Methylated DNA adducts (O6-methylguanine, N7-methylguanine, N3-methyladenine)

Methylated DNA adducts, specifically O6-methylguanine, N7-methylguanine, and N3-methyladenine, are the primary molecular targets formed by the prodrug temozolomide and its active metabolite MTIC [1, 2]. These adducts are created through the covalent transfer of a methyl group from a methyldiazonium cation to DNA bases during the S-phase of the cell cycle [2]. While N7-methylguanine and N3-methyladenine are the most frequent products, O6-methylguanine is the most clinically significant due to its potent cytotoxic effects [3]. In the absence of repair by the enzyme O6-methylguanine-DNA methyltransferase (MGMT), O6-methylguanine mispairs with thymine, triggering the mismatch repair (MMR) system [4]. This leads to a cycle of futile repair, resulting in double-strand breaks and the induction of apoptosis [4, 5]. This mechanism is the cornerstone of treatment for high-grade gliomas, where the efficacy of the drug is heavily dependent on the patient's MGMT expression levels [3].

Other names

O6-methylguanineN7-methylguanineN3-methyladenineTemozolomide-induced DNA adductsMTIC-derived DNA methylation

Covalent methylation of DNA bases, primarily at the O6 position of guanine, which leads to mismatch repair-mediated double-strand breaks and apoptosis [1, 2, 4].