The long range objective of this research is to develop a non-invasive procedure for the early evaluation of the response of breast cancer patients to hormonal therapy, using methods of magnetic resonance imaging (MRI) and spectroscopy (MRS). This proposal will focus on in vivo MRI and MRS studies of human breast cancer implants (e.g. MCF7, T47D and MDA-MB- 231 cell lines) in nude mice during growth and following treatment with antiestrogens (e.g. tamoxifen, ICI 182780). The proposed experiments were designed to test our hypothesis that tamoxifen inhibits estrogen stimulated production of angiogenic growth factors and impairs the function of the vascular system thereby causing enhanced necrosis. Recent histochemical staining of the tumor endothelial cells lended support to this hypothesis. The endothelial staining also indicated stimulation of endothelial growth at the boundary of the necrotic and viable tumor cells regions. These boundary capillaries appeared to exhibit high permeability in the T1 weighted, dynamic, contrast enhanced MR images. In view of this sequence of events we propose to concentrate on the following three areas which are expected to reveal the tumor response to antiestrogens: 1. Characterization of gross histopathological features (e.g. necrosis, fibrosis) obtained by MRI at high spatial resolution during growth and in the course of therapy. This part requires an accurate correlation with histopathological findings. 2. Study of the distribution, functionality and integrity of the tumor vasculature during growth and following treatment. This part will include the use of dynamic, contrast enhanced MRI at high temporal and spatial resolution as well as correlation with immunohistochemical studies of the microvessels and endothelial cells. 3. Monitor the delivery and metabolism of glucose as well as the production and clearance of lactate during growth and therapy. In these measurements we plan to utilize 13C labeled glucose and to apply spatially defined 13C MRS and 13C-1H-detected methods at high temporal resolution. In order to establish the time correlation between the accumulation of the antiestrogen and its products and response to its action by enhanced necrosis we propose to include in this project 19F pharmacokinetic studies of the fluorinated derivatives of tamoxifen and ICI 182780.
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