Comparison of the effects of bischolylglycinatechloro-platinum(II) versus cisplatin on liver regeneration after partial hepatectomy

Abstract

Background: Regional chemotherapy by intraportal administration has been envisaged as a useful strategy to prevent the high rate of recurrence after surgical removal of single liver tumors, even though it may inhibit liver regeneration. New cytostatic drugs, such as Bamet-H2-Na[Pt(cholylglycinate-O,N) (cholylglycinate-O) Cl]- have been developed to enhance the liver organotropism of antiproliferative agents. The aim of the present study was to compare the effects of Bamet-H2 and cisplatin on liver regeneration.

Materials and methods: The ability of both drugs to inhibit liver cell proliferation was investigated using rat hepatocytes in primary culture. Two-thirds partially hepatectomized mice were used to measure the effects of glycocholic acid, cisplatin and Bamet-H2 on DNA synthesis by the regenerating liver in vivo.

Results: Up to 300 microM glycocholic acid, no effect on the growth of rat hepatocytes in primary culture was observed. By contrast, similar dose-dependent in vitro cytostatic effects of cisplatin and Bamet-H2 were found. No effect on mouse liver regeneration was found in animals receiving glycocholic acid. By contrast, both cisplatin and Bamet-H2 were found to induce a significant inhibition of DNA synthesis and slower recovery of liver mass. The effect of cisplatin was significantly stronger than that induced by Bamet-H2. Differences between these two compounds were also observed regarding the content of the drug in several tissues at short- and mid-term. Both drugs were highly concentrated in the liver and kidney, with minor distribution in other tissues at 8 hours after the last injection of the drug. However, Bamet-H2 was more efficiently eliminated from the body in 5 days. Moreover, higher toxicity and lower survival were observed in the group of animals treated with cisplatin as compared to Bamet-H2.

Conclusions: Our results indicate that in agreement with the previously reported effects on several tumor cells lines, cisplatin and Bamet-H2 are similarly efficient as cytostatic drugs in liver cells when these are continuously exposed to the compounds in vitro. However, in the in vivo situation Bamet-H2 is better tolerated by the animals and induces less inhibition of liver regeneration than cisplatin. This is probably due to the enhanced biliary elimination of Bamet-H2.