Further evidence of the usefulness of bile acids as molecules for shuttling cytostatic drugs toward liver tumors.
OBJECTIVE
To use bile acids as shuttles for directing cytostatic drugs toward liver tumors, the ability of the tumor to take up these compounds must be maintained. Thus, we investigated whether glycocholate (GC) derivatives such as the fluorescent FITC-GC and the cytostatic Bamet-R2 are taken up by neoplastic tissue at different stages of chemically-induced rat liver carcinogenesis.


METHODS
Placental glutathione-S-transferase (GST-P) was immunohistochemically detected. Uptake studies were carried out on pure GST-P-positive cell cultures, obtained by treatment with ethacrinic acid. FITC-GC, Bamet-R2 or cisplatin was administered (i.v.) to anaesthetized rats. Platinum in culture cells, liver and kidney was measured by flameless atomic absorption.


RESULTS
Co-localization after FITC-GC i.v. administration revealed that only 15% (20 weeks) and 30% (32 weeks) of GST-P-positive tissue was not able to take up FITC-GC. GC uptake was lower in GST-P-positive cells than in normal hepatocytes. Bamet-R2, uptake was lower than that for GC, but similar in both cell types. The amount of Bamet-R2 or cisplatin retained by GST-P-positive tissue after in vivo administration was progressively increased during carcinogenesis. Moreover, this amount was higher for Bamet-R2 than for cisplatin. By contrast, in the kidney, it was higher for cisplatin than for Bamet-R2.


CONCLUSIONS
These results indicate that at the different stages of rat hepatocarcinogenesis most GST-P-positive tissue is able to take up bile acid derivatives, such as Bamet-R2.
Monte
M J
MJ
Department of Physiology and Pharmacology, School of Pharmacy, University of Salamanca, Spain.
Dominguez
S
S
Palomero
M F
MF
Macias
R I
RI
Marin
J J
JJ
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001647:Bile Acids and Salts / Q000502:physiology*; D002478:Cells, Cultured; D002945:Cisplatin / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004052:Diethylnitrosamine / Q000633:toxicity; D005982:Glutathione Transferase / Q000032:analysis; D006000:Glycocholic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006498:Hepatectomy; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D001647:Bile Acids and Salts; D009944:Organoplatinum Compounds; C108271:diaminneplatinum(II)-chlorocholylglycinate; D004052:Diethylnitrosamine; D015073:2-Acetylaminofluorene; D005982:Glutathione Transferase; D006000:Glycocholic Acid; D002945:Cisplatin