Ribozyme and free alkylated base: a dual approach for sensitizing Mex(+) cells to the alkylating antineoplastic drug

N-alkyl-nitrosoureas and alkyl-triazenes are alkylating antineoplastic drug s, the efficacy of which is strongly affected by the level of expression of the DNA-repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). in t umors, MGMT activity reduces the chemotherapeutic potential of alkylating d rugs; therefore, efforts have been made to down-regulate the protein. A par tial sensitization of Mex(+) cells to alkylating drugs has been obtained us ing either free alkylated bases or oligonucleotides targeted against MCMT m RNA. In the present work, O-6-methylguanine and a chemically modified riboz yme, without a cationic liposome as a carrier, were coadministered to CHO47 cells, which express a high level of human MGMT protein. The reduction of MGMT mRNA and protein Enhanced the genotoxicity of the alkylating drug mito zolomide. Furthermore, the sensitivity of CHO47 cells is the same as that o f CHO5 cells, which lack MCMT protein. These data indicate that a strategy in which both mRNA and protein are degradation targets can he successfully applied to down-regulate the MGMT gene.