Topoisomerase Inhibitors
Topoisomerase inhibitors trap enzyme-DNA cleavage complexes, causing lethal DNA strand breaks in rapidly dividing cancer cells.
## Overview
Topoisomerases resolve topological stress in DNA during replication and transcription by creating transient strand breaks. Anticancer topoisomerase inhibitors stabilize the enzyme-DNA cleavage complex, converting these transient breaks into permanent double-strand breaks that trigger apoptosis.
## Topoisomerase I Inhibitors (Camptothecins)
Topoisomerase I relieves positive supercoils ahead of replication forks by creating single-strand breaks. Camptothecins bind the topo I-DNA cleavage complex, stabilizing it. When the replication fork collides with the stabilized complex, irreversible double-strand breaks occur.
**Irinotecan** is a prodrug converted by carboxylesterases to SN-38 (100-1000x more potent). UGT1A1 genotype influences SN-38 glucuronidation; UGT1A1*28 homozygotes have reduced SN-38 clearance and increased diarrhea/neutropenia risk. Used in colorectal cancer (FOLFIRI), gastric, and lung cancer.
**Topotecan** is used in relapsed ovarian cancer and small cell lung cancer. Renal excretion requires dose adjustment for creatinine clearance.
## Topoisomerase II Inhibitors
Topoisomerase II creates transient double-strand breaks to relieve torsional stress and decatenate daughter chromosomes after replication.
**Epipodophyllotoxins**: Etoposide and teniposide stabilize the topo II-DNA cleavage complex. Etoposide is used in testicular cancer, SCLC, lymphomas, and high-dose conditioning regimens. Risk of secondary AML (11q23 translocations) with cumulative exposure.
**Anthracyclines**: Doxorubicin, daunorubicin, and epirubicin are the most widely used oncologic drugs. They intercalate into DNA AND inhibit topo II. Additional mechanisms include free radical generation (cardiotoxic) and direct membrane disruption. Cardiotoxicity is dose-dependent; lifetime doxorubicin dose should not exceed 550 mg/m² (or 450 mg/m² with prior chest radiation). Dexrazoxane is a cardioprotectant that chelates iron and prevents free radical formation.
## Toxicities
- **Myelosuppression**: All agents; neutropenia is dose-limiting
- **Diarrhea**: Irinotecan — early (cholinergic, treat with atropine) and late (secretory, treat with loperamide)
- **Cardiotoxicity**: Anthracyclines (cumulative, irreversible dilated cardiomyopathy)
- **Secondary AML**: Etoposide and anthracyclines; balanced translocations at 11q23 and 21q22
## Key Takeaways
- Topo I inhibitors (camptothecins) cause S-phase-specific DNA damage via replication fork collision
- Topo II inhibitors (anthracyclines, etoposide) create double-strand breaks during replication and transcription
- Anthracycline cardiotoxicity is cumulative; lifetime dose limits must be respected
- UGT1A1*28 genotyping guides irinotecan dosing to prevent severe toxicity