Topoisomerase Inhibitors

Topoisomerases & Inhibitors - Unwinding Trouble

• Topoisomerases (Topo): Vital enzymes that untangle DNA by cutting and resealing strands, relieving supercoiling during replication, transcription, and repair.
  • Topo I: Induces transient single-strand breaks to alter DNA topology.
  • Topo II: Induces transient double-strand breaks, requiring ATP, to pass another DNA segment through the break.
• General Inhibitor Mechanism:
  • Stabilize the "cleavable complex" (covalent Topo-DNA intermediate).
  • Prevent DNA re-ligation after cleavage.
  • Collision with replication forks converts these complexes into permanent DNA strand breaks, leading to cell cycle arrest and apoptosis.
• Classification Overview:
  • Topo I Inhibitors (e.g., Camptothecins: Irinotecan, Topotecan)
  • Topo II Inhibitors (e.g., Anthracyclines: Doxorubicin, Daunorubicin; Epipodophyllotoxins: Etoposide, Teniposide)

⭐ Topoisomerases are essential for managing DNA topology during cell division, making them prime targets for cancer therapy.

Topo-I Inhibitors - Campto's Crew

• Class: Camptothecins
  • Irinotecan
  • Topotecan
• MOA: Bind Topo I-DNA complex → prevent re-ligation of single-strand breaks. S-phase specific.
• Pharmacokinetics (PK):
  • Irinotecan: Prodrug → SN-38 (active). Metabolized by UGT1A1.
  • Topotecan: Renal excretion.
• Clinical Uses:
  • Irinotecan: Colorectal cancer (FOLFIRI).
  • Topotecan: Ovarian cancer, Small Cell Lung Cancer (SCLC).
• Adverse Effects (AEs):
  • Irinotecan: Severe diarrhea (early cholinergic; late SN-38 mediated 📌 'I-run-to-the-can'), myelosuppression.
  • Topotecan: Myelosuppression.

⭐ Polymorphisms in UGT1A1 gene (e.g., UGT1A1*28) significantly ↑ risk of severe neutropenia & diarrhea with Irinotecan due to impaired SN-38 glucuronidation.

Topo-II Inhibitors: Anthracyclines - Red Alert Toxins

• Class: Doxorubicin, Daunorubicin, Epirubicin, Idarubicin.
• MOA:
  • Intercalation into DNA.
  • Inhibition of Topo II (stabilizes DNA-Topo II complex).
  • Generation of free radicals (via quinone moiety).
• Clinical Uses: Broad spectrum (hematologic malignancies, solid tumors - breast, ovarian, lung, sarcomas).
• Adverse Effects:
  • Cardiotoxicity (acute vs. chronic, dose-dependent, dilated cardiomyopathy; monitor LVEF; Doxorubicin cumulative dose <550 mg/m²). 📌 'Heart' for cardiotoxicity.
  • Myelosuppression (dose-limiting).
  • Alopecia.
  • Nausea/Vomiting.
  • Extravasation injury (potent vesicant).
  • Red/orange discoloration of urine. 📌 Doxo'RUBY'cin -> RUBY red urine.

⭐ Dexrazoxane is an iron-chelating agent used to prevent Doxorubicin-induced cardiotoxicity in patients receiving high cumulative doses (>300 mg/m²).

Topo-II Inhibitors: Epipodophyllotoxins - Pod's Powerful Punch

• Class: Etoposide, Teniposide.
• MOA: Inhibit Topo II → double-strand breaks. Cell cycle specific (late S, G2 phase).
• PK (Etoposide): Oral & IV; variable bioavailability; metabolized; renal/biliary excretion.
• Uses: Testicular cancer (BEP regimen), Small Cell Lung Cancer (SCLC), lymphomas, leukemias.
• AEs: Myelosuppression (dose-limiting), alopecia, N/V, hypotension (rapid infusion), secondary malignancies (e.g., AML). 📌 EtoPOside -> POtential for secondary leukemia.

⭐ Etoposide is notorious for causing therapy-related acute myeloid leukemia (t-AML), particularly with prolonged or high-dose schedules.

High‑Yield Points - ⚡ Biggest Takeaways

• Topoisomerase I inhibitors like Irinotecan and Topotecan cause single-strand DNA breaks.
• Irinotecan (active metabolite SN-38) is notorious for severe diarrhea; UGT1A1 polymorphism increases toxicity.
• Topoisomerase II inhibitors include Etoposide (causes double-strand breaks) and Anthracyclines (e.g., Doxorubicin).
• Anthracyclines (Doxorubicin, Daunorubicin) cause dose-dependent cardiotoxicity (prevent with Dexrazoxane) and red urine.
• Etoposide can lead to myelosuppression, alopecia, and secondary leukemias.