Reversal of lethal, chemotherapeutically induced acute hepatic necrosis in rats by regenerating liver cytosol.

In this report we further evaluate the role of regenerating liver cytosol (RLC) as a stimulator of hepatic regeneration 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 500 mg/kg of 5-fluorouracil (5-FU) and 2.5 mg/kg of mitomycin-C (Mit-C) resulted in 70% (n = 20) and 71% (n = 14) mortality, respectively, from 2 to 7 days after perfusion, with extensive, patchy necrosis and infarction seen on histologic examination and markedly elevated levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) at 6 and 24 hours after perfusion. The intraperitoneal administration of RLC (80 mg total protein/rat) at the time of hepatic perfusion resulted in 70% (5-FU, n = 20, P less than 0.05) and 80% (Mit-C, n = 20, P less than 0.01) survival at 21 days post perfusion. RLC-treated rats demonstrated significantly lower SGOT and SGPT levels at 6 and 24 hours after perfusion and normal liver histologic appearance by 14 days after perfusion in surviving rats. Hepatic regenerative capacity following partial hepatectomy was severely inhibited (P less than 0.001) following isolated hepatic perfusion with sublethal doses of 5-FU (125 mg/kg, 250 mg/kg), Mit-C (1.5 mg/kg) and hyperthermia (41 degrees C and 43 degrees C X 5 minutes). The administration of RLC at the time of partial hepatectomy restored the DNA synthetic response in perfused rats to that seen in normal control rats after partial hepatectomy (P less than 0.05). These results demonstrate that the liver is the source of a factor (s) (RLC) that significantly improves survival after lethal chemotherapeutic injury to the liver by stimulating endogenous hepatic regeneration. A potential clinical application for a stimulator of hepatic regeneration in situations of deliberate, therapeutic insult to the liver is suggested.