Topoisomerase Inhibitors

TOPOISOMERASE INHIBITORS


TOPOISOMERASE INHIBITORS

  • Drug groups included: Camptothecins & Epipodophyllotoxins.

1. Camptothecins:

  • Obtained from Camptotheca acuminata tree.
  • Drug included: 
    • Irinotecan & topotecan.

MOA:

  • Act by inhibiting topoisomerase I enzyme.
  • Topoisomerase I enzyme nicks introduces negative supercoils & reseals DNA strand.

Individual drug details:

  • Topotecan:
    • Excreted by renal route.
    • Used for advanced ovarian carcinoma.
    • Dose-limiting toxicity – Neutropenia.
  • Irinotecan:
    • Prodrug.
    • Converted in liver to active metabolite, SN-38.
    • Eliminated in bile & feces.
      • Hence, dose reduction required in hepatic failure.
    • DOC for advanced colorectal carcinoma in combination with 5-FU.
  • Specific adverse effects:
    • Dose-limiting toxicity – Diarrhea.
    • Myelosuppression.
    • Cause cholinergic syndrome:
      • Manifested as diarrhea, sweating, hypersalivation, lacrimation, rhinorrhea, abdominal cramps & bradycardia.
      • Due to inhibition of acetylcholine esterase.
      • Occurs within 24 hours.

2. Epipodophyllotoxins:

  • Drug included:
    • Podophyllotoxin (Semisynthetic derivatives – Etoposide & teniposide).
    • Used for its emetic, cathartic & antihelminthic effects.
  • MOA:
    • Acts by binding to tubulin.
    • Acts at junction of late S & early G2 phase of cell cycle.
  • General adverse effects:
    • Gastrointestinal distress & myelosuppression.

Individual drug details:

Etoposide:

  • Indicated for testicular, prostatic & oat cell carcinoma of lung.

Specific adverse effects:

  • Cause acute non-lymphocytic (acute monocytic or mono-myelocytic) leukemia.
    • Develops at a short time interval (1 to 3 years) after end of therapy.
    • Compared to alkylating agents induced leukemia (require 4-5 years).
  • Distinguishing feature – Absence of myelodysplastic period preceding leukemia.
  • Hepatotoxic – At high doses.

Exam Important

  • Topoisomerase inhibitors act by inhibiting topoisomerase I enzyme.
  • Topotecan is used for advanced ovarian carcinoma.
  • Dose-limiting toxicity of Topotecan is Neutropenia.
  • Irinotecan is a prodrug converted in liver to active metabolite, SN-38.
  • Irinotecan is DOC for advanced colorectal carcinoma in combination with 5-FU.
  • Irinotecan causes cholinergic syndrome, due to inhibition of acetylcholine esterase.
  • Dose-limiting toxicity of Irinotecan is diarrhea.
  • Semisynthetic derivatives of Podophyllotoxin includes Etoposide & teniposide.
  • Etoposide is indicated for testicular, prostatic & oat cell carcinoma of lung.
  • Etoposide causes acute non-lymphocytic (acute monocytic or mono-myelocytic) leukemia within short time interval (1 to 3 years) after end of therapy with a distinguishing feature of absence of myelodysplastic period preceding leukemia.
  • Etoposide is hepatotoxic at higher doses.
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