Topoisomerase I inhibitors
Topoisomerase I inhibitors
Topoisomerase I inhibitors are derivatives of camptothecin and inhibit the enzyme topoisomerase I. These agents are derived from a naturally occurring alkaloid from the Chinese tree Camptotheca acuminata. Currently available topoisomerase I inhibitors include:
- irinotecan
- topotecan.
Pharmacokinetics
Both irinotecan and topotecan are minimally absorbed and must be given I.V. Irinotecan undergoes metabolic changes to become the active metabolite SN-38. The half-life of SN-38 is about 10 hours; SN-38 is eliminated through biliary excretion. Topotecan is metabolized by the liver, although renal excretion is a significant path for elimination.
Pharmacodynamics
Topoisomerase I inhibitors exert their cytotoxic effect by inhibiting topoisomerase I enzyme, an essential enzyme that mediates the relaxation of supercoiled DNA.
Warning!
Adverse reactions to monoclonal antibodies
All monoclonal antibodies are associated with infusion-related reactions that have occasionally been fatal. These include fever, chills, shortness of breath, low blood pressure, and anaphylaxis.
In addition, the following adverse reactions can occur:
- Alemtuzumab is associated with myelosuppression and an increased risk of opportunistic infections, such as pneumocystitis, pneumonia, and fungal and viral infections.
- Gemtuzumab ozogamicin is associated with significant myelosuppression and liver toxicity.
- Ibritumomab tiuxetan is associated with increased myelosuppression to rituximab.
It’s all about that DNA
Topoisomerase inhibitors bind to the DNA topoisomerase I complex and prevent resealing, thereby causing DNA strand breaks. This results in impaired DNA synthesis.
Pharmacotherapeutics
Topoisomerase I inhibitors act against both solid tumors and hematologic malignancies:
Drug interactions
Topoisomerase I inhibitors, particularly irinotecan, can interact with other drugs.
- Ketoconazole significantly increases SN-38 serum levels, thereby increasing the risk of irinotecan-associated toxicities.
- Irinotecan when taken with diuretics may exacerbate dehydration caused by irinotecan-induced diarrhea.
- Laxatives taken with irinotecan can induce diarrhea.
- Prochlorperazine administered with irinotecan can increase the incidence of extrapyramidal toxicities
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