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 li ver vectoriality, has been synthesized. Our aim was to investigate the usef ulness of this compound to overcome cisplatin resistance and to determine w hether its encapsulation into liposomes increases its water solubility, upt ake by liver tumor cells and cytostatic activity. Highly efficient incorpor ation 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 f or cisplatin. A partially cisplatin-resistant (87-fold) monoclonal cell lin e (Hepa 1-6/10R) was obtained by 2 subcloning steps of a population of mous e hepatoma Hepa 1-6 cells grown in step-wise increasing cisplatin concentra tions up to 10 mu M. 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 ove rcoming (-82%) of resistance when used on Hepa 1-6/10R cells. Inclusion of Bamet-R2 into liposomes further increased the amount of the drug accumulate d in both cell types and, hence, enhanced its cytostatic activity. Since bo th plain liposomes and Bamet-R2 have little toxicity, the formulation of th is compound in liposomes may offer a substantial advantage over cisplatin i n the treatment of tumors resistant to this anti-neoplastic agent. Int. J. Cancer 88:287-292, 2000, (C) 2000 Wiley-Liss, Inc.