Modulation of O6-methylguanine-DNA methyltransferase-mediated 1-(4-amino-2-methyl-5-Pyrimidinyl)- methyl-3-(2-Chloroethyl)-3-nitrosourea resistance by antisense RNA.

Abstract

Mer+ HeLa S3 tumor cells with high levels of O6-methylguanine-DNA methyltransferase (MGMT) gene expression were transduced by retroviral-mediated MGMT antisense RNA. The MGMT mRNA, MGMT protein, and MGMT activity in transduced cells were only 28.7%, 32.7%, and 39. 1% of that in HeLa S3 cells, respectively. The transduced cells showed more sensitive to ACNU than HeLa S3 cells both in cell survival and in nude mice experiments. Pathologic examination confirmed that transduced grafts were killed by ACNU. Our results suggested that MGMT gene expression could be modulated by retroviral-mediated antisense RNA and that Mer+ tumor drug resistance to ACNU could be reversed by modulation of MGMT gene expression.