Protection of thermochemotherapeutic-induced lethal acute hepatic necrosis in the rat by 16,16-dimethyl prostaglandin E2

Abstract These studies further evaluate the hepatocytoprotective properties of 16,16-dimethyl prostaglandin E 2 (dmPGE 2 ) 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°C × 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 dmPGE 2 (10 μg/kg sc) at 30 min before, and at 6 and 24 hr after hepatic perfusion significantly improved survival to 80% ( P P 2 -treated rats demonstrated significantly lower SGOT and SGPT levels at 24 hr after perfusion. dmPGE 2 (2 μg/kg sc) given as above improved the length of time of survival but eventual mortality was not significantly improved. Oral administration (50 μg/kg po at 30 min before, 6 and 24 hr after perfusion) and posttreatment (10 μg/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 dmPGE 2 (10 μg/ kg sc) restored the DNA synthetic response in perfused rats to that seen in normal control rats after partial hepatectomy ( P P 2 as a hepatocytoprotective agent and suggest potential clinical application in situations where there has been deliberate, therapeutic insult to the liver.