Dissecting rapid estrogen signaling with conjugates.

Hypothesizing that rapid estrogen signaling could be modulated from different estrogen receptors with unique localization patterns, a number of groups have attempted to design drug conjugates that target or restrict compounds to specific subcellular compartments. This article will briefly discuss the history of using conjugates to dissect rapid estrogen signaling and different strategies to attempt to target estrogens and antiestrogens to different locations. It will also detail some of the potential issues that can arise with different types of conjugates, using examples drawn from the authors' own work.

Tamoxifen promotes superoxide production in platelets by activation of PI3-kinase and NADPH oxidase pathways.

Background: Tamoxifen is a selective estrogen receptor antagonist that is widely used for treatment and prevention of breast cancer. However, tamoxifen use can lead to an increased incidence of thrombotic events. The reason for this adverse event remains unknown.

Synthesis and characterization of fluorescent 4-hydroxytamoxifen conjugates with unique antiestrogenic properties.

Membrane receptors for steroid hormones are currently a subject of considerable debate. One approach to selectively target these putative receptors has been to couple ligands to substances that restrict cell permeability. Using this approach, an analogue of the estrogen receptor ligand 4-hydroxytamoxifen was attached to fluorescent dyes with differing degrees of predicted cell permeability.

Sensing estrogen's many pathways.

Estrogen receptor (ER) is an important drug target, but it has multiple signaling pathways that are difficult to dissect. A new study reports the development of a multicolor bioluminescent probe that can measure a compound's ability to modulate ER-mediated transcription and to promote an interaction between ER and Src, a key protein in a number of different cell signaling cascades. The discovery provides a new tool for quickly obtaining a more complete picture of the potential effects of a compound on estrogen signaling and could lead to more selective ER modulators with fewer side effects.

Tamoxifen stimulates calcium entry into human platelets.

The anti-estrogenic drug tamoxifen, which is used therapeutically for treatment and prevention of breast cancer, can lead to the development of thrombosis. We found that tamoxifen rapidly increased intracellular free calcium [Ca2+]i in human platelets from both male and female donors. Thus 10 microM tamoxifen increased [Ca2+]i above the resting level by 197 +/- 19%.