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.