Topoisomerase I inhibitors

Topoisomerase I inhibitors

Topoisomerase I inhibitors are derivatives of camptothecin andinhibit the enzyme topoisomerase I. These agents are derived from a naturally occurring alkaloid from the Chinese tree Camptothecaacuminata. Currently available topoisomerase I inhibitors in-clude:

·                 irinotecan

·                 topotecan.

Pharmacokinetics

Both irinotecan and topotecan are minimally absorbed and must be given I.V. Irinotecan undergoes metabolic changes to be-come 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 signifi-cant path for elimination.

Pharmacodynamics

Topoisomerase I inhibitors exert their cytotoxic effect by inhibit-ing topoisomerase I enzyme, an essential enzyme that mediates the relaxation of supercoiled DNA.

It’s all about that DNA

Topoisomerase inhibitors bind to the DNA topoisomerase I com-plex 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:

·                 Irinotecan is used to treat colorectal cancer and small-cell lung cancer.

·                 Topotecan is used to treat ovarian cancer, small-cell lung can-cer, and acute myeloid leukemia.

Drug interactions

Topoisomerase I inhibitors, particularly irinotecan, can interact with other drugs.

·                 Ketoconazole significantly increases SN-38 serum levels, there-by increasing the risk of irinotecan-associated toxicities.

·                 Irinotecan when taken with diuretics may exacerbate dehydra-tion caused by irinotecan-induced diarrhea.

·                 Laxatives taken with irinotecan can induce diarrhea.

·                 Prochlorperazine administered with irinotecan can increase the incidence of extrapyramidal toxicities. (See Adverse reactions totopoisomerase I inhibitors.)