Novel antitumour drugs, such as cationic
tyrosine kinase inhibitors, are useful in many types of
cancer but not in others, such as
cholangiocarcinoma (CCA), where their uptake through specific
membrane transporters, such as OCT1, is very poor. Here we have investigated the usefulness of targeting
cytostatic bile acid derivatives to enhance the delivery of
chemotherapy to tumours expressing the
bile acid transporter ASBT and whether this is the case for CCA. The analysis of paired samples of CCA and adjacent non-tumour tissue collected from human (n=15) and rat (n=29) CCA revealed that ASBT expression was preserved. Moreover, ASBT was expressed, although at different levels, in human and rat CCA cell lines. Both cells in vitro and rat tumours in vivo were able to carry out efficient uptake of
bile acid derivatives. Using
Bamet-UD2 (
cisplatin-ursodeoxycholate conjugate) as a model ASBT-targeted
drug, in vitro and in vivo antiproliferative activity was evaluated. ASBT expression enhanced the sensitivity to
Bamet-UD2, but not to
cisplatin, in vitro. In nude mice,
Bamet-UD2 (more than
cisplatin) inhibited the growth of human
colon adenocarcinoma tumours with induced stable expression of ASBT. As compared with
cisplatin, administration of
Bamet-UD2 to rats with CCA resulted in an efficient liver and tumour uptake but low exposure of extrahepatic tissues to the
drug. Consequently, signs of liver/renal toxicity were absent in animals treated with
Bamet-UD2. In conclusion, endogenous or induced ASBT expression may be useful in pharmacological strategies to treat enterohepatic tumours based on the use of
cytostatic bile acid derivatives.