Definition
Topoisomerase inhibitors are antineoplastic agents that interfere with the activity of topoisomerases, enzymes that regulate DNA topology during replication and transcription. By preventing proper DNA unwinding or religation, these drugs induce DNA damage and cell death, particularly in rapidly dividing cancer cells.
Types of Topoisomerases
- Topoisomerase I (Topo I) – cuts one strand of DNA.
- Inhibitors: Camptothecin derivatives (e.g., irinotecan, topotecan)
- Topoisomerase II (Topo II) – cuts both strands of DNA.
- Inhibitors: Anthracyclines (e.g., doxorubicin, daunorubicin), Epipodophyllotoxins (e.g., etoposide, teniposide)
Representative Agents
| Class | Examples | Primary Indications | Route |
|---|---|---|---|
| Topo I inhibitors | Irinotecan, Topotecan | Colorectal, ovarian, small-cell lung cancer | IV (topotecan also oral) |
| Topo II inhibitors | Doxorubicin, Daunorubicin, Etoposide, Teniposide | Breast, leukemia, lymphoma, sarcoma | IV (etoposide oral in some cases) |
Mechanism of Action
- Topo I inhibitors: stabilize the single-strand DNA-topoisomerase complex → DNA breaks during replication → apoptosis.
- Topo II inhibitors: stabilize the double-strand DNA-topoisomerase II complex → double-strand DNA breaks → apoptosis.
Pharmacist-Relevant Considerations
| Toxicity / Concern | Notes |
|---|---|
| Myelosuppression | Dose-limiting; monitor CBC closely |
| Gastrointestinal | Diarrhea common with irinotecan (early cholinergic vs. late secretory) |
| Cardiotoxicity | Doxorubicin, daunorubicin → cumulative dose-related; monitor LVEF |
| Secondary malignancies | Topo II inhibitors (etoposide) associated with therapy-related AML |
| Mucositis | Common with IV Topo I and II inhibitors |
| Hepatic metabolism | Many agents (irinotecan, etoposide) require dose adjustment in liver dysfunction |
| Drug interactions | CYP3A4 for irinotecan; P-gp substrates (etoposide) |
Supportive Care
- Antiemetics: 5-HT3 antagonists ± NK1 antagonists
- Growth factors: G-CSF for neutropenia prophylaxis
- Diarrhea management: Atropine for early-onset irinotecan diarrhea; loperamide for late-onset
- Cardiac monitoring: Baseline and periodic echocardiogram for anthracyclines