Abstract B24: Detection of O6- and N7-methylguanine adducts by LC/MS in brain tumor tissues obtained from patients treated with temozolomide.

Abstract

The current standard of care for glioblastoma includes surgery, radiotherapy and chemotherapeutic agents such as temozolomide (TMZ), a DNA methylating compound. The cytotoxic effects of TMZ have been linked to guanine methylation at the N7 and O6 positions. These adducts are not currently used as markers of TMZ efficacy. Using liquid chromatography/mass spectrometry (LC/MS), we have established a sensitive analytical assay to directly detect both N7- and O6-methylguanine adducts from DNA following TMZ treatment. A limit of detection below 1 fmol was observed for O6-methylguanine, while N7-methylguanine was observed below 5 fmol. O6- and N7-methylguanine were successfully detected by LC/MS in tumour and normal brain tissue samples from patients treated with a neoadjuvant TMZ regimen for 14 days (75 mg/m2). Variations in levels of both methylated guanines were detected between patients as well as within different locations of the same tumour sample. This technique provides a direct detection of the damage inflicted by TMZ. This could potentially indicate the efficacy of the drug, allowing for prompt analysis and response. It also holds potential for determining efficacy of treatment dose, schedule and possible concomitant drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B24.