Irinotecan (
CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of
carcinomas by inhibiting
DNA topoisomerase I (
Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe
diarrhea) hinder its clinical use. The latter consists of early and late-onset
diarrhea, occurring within 24 hr or > or = 24 hr after
CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced
diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset
diarrhea is observed immediately after
CPT-11 infusion and probably due to the inhibition of
acetylcholinesterase activity, which can be eliminated by administration of
atropine. Late-onset
diarrhea appears to be associated with intestinal exposure to
SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of
CPT-11, which may bind to
Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa.
CPT-11 and
SN-38 may also stimulate the production of pro-inflammatory
cytokines and
prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset
diarrhea with oral high-dose
loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate
diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral
antibiotics,
enzyme inducers,
P-glycoprotein (PgP)
inhibitors, cyclooxygenase-2 (COX-2) inhibitors,
tumor necrosis factor-alpha (
TNF-alpha) inhibitors, or blockers of biliary excretion of
SN-38. Further studies are needed to identify the molecular targets associated with
CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced
diarrhea.