Does the response of the intestinal epithelium to keratinocyte growth factor vary according to the method of administration?
BACKGROUND
Keratinocyte growth factor (KGF) is a potent mitogen and may be of value for the treatment of conditions such as short bowel syndrome and chemotherapy-induced mucositis. However the most efficacious route and method of administration is unclear.


METHODS
Rats maintained by total parenteral nutrition (TPN) were given KGF (1 mg/kg/rat/day, i.v.) infused continuously or as a once-daily injection. The same dose was also given s.c. to chow-fed rats. Changes in gut growth were assessed by measurement of wet weight, proliferation (vincristine induced metaphase arrest) and crypt branching index. Changes in gut hormone profile were also determined to examine if any trophic effects were mediated via this mechanism.


RESULTS
KGF caused a 70-100% increase in wet weight of the stomach, small and large intestine of TPN-fed rats (P < 0.01) with no significant differences seen between the two methods of administration. The increase in metaphase counts was greatest in the stomach (about seven-fold P < 0.01), but was less pronounced in the distal small intestine and colon (about 50% increase). The trophic effect of KGF was much less prominent in orally-fed rats. Crypt branching index was significantly reduced by KGF in the proximal small intestine of TPN, but not orally-fed rats. Plasma gastrin, PYY, total glucagon, enteroglucagon and GLP-1 all increased by two-three-fold (all P < 0.01) in response to KGF whereas insulin levels fell by about 25% in the TPN group.


CONCLUSIONS
The mitogenic action of KGF occurred predominantly in the stomach and proximal small intestine. Its efficacy was less pronounced in orally-fed animals, suggesting KGF may be of greatest benefit in conditions associated with lowered intestinal proliferation. Clinical trials of KGF can probably use single daily i.v. injections without reduction in efficacy.
Goodlad
R A
RA
Histopathology Unit, Imperial Cancer Research Fund, London, UK. goodlad@icrf.icnet.uk
Mandir
N
N
Meeran
K
K
Ghatei
M A
MA
Bloom
S R
SR
Playford
R J
RJ
D000818:Animals; D001835:Body Weight; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D005755:Gastrins / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides / Q000378:metabolism; D006133:Growth Substances / Q000008:administration & dosage / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008677:Metaphase; D009929:Organ Size; D010446:Peptide Fragments / Q000378:metabolism; D019894:Peptide YY / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
C496455:Fgf7 protein, rat; D051526:Fibroblast Growth Factor 10; D005755:Gastrins; D006133:Growth Substances; D010446:Peptide Fragments; D011498:Protein Precursors; D019894:Peptide YY; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon