Figure 2.

Mechanism of TMZ metabolism, DNA damage and DNA repair. Under physiological conditions TMZ is metabolized to MTIC and then to its active form, a methyl diazonium ion. The electrophilic methyl diazonium ion acts as a methyl donor, transferring its methyl group to negatively charged DNA and creating DNA adducts. This alkylating activity occurs preferentially at N7 of guanine, O3 of adenine and O6 of guanine and, if left unrepaired, results in improper base pairing and single and double-stranded DNA breaks. The primary endogenous DNA repair mechanisms that counteract the DNA damage caused by TMZ, and are thus commonly implicated in TMZ resistance, include MGMT, BER and MMR. TMZ: temozolomide; MTIC: metabolite 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide; MGMT: O6-methylguanine-DNA methyltransferase; BER: base excision repair; MMR: mismatch repair