The Breast (1996) 5.202-208 0 1996 Pearson Professional Ltd ES0 TASK FORCE ARTICLE Pharmacology of new aromatase inhibitors P. E. Lonning Department of Oncology, Haukeland University Hospital, Bergen, Norway S UM M A R Y. Recent investigations of novel aromatase inhibitors have addressed several important questions related to the biochemical effects of this class of drugs. While aromatase inhibitors such as aminoglutethimide, formestane (given by the oral and i.m. route), rogletimide and fadrozole administered at different doses have been found to inhibit in vivo aromatization by 60-93%, the novel aromatase inhibitors, letrozole and anastrozole, are shown to inhibit in vivo aromatization by about 98%. Contrary to previous studies on aromatase inhibitors reporting plasma oestrogens sustained at 30-50% of their control levels letrozole and anastrozole suppress plasma oestrone sulphate by approximately 95%. Future studies should explore cross-resistance of aromatase inhibitors and steroidal antioestrogens and between different types of aromatase inhibitors. A major goal is to evaluate alterations in tissue oestrogen concentration as well as growth factor expression in response to oestrogen deprivation with aromatase inhibitors. INTRODUCTION It has bean known for about 50 years that ablative therapy by adrenalectomy or hypophysectomy can cause tumour regression in postmenopausal women.‘*2 The first generation aromatase inhibitor, an unsuccessful anti-epileptic named aminoglutethimide, was introduced for breast cancer treat- ment in an attempt to achieve a ‘medical adrenalectomy’ because of its toxic influence on adrenocortical hormone synthesis.3 It was discovered later that, in spite of the fact that aminoglutethimide inhibits several steps in adrenal steroid synthesis,4 androgen synthesis is sustained. On the other hand, treatment with aminoglutethimide was found to produce a substantial fall in plasma oestrogen levels.5 In a classical experiment published in 1978, Santen and co-workers6 were able to show that the conversion of radio- active androstenedione (A) into oestrone (E,) was inhibited by aminoglutethimide in vivo. This introduced the term ‘aromatase inhibition’ as a treatment option for postmeno- pausal women suffering from advanced breast cancer. Owing to substantial side-effects associated with use of aminoglutethimide and its lack of specificity, many attempts have been made to develop novel, less toxic and more specific aromatase inhibitors. The first selective aromatase inhibitor, formestane (4-hydroxyandrostenedione) was in- troduced for clinical treatment in 1984.’ Since then, a sub- Address correspondence to: P. E. Lpnning, Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway stantial number of aromatase inhibitors have been taken into clinical trials. DIFFERENT CLASSES OF AROMATASE INHIBITORS Aromatase inhibitors in clinical use may be divided into two major classes based on their effect on the aromatase enzyme. Steroidal aromatase inhibitors (Fig. 1) are all de- rivatives of the natural androgen A substituted in different positions. The second are non-steroidal inhibitors with an imidazole or triazole structure (Fig. 2) or a chemical struc- ture resembling aminoglutethimide (Fig. 1). CURRENT CONTROVERSIES RELATED TO TREATMENT WITH AROMATASE INHIBITORS The major goal in developing novel aromatase inhibitors was to obtain drugs with a better specificity (lack of influence on other steroid synthesizing enzymes) and a less toxic pro- file than aminoglutethimide. A major concern in relation to treatment with aminoglutethimide (and later also during treatment with second and third generation aromatase in- hibitors) is the discrepancy between the degree of aromatase inhibition as measured by in vivo tracer studies and the percentage suppression of plasma oestrogen levels. Thus, while aminoglutethimide as well as the second generation 202