DNA (deoxyribonucleic acid) as a substrate for methylation by temozolomide (DNA)

Temozolomide is an oral alkylating chemotherapy agent primarily used for glioblastoma treatment. It is a prodrug that spontaneously hydrolyzes to form a highly reactive methyl diazonium cation in vivo, which methylates DNA at the N7 and O6 positions of guanine and the N3 position of adenine. The O6-methylguanine (O6-MeG) lesion is particularly cytotoxic; if unrepaired by the MGMT enzyme, it triggers futile mismatch repair cycles, culminating in DNA strand breaks and apoptosis. Tumors deficient in MGMT and possessing intact mismatch repair pathways are most sensitive to temozolomide, while those expressing MGMT or lacking mismatch repair show resistance. The drug’s efficacy and toxicity are modulated by the status of DNA repair pathways and are the basis for therapeutic and biomarker-based strategies to improve responses in cancer, especially gliomas.

Other names

Genomic DNACellular DNADNA (when discussing cytotoxic drug-DNA interactions)

Methylation/alkylation of DNA bases (primarily guanine at N7 and O6 positions, adenine at N3). Formation of DNA adducts triggers futile repair, DNA strand breaks, and apoptosis, especially in tumor cells deficient in DNA repair proteins such as MGMT or mismatch repair enzymes. Combination therapies: Inhibition of PARP and APE1 (abasic endonuclease 1) can increase cytotoxicity by preventing repair of temozolomide-induced lesions.