Hepatotoxins and Liver Transplantation Decrease Pulmonary Metastases in Rats with Hepatoma

Abstract

Results following liver transplantation for hepatocellular carcinoma have been dismal, attributed largely to recurrent disease locally or at distant sites. Undetected micrometastases or tumor that embolizes at the time of liver transplant from manipulation of the liver may account for these recurrences. A model and treatment protocol were developed to address this clinical problem. The protocol is modeled on the concept of bone marrow transplantation for leukemia. Hepatotoxins that are lethal to both normal hepatocytes and hepatoma cells are administered followed by liver transplantation to “rescue” the failing liver. The feasibility of this protocol was examined in a rat model. Male Buffalo rats were injected with 1 million Morris hepatoma MH-7777 cells intravenously at Day 0 as a model for micrometastatic disease. Three treatment groups were established. Group 1 received no treatment. Group 2 received 5% dextrose in water (D5W) followed by a syngeneic orthotopic liver transplant (OLTX). Group 3 received the hepatotoxin pyrazofurin (10 mg/kg) followed by OLTX. Animals were followed to Day 35, at which time they were sacrificed and examined for evidence of pulmonary metastases and quantitation of nodules with India ink insufflation. There was a significant decrease in the number of pulmonary nodules as well as the number of animals with pulmonary metastatic disease in the pyrazofurin-treated group compared with groups 1 and 2 (4.8 ± 4.0 nodules/animal vs 45.2 ± 11.2 nodules/animal—no treatment and 60.8 ± 21.4 nodules/animal—D5W/OLTX group) These data indicate that this model is reliable for examining metastatic hepatoma and that pyrazofurin is effective in preventing hematogenous micrometastases of hepatoma cells. Other hepatotoxins and the effect of allogeneic transplantation and immunosuppression could be examined in this model.