Temozolomide — oral alkylating chemotherapy for brain tumors

How it works

Temozolomide is a prodrug that is spontaneously converted at physiological pH to an active methylating species. That metabolite transfers methyl groups to DNA bases (especially at the O6 and N7 positions of guanine), producing lesions that interfere with DNA replication and trigger tumor cell death. Cellular repair systems — most notably the DNA repair enzyme O6‑methylguanine‑DNA methyltransferase (MGMT) and the mismatch repair pathway — influence both sensitivity and resistance to the drug.

Clinical uses and administration

Its principal indications are newly diagnosed and recurrent high‑grade gliomas, including glioblastoma multiforme and anaplastic astrocytoma. Temozolomide is commonly given orally in cycles; a frequent approach combines daily temozolomide with radiotherapy followed by adjuvant cyclic dosing. It has also been tested in other cancers such as metastatic melanoma and in cases of brain metastases, though its routine use outside primary brain tumours is more limited.

Typical regimen and practical points

• Route: oral capsules; easily administered in outpatient settings and compatible with concomitant radiotherapy.
• Dosing pattern: most regimens use short daily courses repeated every 28 days, with dose modifications for toxicity.
• Important biomarker: tumour MGMT promoter methylation status is predictive of better response and is often used in treatment planning.

Side effects and monitoring

Common toxicities include nausea, fatigue and dose‑dependent myelosuppression (neutropenia and thrombocytopenia). Blood counts require regular monitoring during treatment. Less common but important concerns are infections related to low white cell counts and rare reports of secondary haematological malignancies after prolonged exposure. Supportive care and dose adjustments help manage adverse effects.

Resistance, research and notable facts

Resistance mechanisms principally involve active DNA repair by MGMT and defects in mismatch repair. Research continues into combining temozolomide with agents that inhibit repair pathways, immunotherapies, and personalised strategies guided by molecular tumour profiling. Introduced into clinical practice in the late 1990s and adopted more broadly following trials demonstrating improved outcomes when combined with radiotherapy, temozolomide remains a cornerstone of contemporary care for many patients with high‑grade gliomas.