Aromatase inhibitors: from bench to bedside and back.

The development of the novel "third generation" aromatase inhibitors (anastrozole, letrozole) and inactivators (exemestane) is one of the most successful contemporary achievements in breast cancer therapy. While clinical studies evaluated toxicity and efficacy in metastatic disease, the endocrine effects of multiple compounds were evaluated in parallel, identifying the most potent aromatase inhibitors based on estrogen deprivation in plasma and tissue samples in addition to "total body aromatase inhibition" in vivo. Thus, "translational" studies have been of vital importance identifying the unique characteristics of these drugs. While first- and second generation aromatase inhibitors inhibit estrogen synthesis in vivo by up to 90%, third generation compounds like anastrozole, exemestane and letrozole were shown to cause > or = 98% aromatase inhibition in humans. The present paper summarises and discusses the "translational research" that provided the background for the implementation of the third generation aromatase inhibitors and inactivators into large clinical trials and later on in clinical use. Finally, some of the major topics of currently ongoing translational research programs are presented. These programs focus on aromatase regulation in different tissues, mechanisms of resistance to aromatase inhibition and strategies to overcome resistance like combined therapy with aromatase inhibitors and intracellular signal transduction inhibitors.