New approaches to prevent intestinal toxicity of irinotecan-based regimens.
BACKGROUND
Irinotecan is a selective inhibitor of topoisomerase I, an enzyme part of the replication and transcription system of DNA. Irinotecan is employed, with different modalities, in the treatment of metastatic colorectal cancer, and recently it has been officially approved in association with fluorouracil (FU) and leucovorin (LV) as a first-line option in metastatic colorectal cancer.


RESULTS
One of the problems linked to the administration of this drug is the high intestinal toxicity, which constitutes its dose limiting toxicity (DLT). In routine practice, loperamide is employed as symptomatic drug for the treatment of CPT-11-induced diarrhoea, but is not completely adequate to control the problem. The role of the intestinal bacterial microflora in the pathogenesis of CPT-11-induced intestinal toxicity has been recently discovered. The active metabolite of CPT-11, SN38, is generated from CPT-11 by sieric carboxylesterase, and subsequently conjugated to SN38-G by hepatic UDP-glucuronyltransferase. SN38-G is the inactive metabolite of CPT-11 and is excreted into the small intestine, from which it is eliminated in the faeces. Some studies have shown the ability of intestinal bacterial beta-glucoronidases to transform SN38-G into SN38, causing direct damage to the intestinal mucosa. Thus, alternative strategies such as intestinal alkalinization and anti-cyclooxygenase 2 (COX-2) therapy have been explored.


CONCLUSIONS
In this review, we will illustrate the mechanisms which cause the CPT-11-induced diarrhoea and the potential measures available to prevent it.
Alimonti
Andrea
A
Division of Medical Oncology, San Pietro Hospital, FBF International, Rome, Italy.
Gelibter
Alain
A
Pavese
Ida
I
Satta
Francesco
F
Cognetti
Francesco
F
Ferretti
Gianluigi
G
Rasio
Debora
D
Vecchione
Aldo
A
Di Palma
Mario
M
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D005966:Glucuronidase / Q000037:antagonists & inhibitors; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors; D006801:Humans; D007422:Intestines / Q000187:drug effects* / Q000382:microbiology*; D000077146:Irinotecan; D008139:Loperamide / Q000008:administration & dosage; D059004:Topoisomerase I Inhibitors
C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D020719:Glucuronides; D059004:Topoisomerase I Inhibitors; D008139:Loperamide; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D005966:Glucuronidase; D002166:Camptothecin