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


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.
Herrera
M C
MC
Department of Physiology, Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Salamanca, Spain.
Palomero
M F
MF
Macias
R I
RI
Serrano
M A
MA
Marin
J J
JJ
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D002945:Cisplatin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051379:Mice; D009942:Organometallic Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C112413:bamet H2; D004247:DNA; D002945:Cisplatin