Gastrointestinal
mucositis involves many changes at the gene level, affecting epithelial/subepithelial interactions and leading to overt damage. The regional specificity and time course of these changes, and how they relate to subsequent
mucositis development however remain unknown. The aim of this study was to determine the early time course of gene expression changes along the gastrointestinal tract of the DA rat following
chemotherapy. Female DA rats were treated with a single dose of 200 mg/kg
irinotecan to induce
mucositis, and were killed at short intervals following treatment. Small sections of stomach, jejunum and colon were harvested for analysis of genetic profiles.
RNA was hybridised to high density Affymetrix
oligonucleotide microarrays. Data analysis was carried out with software package, TimeCourse, freely available through Bioconductor. As early as 1 hr following
chemotherapy, expression of hundreds of genes was altered, including those for
transcription factors, stress response
proteins and
protein turnover. These genes are involved in cell proliferation, differentiation and apoptosis along with other cellular processes. At early time points, there was a significant response involving the
mitogen-activated protein kinase pathway, cell cycle regulation and
cytokine receptor signalling. At later time points, changes to the
complement cascade became prominent. We have shown that changes in gene expression following
chemotherapy occur by 1 hr, and persist for at least 72 hr
after treatment. Many of these changes are highly likely to be specifically related to the subsequent development of gastrointestinal
mucositis.