The alkylating drug resistance is frequently related to the DNA repair activity O-6-alkylguanine-DNA alkyltransferase (O-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 O-6-AT by O-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.

The genotoxicity of the chlroethylating agent Mitozolomide is enhanced in CHO MEX+ cells by the administration of antimessenger oligonucleotide targeted against Methylguanine-DNA methyltransferase gene (MGMT)

BOLDRINI, LAURA;
1994

Abstract

The alkylating drug resistance is frequently related to the DNA repair activity O-6-alkylguanine-DNA alkyltransferase (O-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 O-6-AT by O-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.
L., Citti; Boldrini, Laura; G., Rainaldi
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/27938
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