Stimulation of intestinal epithelial restitution by prostaglandin E(1) analogue.
BACKGROUND
5-Fluorouracil (5-FU) causes intestinal mucosal damage and malabsorption. We have recently reported that coadministration of 17 S,20-dimethyl- trans- lower right triangle (2)-prostaglandin E(1) (OP-1206), a stable synthetic analogue of prostaglandin E(1), with 5-FU to rats protects the small intestine from 5-FU-induced damage. Enterocyte proliferation would contribute to the restitution of the wounded intestinal mucosa. Thus, we investigated the effect of OP-1206 on the proliferation of rat jejunal crypt cells (IEC-6 cells) treated with 5-FU.


METHODS
Proliferation of IEC-6 cells was evaluated in terms of [(3)H]-thymidine incorporation and using the 3-(4,5-dimethyl-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Mucosal healing was assessed by measuring the speed of resealing across the denuded area of an IEC-6 cell monolayer.


RESULTS
OP-1206 stimulated [(3)H]-thymidine incorporation into subconfluent IEC-6 cells pretreated with 5-FU and increased the number of IEC-6 cells. AH23848B, an EP4 prostaglandin receptor antagonist, blocked the OP-1206-stimulated [(3)H]-thymidine incorporation into IEC-6 cells. The speed of resealing across the denuded area of a wounded IEC-6 cell monolayer was found to increase following treatment with OP-1206.


CONCLUSIONS
OP-1206 stimulated the proliferation of IEC-6 cells treated with 5-FU, indicating a possible mechanism for the protective effect of OP-1206 against 5-FU-induced damage to the small intestine. OP-1206 was shown to be active in intestinal mucosal healing.
Hirata
Kohji
K
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, 263-8522, Chiba, Japan.
Horie
Toshiharu
T
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects; D005472:Fluorouracil / Q000009:adverse effects*; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects*; D007583:Jejunum / Q000166:cytology / Q000187:drug effects; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology*; D051381:Rats
D000964:Antimetabolites, Antineoplastic; D011459:Prostaglandins E, Synthetic; C025090:ONO 1206; D000527:Alprostadil; D005472:Fluorouracil