Adenoviral transfer of antisenses or ribozyme to O6-methylguanine-DNA methyltransferase mRNA in brain-tumor model resistant to chloroethyl-nitrosourea.

Chloroethyl-nitrosourea is a potent chemotherapeutic agent for brain tumors. However, acquired resistance to this drug has become a serious problem for the treatment of patients. Previously, we established an animal model resistant to nitrosourea (Anticancer Res 19: 5313-5318, 1999). In this study, we evaluate the efficacies of antisense sequences and ribozyme transduction by an adenoviral vector utilizing this model. Adenoviral vectors encoding antisense sequences or ribozyme to MGMT mRNA were constructed, then MGMT-expressing glioma cells were infected with these viruses and 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) sensitivities were quantified. The adenoviral transfer of antisense RNA and ribozyme down-regulated the transcription and expression of MGMT in vitro. It also conferred sensitivity to nitrosourea in vitro and in vivo. However, the effect was minimal. These data suggest that incomplete depletion of MGMT is not sufficient to overcome the resistance and that additional optimization will be required for the complete reversion of drug resistance.