Thiotepa

• Class: Alkylating agent (polyfunctional aziridine derivative).
• Structure: Triethylenethiophosphoramide (TEPA).
• Mechanism of Action:
  • Alkylates DNA at the N7 position of guanine.
  • Crosslinks DNA strands → inhibits DNA replication and RNA transcription → apoptosis.
  • Non–cell cycle specific (works in resting and dividing cells).

Clinical Use

• Conditioning regimens for hematopoietic stem cell transplantation (HSCT) (esp. in leukemia, lymphoma, solid tumors, pediatric indications).
• Intravesical therapy for superficial bladder cancer.
• Intrathecal therapy (rare, for leptomeningeal metastases).
• Sometimes in ovarian and breast cancer (historical/less common now).

Pharmacokinetics

• Highly lipophilic, crosses the blood–brain barrier (useful in CNS malignancies).
• Rapid metabolism in liver → TEPA (active metabolite).
• Excretion: Mainly renal.

Toxicities / Monitoring

• Dose-limiting: Myelosuppression (neutropenia, thrombocytopenia).
• Other: Nausea, vomiting, mucositis, hepatotoxicity, neurotoxicity at high doses, alopecia, skin hyperpigmentation.
• Intravesical: chemical cystitis, local irritation.
• Monitoring: CBC, liver/renal function, signs of infection/bleeding.

Summary:

Thiotepa is a polyfunctional alkylating agent mainly used in HSCT conditioning and CNS/bladder cancers, with myelosuppression as its main limiting toxicity. Its CNS penetration makes it unique compared to many other alkylators.