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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 5/2008

01-04-2008 | Original Article

Role of cytokines (TNF-α, IL-1β and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide

Authors: Maria Luisa P. Melo, Gerly A. C. Brito, Rudy C. Soares, Sarah B. L. M. Carvalho, Johan V. Silva, Pedro M. G. Soares, Mariana L. Vale, Marcellus H. L. P. Souza, Fernando Q. Cunha, Ronaldo A. Ribeiro

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2008

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Abstract

Introduction

Irinotecan (CPT-11) is an inhibitor of DNA topoisomerase I and is clinically effective against several cancers. A major toxic effect of CPT-11 is delayed diarrhea; however, the exact mechanism by which the drug induces diarrhea has not been established.

Purpose

Elucidate the mechanisms of induction of delayed diarrhea and determine the effects of the cytokine production inhibitor pentoxifylline (PTX) and thalidomide (TLD) in the experimental model of intestinal mucositis, induced by CPT-11.

Materials and methods

Intestinal mucositis was induced in male Swiss mice by intraperitoneal administration of CPT-11 (75 mg/kg) daily for 4 days. Animals received subcutaneous PTX (1.7, 5 and 15 mg/kg) or TLD (15, 30, 60 mg/kg) or 0.5 ml of saline daily for 5 and 7 days, starting 1 day before the first CPT-11 injection. The incidence of delayed diarrhea was monitored by scores and the animals were sacrificed on the 5th and 7th experimental day for histological analysis, immunohistochemistry for TNF-α and assay of myeloperoxidase (MPO) activity, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and KC ELISA.

Results

CPT-11 caused significant diarrhea, histopathological alterations (inflammatory cell infiltration, loss of crypt architecture and villus shortening) and increased intestinal tissue MPO activity, TNF-α, IL-1β and KC level and TNF-α immuno-staining. PTX inhibited delayed diarrhea of mice submitted to intestinal mucositis and reduced histopathological damage, intestinal MPO activity, tissue level of TNF-α, IL-1β and KC and TNF-α immuno-staining. TLD significantly reduced the lesions induced by CPT-11 in intestinal mucosa, decreased MPO activity, TNF-α tissue level and TNF-α immuno-staining, but did not reduce the severity of diarrhea.

Conclusion

These results suggest an important role of TNF-α, IL-1β and KC in the pathogenesis of intestinal mucositis induced by CPT-11.
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Metadata
Title
Role of cytokines (TNF-α, IL-1β and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide
Authors
Maria Luisa P. Melo
Gerly A. C. Brito
Rudy C. Soares
Sarah B. L. M. Carvalho
Johan V. Silva
Pedro M. G. Soares
Mariana L. Vale
Marcellus H. L. P. Souza
Fernando Q. Cunha
Ronaldo A. Ribeiro
Publication date
01-04-2008
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 5/2008
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-007-0534-4

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