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Title: Effects of aromatase inhibitors on aromatase in breast
Author: Vidya, Raghavan
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2009
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The aims of this study were to determine the effects of both type I (exemestane, formestane) and type II aromatase inhibitors (letrozole, anastrozole, fadrazole, aminoglutethimide) on aromatase activity. Studies based on in vitro incubations of culture mammary adipose tissue fibroblasts demonstrate that the new aromatase inhibitors are highly effective with IC50 values in the lower nanomolar range (1 – 50 nM). The effect of aromatase inhibitors such as letrozole (100nm) was tested and it produced almost total inhibition of aromatase activity (97%) demonstrating its remarkable potency. The fibroblast cultures were induced to display aromatase activity by preincubation with either dexamethasone or dibutyryl cyclic AMP. The induced aromatase activity shows classic sensitivity to aromatase inhibitors. However if during the preincubation period aromatase inhibitors are included in the culture media, enhanced activity is displayed with type II inhibitors (letrozole, anastrozole, aminoglutethimide) but with type I inhibitors (exemestrane, formestane). This effect may reflect the possibility of developing resistance with the long term use of type II inhibitors and suggests the sequential use of type II followed by type I aromatase inhibitors in the treatment of breast cancer. Sixteen postmenopausal patients with large, oestrogen receptor positive breast cancers were treated with aromatase inhibitors – letrozole, anastrozole and exemestane prior to surgery and aromatase activity was measured [in vitro] before and after 3 months of treatment. A significant reduction in the aromatase activity was found following treatment in malignant tissues. The non-malignant tissues had a variable response with some displaying enhanced aromatase activity following treatment. There may be a switch in the regulatory mechanism of aromatase activity from normal breast tissue to cancerous tissue.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available