-DNA alkyltransferase (0(6)-AT), a protein coded by the methylguanine-DNA methyltransferase gene (MGMT). We synthesized one antisense oligodeoxyribonucleotide (AS-ODN) targeted against the mRNA of the MGMT gene. The administration of this "antimessenger" sequence to a Chinese hamster ovary cell line, expressing the transfected human MGMT gene, caused a moderate decrease of the resistance to the chloroethylating drug mitozolomide (MTZ), measured as induction of sister chromatid exchanges (SCE). The AS-ODN administration combined with depletion and recovery of 0(6)-AT by 0(6)-methylguanine inhibitor treatment showed an enhancement of SCE induction. The results support the inhibition of the MGMT translation mechanism by AS-ODN and suggest that the pre-existing protein could compromise the reversion of the resistant phenotype if is still active during the administration of the "antimessenger" sequence.