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The effect of cytostatic drug treatment on intestine-specific transcription factors Cdx2, GATA-4 and HNF-1alpha in mice.

Abstract：

:Chemotherapy-induced intestinal damage is a very important dose-limiting side effect for which there is no definitive prophylaxis or treatment. This is in part due to the lack of understanding of its pathophysiology and impact on intestinal differentiation. The objective of this study was to investigate the gene expression of the small intestinal transcription factors HNF-1alpha, Cdx2, GATA-4 in an experimental model of methotrexate (MTX)-induced intestinal damage, and to correlate these alterations with histological damage, epithelial proliferation and differentiation. HNF-1alpha, Cdx2 and GATA-4 are critical transcription factors in epithelial differentiation, and in combination they act as promoting factors of the sucrase-isomaltase (SI) gene, an enterocyte-specific differentiation marker which is distinctly downregulated after MTX treatment. Mice received two doses of MTX i.v. on two consecutive days and were sacrificed 1, 3 and 7 or 9 days after final injection. Segments of the jejunum were taken for morphological, immunohistochemical and quantitative analyses. Intestinal damage was most severe at day 3 and was associated with decreased expression of the transcriptional factors HNF-1alpha, Cdx2 and GATA-4, which correlated well with decreased expression of SI, and seemed inversely correlated with enhanced proliferation of epithelial crypt cells. During severe damage, the epithelium was preferentially concerned with proliferation rather than differentiation, most likely in order to restore the small intestinal barrier function rather than maintaining its absorptive function. Since HNF-1alpha, Cdx2 and GATA-4 are critical for intestine-specific gene expression and therefore crucial in epithelial differentiation, these results may explain, at least in part, why intestinal differentiation is compromised during MTX treatment.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

de Koning BA,Lindenbergh-Kortleve DJ,Pieters R,Rings EH,Büller HA,Renes IB,Einerhand AW

doi

10.1007/s00280-005-0119-z

keywords:

subject

Has Abstract

pub_date

2006-06-01 00:00:00

pages

801-10

issue

eissn

0344-5704

issn

1432-0843

journal_volume

pub_type

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The effect of cytostatic drug treatment on intestine-specific transcription factors Cdx2, GATA-4 and HNF-1alpha in mice.