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6th ESACP Congress, Heidelberg, April 7-11, 1999 |
A093
The remarkable tissue-specific behaviour of Tamoxifen was recently
demonstrated in the BCPT Trial. In the group of women at high risk for breast
cancer who received Tamoxifen treatment, there was an increase of endometrial
cancer but a reduced occurrence of certain bone fractures and a dramatic 45%
reduction in breast cancer incidence. Thus, considering the systemic effects,
there is a great need to improve existing therapies for the prevention of
breast cancer. Tamoxifen belongs to a class of molecules known as selective
estrogen receptor modulators (SERMs) The selective antagonist 4-OH-Tamoxifen
(4-OHT) is the active metabolite of Tamoxifen. The rational design for the
optimisation of SERMs like 4-OHT is to concentrate their activity in the
breast and to avoid as much as possible systemic circulation. It was
demonstrated that 4-OHT penetrates through the skin. Thus a percutaneous
selective concentration in breast tissues could be envisaged. A major
contribution to the understanding of the 4-OHT ligand chemistries upon
Estrogen Receptor alpha (ERa) ligand binding domain (LBD) was reported
recently. Hitherto the modulation of biomarkers after Tamoxifen therapy
has focused on proliferation and apoptosis related molecules. Here in we
demonstrate in patients treated with Tamoxifen per Os or with 4-OHT
percutaneously a supramolecular remodelling of the chromatin in breast
epithelial cells by DNase I genome exposure analysis in paraffin embedded
tissues. We suggest that chromatin remodelling could be used as a monitoring
parameter in cancer prevention in 4-OHT percutaneous therapy.
4-OH TAMOXIFEN INDUCES SUPRAMOLECULAR REMODELLING OF CHROMATIN IN NORMAL
HUMAN BREAST EPITHELIAL CELLS IN VIVO
Linares-Cruz G 1, Chassoux D 2, Simony J 3, Fournier S 5,
Rouanet Ph 4, Calvo F 1
1) Laboratoire de Pharmacologie Expérimentale, Institut de Génétique
Moléculaire Saint Louis, Paris, 2) INRA 806, IBPC, Paris, 3) Laboratoire de
Pathologie, CRLCC Val d'Aurelle, Montpellier, 4) Department de Chirurgie,
CRLCC Val d'Aurelle, Montpellier. 5) Laboratoires Besins ISCOVESCO, Paris.