The effects of keratinocyte growth factor in preclinical models of mucositis

Abstract

The epithelium of the oral cavity and small intestine of the gastrointestinal tract have a high rate of cell renewal and as such, are sensitive to cytotoxic therapies that kill rapidly dividing cells. Mucositis is a complication of cancer therapy where impairment of the regenerative capacity of the epithelium leads to atrophy, ulceration and a loss of barrier function. Keratinocyte growth factor (KGF) is an epithelial cell-specific growth and differentiation factor that is trophic for the mucosal epithelium of the gastrointestinal tract. In this study, KGF in normal animals caused epithelial thickening in the squamous epithelium of the oral cavity and increased crypt depth and villus height of the small intestine. It also appeared to regulate gene expression in these tissues including that of some antioxidant enzymes and intestinal trefoil protein. KGF has been shown to be efficacious in several preclinical models of mucositis where KGF pretreatment reduced weight loss typically seen during and after the course of therapy and significantly improved survival. At a tissue level KGF reduced atrophy, accelerated regrowth, and decreased ulcer formation of the oral epithelium after irradiation, and improved crypt survival and prevented villus atrophy in the small intestine of irradiated or chemotherapy-treated mice. Preliminary studies suggest that its efficacy may be partly a consequence of the growth and differentiation effect, and also partly due to regulation of the expression of genes that play a role in mucosal protection. These data suggest that KGF may be useful for the prevention or treatment of mucositis in patients treated with regimens of cancer therapy that have gastrointestinal toxicity.

Figure 1

Semi‐thin sections of the ventral surface of the mouse tongue in normal, control mice and mice that were treated with 5 mg/kg KGF for 3 consecutive days. Increased cellularity as well as increased granule size and number are evident.

Figure 2

The effect of KGF on several measures of epithelial growth as assessed in cross‐sections of the ventral tongues of mice. Each bar represents the mean ± standard error of the mean (SEM) where n = 5 mice/group. * P  < 0.05 compared to control. The granule counts were performed on photographs of cross sections enlarged to the same final magnification so that data are expressed per an identical unit area. The BrdU and mitotic figure counts were also done in cross‐sections of tongue where the numbers of BrdU‐positive cells or mitotic figures were counted in an identical unit length of tongue for each mouse in both treatment groups.

Figure 3

In situ hybridization for mRNA of GST and nsGPX in the epithelium of the ventral tongues of mice. These photomicrographs show that the mRNA transcript for these genes is upregulated in the oral squamous epithelium by treatment of the mice with 5 mg/kg/day for 3 consecutive days.

Figure 4

In situ hybridization of rat small intestine showing mRNA expression for ITF. These photomicrographs show ITF that is normally expressed in the goblet cells of the small intestinal epithelium is apparently up‐regulated in response to systemic administration of 5 mg/kg for 6 days.

Figure 5

The effect of KGF pretreatment on the small intestines of mice irradiated with 12 Gy. While these measures of tissue wet weight, DNA and protein are reduced to less than half of that in normal, unirradiated mice (data not shown), the mice pretreated with KGF show that there measures of growth are improved relative to the radiated group.