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New approaches to prevent intestinal toxicity of irinotecan-based regimens
- Publication Year :
- 2004
-
Abstract
- 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 β-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.
- Subjects :
- Diarrhea
Loperamide
Colorectal cancer
Metabolite
Pharmacology
Irinotecan
chemistry.chemical_compound
Glucuronides
Intestinal mucosa
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
heterocyclic compounds
Radiology, Nuclear Medicine and imaging
Enzyme Inhibitors
Glucuronosyltransferase
Active metabolite
Glucuronidase
biology
business.industry
Topoisomerase
General Medicine
bacterial β-glucuronidase inhibitors
medicine.disease
Antineoplastic Agents, Phytogenic
diarrhoea
irinotecan
digestive system diseases
Intestines
Oncology
chemistry
Fluorouracil
biology.protein
Camptothecin
Topoisomerase I Inhibitors
Colorectal Neoplasms
business
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....be6bef00d121e896302fa1939715df51