Topoisomerase I inhibitors
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
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.
Topoisomerase I inhibitors exert their cytotoxic
effect by inhibit-ing topoisomerase I enzyme, an essential enzyme that mediates
the relaxation of supercoiled 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.
Topoisomerase I inhibitors act against both solid
tumors and hematologic malignancies:
Irinotecan is used to treat colorectal cancer and small-cell lung
Topotecan is used to treat ovarian cancer, small-cell lung can-cer, and
acute myeloid leukemia.
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.)