Relationship between DNA-reactivity and cytostatic effect of two novel bile acid-platinum derivatives, Bamet-UD2 and Bamet-D3.
Klíčová slova
Abstraktní
OBJECTIVE
Several platinum(II)-bile acid derivatives, named Bamets, have been previously synthesized. Their ability to interact with DNA, their cytostatic activity and their liver organotropic properties have been characterized. Two new compounds of this family, with particular structural properties, have been developed. Bamet-UD2 was formed by two ursodeoxycholic acid moieties bound by the carboxylate groups to cisplatin. In contrast, in Bamet-D3, glycine and a polyamine were used as tandem spacer elements to separate a cholic acid moiety from the platinum(II) atom. The aim of this work was to evaluate how these changes affect the ability of these compounds to interact with DNA and reduce tumour cell growth.
METHODS
Drug reactivity with DNA was determined by changes in the electrophoretic mobility of the pUC18 plasmid test and by the ethidium bromide (EthBr) displacement assay. Cytostatic activity was measured against two mouse-derived cell lines from lymphocytic leukemia (L1210) and sarcoma (S-180-II).
RESULTS
Bamet-UD2, and more markedly Bamet-D3, induced changes in the electrophoretic mobility of pUC18, suggesting the formation of DNA-drug interactions. Bamet-UD2 displaced EthBr from its binding to DNA. This effect was stronger in the case of Bamet-D3. Scatchard plots revealed that pre-incubation with both Bamet-UD2 and Bamet-D3 decreased the number of DNA sites available and their ability to bind EthBr. In spite of the enhanced DNA-reactivity of Bamet-D3, its ability to reduce tumour cell growth was much weaker than that of Bamet-UD2, which was seen to exert a very strong cytostatic effect.
CONCLUSIONS
Although the distance between the platinum atom and the bile acid moiety affects the in vitro Bamet reactivity with DNA, other factors determine the overall cytostatic activity of these compounds.
