Definition
Topoisomerase I inhibitors are chemotherapeutic agents that inhibit Topoisomerase I, an enzyme that relaxes supercoiled DNA by creating single-strand breaks. By stabilizing the DNA-Topoisomerase I complex, these drugs prevent DNA religation, leading to single-strand DNA breaks, replication fork collapse, and apoptosis. They are particularly effective against rapidly proliferating tumor cells.
Common Agents
| Drug | Brand Name | Indications | Route |
|---|---|---|---|
| Irinotecan | Camptosar | Colorectal cancer (advanced/metastatic) | IV |
| Topotecan | Hycamtin | Ovarian cancer, small-cell lung cancer, cervical cancer | IV or oral |
Mechanism of Action
- Drug binds to Topo I-DNA complex, preventing religation of single-strand breaks.
- Accumulation of DNA breaks occurs during DNA replication.
- Replication fork collapse leads to double-strand breaks and apoptosis.
Pharmacist-Relevant Considerations
| Toxicity / Concern | Notes / Monitoring |
|---|---|
| Myelosuppression | Dose-limiting; monitor CBC closely |
| Diarrhea (Irinotecan) | Early-onset: cholinergic (treat with atropine); late-onset: secretory, treat with loperamide |
| Mucositis | Especially with topotecan; oral hygiene important |
| Hepatic metabolism | Irinotecan metabolized by CYP3A4; dose adjustment in hepatic impairment |
| Drug interactions | CYP3A4 inhibitors/inducers can alter irinotecan levels |
| Supportive care | Antiemetics (5-HT3 ± dexamethasone), hydration, diarrhea management, growth factors if needed |
Dosing Highlights
- Irinotecan: Often given IV weekly or every 2–3 weeks depending on regimen; monitor for cumulative toxicity.
- Topotecan: IV or oral; dosing adjusted for renal function.