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.

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