Semustine

• Class: Alkylating agent – Nitrosourea derivative (structurally related to lomustine).
• Mechanism of Action:
  • Alkylates DNA → induces cross-links and strand breaks → inhibition of DNA/RNA synthesis.
  • Highly lipid-soluble → crosses the blood–brain barrier effectively.
• Clinical Uses (historical/limited today due to toxicity):
  • Primary and metastatic brain tumors (gliomas, astrocytomas).
  • Gastrointestinal cancers (stomach, colon) in the past.
  • Investigational in various solid tumors.
  • Rarely used today because of cumulative carcinogenicity and severe long-term toxicities.
• Dosing:
  • Oral agent, usually given every 6 weeks.
  • Typical range: 100–150 mg/m² as a single oral dose (similar to lomustine).
• Toxicities:
  • Delayed myelosuppression (nadir at 4–6 weeks) → dose-limiting.
  • Pulmonary fibrosis (dose- and cumulative-dependent).
  • Nephrotoxicity and hepatotoxicity (with chronic use).
  • Carcinogenic/Leukemogenic risk – secondary malignancies (especially acute leukemia, myelodysplastic syndromes).
  • Nausea/vomiting, moderate emetogenic potential.
• Monitoring:
  • CBC weekly × 6 weeks after each dose.
  • Pulmonary function tests (baseline and periodically).
  • Renal and liver function tests.
  • Monitor cumulative dose strictly (risk of pulmonary fibrosis and leukemia increases sharply).

In summary:

Semustine is an oral nitrosourea with strong CNS penetration, historically used in brain and GI cancers. Its use is now very limited due to cumulative pulmonary fibrosis and significant leukemogenic/carcinogenic risk, which outweigh its clinical benefits compared to newer agents.