Based on the organotropic characteristics of
bile acids towards the liver and the intestine, two novel compounds of the Bamet family, containing at least one
bile acid moiety bound to
platinum(II), have been synthesized and their
cytostatic effect compared to their ability to become accumulated in
tumor cells of hepato-intestinal origin.
Bamet-UD2 [cis-diammine-bis-ursodeoxycholic
platinum(II)] induced a marked inhibition of cell growth, which was more marked in human
hepatoblastoma HepG2 and mouse
hepatoma Hepa 1-6 cells than in rat
hepatoma McA-RH7777 and human
colon adenocarcinoma LS 174T cells. This effect was similar to that observed for
cisplatin and stronger than that previously reported for other members of this family, such as
Bamet-H2 and
Bamet-R2. By contrast,
Bamet-D3 [(N'N'' cis-dichloro N(3-3-amminepropylammine)propyl) glycocholamide
platinum (II)] was only effective in reducing growth in human
hepatoblastoma HepG2 cells. Because the in vitro
DNA-reactivity was approximately 5-fold higher for
Bamet-D3 than for
Bamet-UD2, an additional cause for the difference in their
cytostatic abilities was sought, investigating the relationship between cell load and the
cytostatic effect of the drugs.
Drug uptake by two cell lines, Hepa 1-6 and HepG2, with different sensitivities to these compounds was measured. The cellular uptake of
Bamet-D3 and
Bamet-UD2 was several-fold higher than that of
cisplatin. No significant difference in the amount of both drugs taken up by these cell types was found. A study on
sodium-dependency and substrate specificity indicated that Hepa 1-6 cells take up
Bamet-D3 and
Bamet-UD2 via similar mechanism(s), whereas these compounds do not seem to share the uptake pathways in HepG2 cells. Measurement of cell viability by
formazan formation from
tetrazolium salts and by
neutral red uptake, after short-term (6 h) exposure to the desired
drug, indicated that no acute toxic effect occurs in the presence of
cisplatin or
Bamet-D3 in either HepG2 or Hepa 1-6 cells. By contrast, in both cell lines
Bamet-UD2 induced acute cell toxicity in a dose-dependent fashion. In sum, the results indicate that
tumor cells efficiently take up these two novel compounds of the Bamet family. Although the exact uptake mechanism remains unknown, it seems to be dependent on the cell type. However, the cell load does not account for the differences in the anti-proliferative properties of the drugs. The strong and promising
cytostatic activity of
Bamet-UD2 is additionally related to its ability, absent in
Bamet-D3, to acutely alter cellular functions other than proliferation.