Idoxifene antagonises E2-dependent breast cancer xenograft growth through apoptosis

Excerpt

Idoxifene is an analogue of tamoxifen currently being developed for the treatment of breast cancer. In comparison to tamoxifen, idoxifene is metabolically more stable and demonstrates a higher relative binding affinity for the estrogen receptor (ER). As a result, idoxifene is more effective in inhibiting tumour cell growth in both in vitro and in vivo models. Idoxifene also inhibits calmodulin, a calcium-binding protein that is involved in cell signal transduction pathways. The formation of calmodulin-ER complexes is thought to be a key step in tumour growth and it has been shown that the cytotoxicity of tamoxifen analogues correlates with their calmodulin antagonism. The cis isomer of idoxifene has a lower binding affinity for ER than the clinically used transisomer, but it still has potent calmodulin antagonism. This difference between the two isomers opens up the possibility of examining which of the two properties (ER antagonism and calmodulin antagonism) is more important in inhibiting tumour growth. Finally, idoxifene demonstrates reduced agonist activity on breast and uterine cells. …