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.
Citti
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Istituto di Mutagenesi e Differenziamento, CNR, Pisa, Italy.
Boldrini
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L
Rainaldi
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G
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001483:Base Sequence; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells; D003114:Colony-Forming Units Assay; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004357:Drug Synergism; D006801:Humans; D007700:Kinetics; D008780:Methyltransferases / Q000096:biosynthesis / Q000235:genetics*; D008969:Molecular Sequence Data; D009588:Nitrogen Mustard Compounds / Q000633:toxicity*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D016376:Oligonucleotides, Antisense / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics*; D012854:Sister Chromatid Exchange / Q000187:drug effects; D014162:Transfection
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C040369:mitozolomide; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase