Many experiments have shown that the bisphosphonates ,such as clodronate, pamidronate and zoledronate have cytotoxic effect on endothelial as well as on human and mouse tumor cells, all representing component of the tumor stroma. The IC 50 values of all bisphosphonates are in the mM range. Clodronate shows the lowest efficiency in all cases. The nitrogen containing bisphosphonates such as pamidronate and zoledronate have higher activity compare to non-nitrogen containing bisphosphonates such as clodronate. Human Umbilical Vein Endothelial Cells (HUVEC) have shown the highest sensibility for all bisphosphonates tested, especially for zoledronate the cytotoxic activity is twice as high as for tumor cells. The enhanced cytotoxicity of zoledronate on HUVECs compared to other bisphosphonates has already been reported by several groups. This is due to the difference in mechanism of action of nitrogen containing bisphosphonates (e.g. zelodronate and pamidronate) compare to non-nitrogen containing bisphosphonate such as Clodronate.
Both groups of bisphosphonates (non-nitrogen containing and nitrogen containing) inhibit bone resorption by induction of osteoclast apoptosis. However, at the molecular level the mechanism of action of these molecules differ. Non-nitrogen containing bisphosphonates such as Clodronate are metabolically incorporated into analogues of ATP that are resistant to hydrolysis by ATP-dependent metabolic enzymes. On the other hand, nitrogen containing bisphosphonates such as pamidronate and zoledronate are inhibitors of the mevalonate pathway and thereby they prevent prenylation of small GTPase signaling protein required for osteoclast function.
The table below summarizes the toxicity of free and encapsulated bisphosphonates that were reported in various scientific papers.
** The IC50 unit is mM.
Table 1- IC50 values (after 4 hours of incubation) of free and liposomal encapsulated clodronate, pamidronate and zoledronate in human rhabdomyosarcoma (A673), murine teratocarcinoma cells (F9) and human umbilical vein endothelial cells (HUVECs) and non activated and activated mouse peritonial macrophages. (Source: Comparison of cytotoxic properties of free and liposomal bisphosphonates in vitro, Renate Frei, Thesis, Swiss Federal Institute of Technology Zurich, 2005)