Development of gene therapy against drug-resistant brain tumors using nitrosourea-resistant rat brain-tumor model

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ChloroethyHtorourea (CENU) is one of the most potent chemotherapeutic agents for brain tumors. However, acquired resistance to the drug has become aserious problem in the treatment of brain tumor patients. The main mechanism of the resistance is a recruitment of the 06'methylguanine DNA methyltransferase (MGMT) in tumor cells. Previously, we established an animal model resistant to nitrosourea (Anticancer Research 19: 5313-5318, 1999) by retroviral transduction of MGMT CDNA into 9L rat brain tumor cells. In this study, we evaluate the efficacies of antisense sequences and ribozyme transduction by plasmid, retroviral, or adenoviral vector utilizing this model. Retroviral or plasmid DNA transduction of an antisense sequence did not confer the sensitivity of l-(4-amino-2-methyl'5-pyrimidinyl) methyll-3-(2-chloroethyl)-3jnitrosourea (ACNU) to the resistant brain tumor cells. In order to increase the potency of this approach, adenoviral vectors encodingantisense sequences or ribozyme to MGMT mRNA were constructed, then MGMT-expressing glioma cells were infected with these viruses and sensitivities were quantified. The adenoviral transfer of antisense RNA and ribozyme down-regulated the transcription and expression of MGMT in vitro. It also conferred significant sensitivity to nitrosourea in vitro and in vivo. However, theeffect was minimal. These data suggest that incomplete depletion of MGMJT is not sufficient to overcome the resistance and that additional optimization will be fequired for the complete reversion of drug resistance.