Protection of thermochemotherapeutic-induced lethal acute hepatic necrosis in the rat by 16,16-dimethyl prostaglandin E2.
These studies further evaluate the hepatocytoprotective properties of 16,16-dimethyl prostaglandin E2 (dmPGE2) by assessing its effect on survival, liver function, and hepatic regeneration in a model of in vivo isolated perfusion of the rat liver with high concentrations of cytotoxic drugs and regional hyperthermia. Isolated perfusion with 1.0 g/kg of 5-FU or hyperthermia of 41 degrees C X 10 min resulted in 90-100% mortality in control rats, with extensive, patchy necrosis and infarction on histologic examination, and markedly elevated levels of SGOT and SGPT at 24 hr after perfusion. Pretreatment with dmPGE2 (10 micrograms/kg sc) at 30 min before, and at 6 and 24 hr after hepatic perfusion significantly improved survival to 80% (P less than 0.01) following 5-FU perfusion and to 40% (P less than 0.05) following hyperthermic perfusion. Animals were followed for at least 21 days after perfusion and demonstrated normal liver histology, dmPGE2-treated rats demonstrated significantly lower SGOT and SGPT levels at 24 hr after perfusion. dmPGE2 (2 micrograms/kg sc) given as above improved the length of time of survival but eventual mortality was not significantly improved. Oral administration (50 micrograms/kg po at 30 min before, 6 and 24 hr after perfusion) and posttreatment (10 micrograms/kg sc at 1, 6, and 24 hr after perfusion) had no significant effect on survival. Hepatic regenerative capacity following partial hepatectomy was severely suppressed following isolated hyperthermochemotherapeutic hepatic perfusion. Pretreatment with dmPGE2 (10 micrograms/kg sc) restored the DNA synthetic response in perfused rats to that seen in normal control rats after partial hepatectomy (P less than 0.05 and P less than 0.01). The results from these studies further confirm the role of dmPGE2 as a hepatocytoprotective agent and suggest potential clinical application in situations where there has been deliberate, therapeutic insult to the liver.
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology*; D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D001219:Aspartate Aminotransferases / Q000032:analysis; D005472:Fluorouracil / Q000633:toxicity; D006358:Hot Temperature; D008099:Liver / Q000473:pathology*; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D009336:Necrosis; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D011459:Prostaglandins E, Synthetic; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D015064:16,16-Dimethylprostaglandin E2; D005472:Fluorouracil