Effect of iloprost on impaired anastomotic healing caused by 5-fluorouracil plus leucovorin.
OBJECTIVE
This experimental study was designed to investigate whether iloprost can reverse impaired colonic healing caused by immediate postoperative intraperitoneal administration of 5-fluorouracil plus leucovorin.


METHODS
Eighty Wistar rats were randomized into four groups. After resection of a 1-cm segment of transverse colon, an end-to-end sutured anastomosis was generated. Rats received saline solution (Group 1), 5-fluorouracil plus leucovorin (Group 2), iloprost (Group 3), and 5-fluorouracil plus leucovorin plus iloprost (Group 4) intraperitoneally from the day of operation and once daily until killing. Each group was further randomized into two subgroups. Subjects were killed on the fifth (Subgroup a) and eighth (Subgroup b) postoperative days. After killing, anastomoses were examined macroscopically and graded histologically. Rats were measured for anastomotic bursting pressures and tissue hydroxyproline levels.


RESULTS
The leakage rate of the anastomoses was significantly higher in the 5-fluorouracil plus leucovorin group compared with the other groups (P = 0.049). Bursting pressure was significantly lower in 2a subgroup (5-fluorouracil plus leucovorin, postoperative Day 5) than in 4a (5-fluorouracil plus leucovorin plus iloprost, postoperative Day 5; P < 0.001). Adhesion formation was significantly higher in all b subgroups compared with the Control b subgroup. Neoangiogenesis was significantly higher in iloprost and iloprost plus 5-fluorouracil plus leucovorin subgroups compared with the 5-fluorouracil plus leucovorin subgroups. Hydroxyproline levels, collagen deposition, fibroblasts, and white cell count were significantly higher in the iloprost plus 5-fluorouracil plus leucovorin b subgroup (postoperative Day 8) compared with the 5-fluorouracil plus leucovorin b subgroup (postoperative Day 8).


CONCLUSIONS
The immediate postoperative, intraperitoneal administration of iloprost counteracts and reverses the negative effects of 5-fluorouracil plus leucovorin chemotherapy and protects colonic healing in rats.
Vasiliadis
K
K
Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece. keva@med.auth.gr
Pramateftakis
M G
MG
Blouhos
K
K
Mantzoros
I
I
Koliakos
G
G
Zaraboukas
T
T
Kanellos
I
I
Demetriades
H
H
Alamdari
D H
DH
Betsis
D
D
D000714:Anastomosis, Surgical / Q000009:adverse effects; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000601:surgery*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006909:Hydroxyproline / Q000378:metabolism; D016285:Iloprost / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008365:Manometry; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011183:Postoperative Complications / Q000139:chemically induced / Q000188:drug therapy*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D000267:Tissue Adhesions / Q000139:chemically induced / Q000517:prevention & control; D014665:Vasodilator Agents / Q000494:pharmacology*; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000009:adverse effects; D014945:Wound Healing / Q000187:drug effects*
D000964:Antimetabolites, Antineoplastic; D014665:Vasodilator Agents; D014803:Vitamin B Complex; D003094:Collagen; D016285:Iloprost; D002955:Leucovorin; D006909:Hydroxyproline; D005472:Fluorouracil