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.
Original language | English |
---|---|
Pages (from-to) | 555-562 |
Number of pages | 8 |
Journal | Cancer Treatment Reviews |
Volume | 30 |
Issue number | 6 |
DOIs | |
Publication status | Published - Oct 2004 |
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Keywords
- Bacterial β-glucuronidase inhibitors
- Diarrhoea
- Irinotecan
ASJC Scopus subject areas
- Oncology
- Urology
Cite this
New approaches to prevent intestinal toxicity of irinotecan-based regimens. / Alimonti, Andrea; Gelibter, Alain; Pavese, Ida; Satta, Francesco; Cognetti, Francesco; Ferretti, Gianluigi; Rasio, Debora; Vecchione, Aldo; Di Palma, Mario.
In: Cancer Treatment Reviews, Vol. 30, No. 6, 10.2004, p. 555-562.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - New approaches to prevent intestinal toxicity of irinotecan-based regimens
AU - Alimonti, Andrea
AU - Gelibter, Alain
AU - Pavese, Ida
AU - Satta, Francesco
AU - Cognetti, Francesco
AU - Ferretti, Gianluigi
AU - Rasio, Debora
AU - Vecchione, Aldo
AU - Di Palma, Mario
PY - 2004/10
Y1 - 2004/10
N2 - 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.
AB - 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.
KW - Bacterial β-glucuronidase inhibitors
KW - Diarrhoea
KW - Irinotecan
UR - http://www.scopus.com/inward/record.url?scp=4444241175&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4444241175&partnerID=8YFLogxK
U2 - 10.1016/j.ctrv.2004.05.002
DO - 10.1016/j.ctrv.2004.05.002
M3 - Article
C2 - 15325035
AN - SCOPUS:4444241175
VL - 30
SP - 555
EP - 562
JO - Cancer Treatment Reviews
JF - Cancer Treatment Reviews
SN - 0305-7372
IS - 6
ER -