Temporal and mechanistic studies on the resistance of glioma cells to temozolomide

The methylating agent temozolomide is routinely used in the treatment of malignant gliomas. Here we report on the mechanisms glioma cells utilize in protecting themselves against the clinical relevant DNA lesion, O6-methylguanine, induced by temozolomide. Making use of interference RNA, pharmacological inhibition and protein expression approaches we showed that the secondary lesions that form due to the mismatch repair dependent processing of O6-methylguanine causes a block in DNA replication, which, when not resolved, collapses into DNA double-strand breaks (DSBs). Bypass of the DNA replication blocking lesions…