Alquilan el ADN en los residuos N7-meG y O6-meG de guanina. Esta metilación daña el ADN y desencadena la muerte celular.
Las células tumorales pueden reparar el ADN mediante la expresión de las proteínas O6 Alquilguanina alquiltranferasa.
FIGURE 1. Temozolomide function and activated DNA repair pathway. Temozolomide (TMZ) is chemically converted to MTIC (5-3-(methyltriazen-1-yl) imidazole-4-carboximide) at physiologic pH and degrades to a methyldiazonium cation, which transfers a methyl group to DNA. The most common site of methylation is N7-MeG (60–80%) followed by N3-MeA (10–20%) and O6-MeG (5–10%). When active MGMT is present, O6-MeG is repaired without cytotoxicity. When MGMT is inactivated or does not have the potential to completely repair O6-MeG, unrepaired O6-MeG is continuously repaired by the futile cycle of MMR, which ultimately induces cell death by provoking double-strand breaks (DSB). When MMR does not function properly, genomic instability is amplified. N7-MeG and N3-MeA is repaired by BER. If not repaired, alkylated bases cause a replication stall and collapse of the replication fork, generating single-strand breaks (SSBs), which ultimately induce DSB. It is possible that SSB and DSB repair pathways are activated and diminish the cytotoxic effects of TMZ.