抄録
1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) is commonly used for adjuvant chemotherapy to treat malignant glioma including glioblastoma multiforme (GBM). BCNU kills tumor cells via multiple actions including carbamoylation and alkylation. Herein we test the effects of NO donors on alkylating cytotoxicity to rat C6 glioma cells. The alkylating agents tested included methyl methanesulfonate (MMS), N-methyl-N-nitrosourea (MNU), and N-ethyl-N-nitrosourea (ENU). The synergistic effects of three NO donors, namely S-nitrosoglutathione (GSNO), diethylamine NONOate (DEA/NO), and sodium nitroprusside (SNP) on alkylating agents were determined by colony-formation assay. We found that inclusion of NO donors substantially reduced the extents of colony formation following exposure of glioma cells to all three alkylating agents. Among the three NO donors, GSNO appeared to be the most potent one. GSNO also exerted similar synergistic actions reducing the extents of colony formation when co-administrated with 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-hydrazine, another alkylating agent that mimics the chloroethylating action of BCNU. O6-Methylguanine methyl-DNA transferase (MGMT) is a DNA repair enzyme that removes the cytotoxic O6-alkylguanine adducts induced by alkylating agents. Western analysis indicated that expression of MGMT was reduced in the presence of GSNO, suggesting the possibility that GSNO enhanced alkylating cytotoxicity via, at least in part, decreasing cellular MGMT contents. [J Physiol Sci. 2006;56 Suppl:S120]
