Camptothecins

CAMPTOTHECINS

The camptothecins are natural products derived from the Camptotheca acuminata tree originally found in China; theyinhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of this enzyme results in DNA damage. Topotecan and irinotecan are the two camptothecin analogs used in clinical practice in the USA. Although they both inhibit the same molecular target, their spec-trum of clinical activity is quite different. Topotecan is indicated in the treatment of advanced ovarian cancer as second-line therapy following initial treatment with platinum-based chemotherapy. It is also approved as second-line therapy of small cell lung cancer. The main route of elimination is renal excretion, and dosage must be adjusted in patients with renal impairment.

Irinotecan is a prodrug that is converted mainly in the liver by the carboxylesterase enzyme to the SN-38 metabolite, which is 1000-fold more potent as an inhibitor of topoisomerase I than the parent compound. In contrast to topotecan, irinotecan and SN-38 are mainly eliminated in bile and feces, and dose reduction is required in the setting of liver dysfunction. Irinotecan was originally approved as second-line monotherapy in patients with metastatic colorectal cancer who had failed fluorouracil-based therapy. It is now approved as first-line therapy when used in combination with 5-FU and leucovorin. Myelosuppression and diarrhea are the two most common adverse events (Table 54–4). There are two forms of diarrhea: an early form that occurs within 24 hours after administra-tion and is thought to be a cholinergic event effectively treated with atropine, and a late form that usually occurs 2–10 days after treat-ment. The late diarrhea can be severe, leading to significant electro-lyte imbalance and dehydration in some cases.