Temozolomide (TMZ) is an antineoplastic from the alkylating agent drug class. This molecule is an imidazotetrazine prodrug that is stable at acidic pH but undergoes spontaneous nonenzymatic hydrolysis at neutral or slightly basic pH; allowing its administration to be oral and intravenous too. Temozolomide is indicated in the treatment of newly diagnosed glioblastoma and refractory anaplastic astrocytoma. This molecule is a very small lipophilic, it can then easily get through the blood-brain barrier. The mechanism of action of this drug needs many reactions beforehand: TMZ undergoes spontaneous nonenzymatic breakdown at physiological pH to form 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which then reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation. TMZ is a bit specific to tumor cells because glioblastoma typically possesses a more alkaline pH than healthy tissue, favoring its activation in tumor cells. The methyl diazonium cation formed methylates DNA at the N7 and O6 position of guanine, and the N3 position of adenine. The cellular repair system will eventually lead to DNA strand breaks that will end in the apoptosis of the cell.

Temozolomide Pathway References