B177
The aromatase inhibitor letrozole enhances the effects of doxorubicin and docetaxel in an MCF7 cell line model
Mary O'Neill, Fiona Paulin, Julie Vendrell, Alastair Thompson
University of Dundee, Dundee, UK
Estrogen receptor (ER) positive tumours in post-menopausal patients may require treatment with both chemotherapy and aromatase inhibitorssuch as letrozole. Whereas adjuvant chemotherapy then tamoxifen given sequentially showed an 18% disease free survival advantage compared to concurrent therapy (SWOG-8814 trial), little is known about the effects of concurrent chemotherapy with aromatase inhibitors. The aim of this study was to compare the therapeutic efficacy of doxorubicin and docetaxel with letrozole in a cell line model.
MCF-7aro cells, a derivative of MCF-7 cells stably transfected with aromatase, were treated in vitro with letrozole, doxorubicin and docetaxel (using IC50 values) as single agents or in combinations including pretreatment or concurrent treatment scheduling. Cytotoxicy assays were performed and protein immunoblotting of key genes examined.
The anti-tumour activity of both doxorubicin and docetaxel against the MCF-7aro was significantly enhanced by pre-treatment with letrozole. This was most evident when letrozole pre-treatment for 2 days was followed by a combination of doxorubicin and docetaxel. With both the sequential and concurrent combined therapies an up-regulation of p53 and its downstream targets p21 and Noxa were observed.
These data suggest that, in contrast to tamoxifen, concurrent chemo-hormonal therapy using letrozole, doxorubicin and docetaxel should be tested in vivo in ER positive breast cancer.
