A hepatic artery infusion model in Yucatan minipigs

Abstract

Introduction. Hepatic artery infusion (HAI) chemotherapy has long been studied, but its appropriate use remains controversial; there has been no available animal model. Methods. The Yucatan minipig was chosen because it has liver anatomy and biochemistry similar to human. An HAI catheter was placed via the gastroduodenal artery; liver biopsy was performed, and adequate perfusion was confirmed via fluorescein injection. The animals were maintained on various doses, 0.3, 0.6, 3.0 mg/kg/day, of FUDR or saline continuously for 4–10 weeks. Liver biopsies were performed laparoscopically at 4-week intervals. Tissue was examined by light (LM) and transmission electron microscopy (TEM) and also phenotyped for levels of P450 isoforms 2C9 and 3A4. Serum liver function tests were done every 2 weeks. Results. Eight pigs had HAI with saline or FUDR. Serum liver function tests remained normal throughout the infusion for all doses. LM revealed no change during infusion, with each pig used as its own control. TEM showed increasingly edematous and dilated endoplasmic reticulum with FUDR but not saline. This phenomenon was more pronounced at higher doses and when infusion had progressed in time, but reverted to baseline when infusion was stopped. The P450 3A4 isozyme was up regulated with increasing doses of FUDR, but was down regulated when a toxic dose (10× the maximum human dose) was used. The P450 2C9 isozyme remained relatively constant at the lower doses of FUDR but showed a 2-fold increase at the toxic dose. Conclusion. The Yucatan minipig can be used as a model for HAI chemotherapy to study the effects of various chemotherapeutic agents on liver morphology and biochemistry. Our data with FUDR have shown changes in electron microscopy and liver biochemistry occur earlier than changes seen in tests used clinically. Because these changes can affect the metabolism of other drugs before clinical liver malfunction is apparent, unsuspected systemic toxicity may accompany HAI. Other antitumor agents may produce significantly different results and should be evaluated in this model before widespread application in man.