Overcoming cisplatin resistance in vitro by a free and liposome-encapsulated bile acid derivative: BAMET-R2.
Low water solubility and development of resistance are important drawbacks in the use of cisplatin as a cytostatic agent. A novel bile acid-cisplatin complex, Bamet-R2 [cis-diamminechlorocholylglycinateplatinum (II)], with liver vectoriality, has been synthesized. Our aim was to investigate the usefulness of this compound to overcome cisplatin resistance and to determine whether its encapsulation into liposomes increases its water solubility, uptake by liver tumor cells and cytostatic activity. Highly efficient incorporation of Bamet-R2 into liposomes permitted an increase in the concentration of the drug compared with that in the initial free solution by more than 6 x 10(6)-fold, which is 10(3)-fold higher than the encapsulation obtained for cisplatin. A partially cisplatin-resistant (87-fold) monoclonal cell line (Hepa 1-6/10R) was obtained by 2 subcloning steps of a population of mouse hepatoma Hepa 1-6 cells grown in step-wise increasing cisplatin concentrations up to 10 microM. Decreased sensitivity to cisplatin was accompanied by a 3.2-fold lower drug accumulation compared to wild-type cells. Uptake was markedly increased by the binding of cisplatin to glycocholic acid in both Hepa 1-6 and Hepa 1-6/10R cells. This probably accounts for the partial overcoming (-82%) of resistance when used on Hepa 1-6/10R cells. Inclusion of Bamet-R2 into liposomes further increased the amount of the drug accumulated in both cell types and, hence, enhanced its cytostatic activity. Since both plain liposomes and Bamet-R2 have little toxicity, the formulation of this compound in liposomes may offer a substantial advantage over cisplatin in the treatment of tumors resistant to this anti-neoplastic agent.
Briz
O
O
Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.
Serrano
M A
MA
Macias
R I
RI
Marin
J J
JJ
D000818:Animals; D002784:Cholesterol; D002945:Cisplatin / Q000493:pharmacokinetics / Q000633:toxicity*; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm; D007700:Kinetics; D008081:Liposomes / Q000737:chemistry; D008114:Liver Neoplasms, Experimental; D051379:Mice; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity*; D010713:Phosphatidylcholines; D010743:Phospholipids; D014407:Tumor Cells, Cultured; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity
D004337:Drug Carriers; D008081:Liposomes; D009944:Organoplatinum Compounds; D010713:Phosphatidylcholines; D010743:Phospholipids; C408382:diamminebis(ursodeoxycholate(O,O'))platinum(II); C024990:asolectin; D014580:Ursodeoxycholic Acid; D002784:Cholesterol; D002945:Cisplatin