Temozolomide

• Class: Alkylating-like agent – Triazene derivative (oral analog of dacarbazine).
• Mechanism of Action:
  • Temozolomide undergoes spontaneous non-enzymatic conversion at physiologic pH to the active compound MTIC (monomethyl triazeno imidazole carboxamide).
  • MTIC methylates DNA at the O6 and N7 positions of guanine → mispairing and strand breaks → inhibition of DNA replication and induction of apoptosis.
  • Unlike dacarbazine, it does not require hepatic activation → predictable oral bioavailability.
• Clinical Uses:
  • Glioblastoma multiforme (GBM) – frontline in combination with radiotherapy (the “Stupp protocol”), and as maintenance.
  • Anaplastic astrocytoma (recurrent or refractory).
  • Investigational/off-label in metastatic melanoma and other tumors.
• Dosing:
  • Oral, once daily.
  • Standard Stupp protocol (GBM):
    • 75 mg/m²/day during radiotherapy (concurrent phase, up to 42 days).
    • Then 150–200 mg/m²/day × 5 days every 28 days (adjuvant/maintenance phase, typically 6 cycles).
  • Dose adjustments required for renal/hepatic impairment and hematologic toxicity.
• Toxicities:
  • Myelosuppression (dose-limiting; neutropenia, thrombocytopenia).
  • Nausea and vomiting (moderately emetogenic; premedication recommended).
  • Opportunistic infections (especially Pneumocystis jirovecii pneumonia [PJP] during concurrent chemoradiation) → prophylaxis indicated.
  • Fatigue, headache, constipation, alopecia.
  • Rare: hepatotoxicity, pulmonary toxicity.
• Monitoring:
  • CBC (weekly during concurrent phase; before each cycle during maintenance).
  • Liver function tests.
  • Assess infection risk; PJP prophylaxis (TMP-SMX or alternative) if given with radiotherapy.

In summary:

Temozolomide is an oral triazene alkylating agent, widely used in glioblastoma and astrocytomas. It offers reliable oral bioavailability, avoids hepatic activation, but requires close monitoring for myelosuppression and infection risk, especially PJP during chemoradiation.