A Comprehensive Monograph on Temozolomide: Pharmacology, Clinical Efficacy, and Mechanisms of Resistance

Executive Summary

Temozolomide is an oral and intravenous alkylating agent that has fundamentally altered the therapeutic landscape for patients with high-grade malignant gliomas. As an imidazotetrazine derivative, it functions as a prodrug, undergoing non-enzymatic conversion at physiological pH to a reactive species that methylates tumor cell DNA, inducing cytotoxic lesions that lead to apoptosis. Its excellent oral bioavailability and ability to penetrate the blood-brain barrier make it uniquely suited for treating central nervous system malignancies.

The clinical utility of Temozolomide was definitively established by the landmark 2005 phase III trial by Stupp et al., which demonstrated that adding concomitant and adjuvant Temozolomide to standard radiotherapy significantly improved median and long-term survival for patients with newly diagnosed glioblastoma (GBM). This regimen, now known as the "Stupp protocol," was rapidly adopted as the global standard of care. The drug has also proven its efficacy in anaplastic astrocytoma (AA), first in the refractory/recurrent setting and more recently as an adjuvant therapy for newly diagnosed, IDH-mutant tumors.