MRI AND MRS OF HORMONAL INDUCED CHANGES IN BREAST CANCER

这项研究的长期目标是开发一种非侵入性 早期评价乳腺癌疗效的程序 患者接受激素治疗，采用磁共振成像的方法 (MRI)和波谱(MRS)。这项提案将重点放在体内核磁共振和 人乳腺癌植入物的MRS研究(例如MCF7、T47D和MDA-MB- 231细胞株)在裸鼠体内生长及用药后 抗雌激素(如他莫昔芬，ICI 182780)。 拟议的实验旨在验证我们的假设 他莫昔芬抑制雌激素刺激的血管生成 影响和损害血管系统的功能，从而导致 强化的坏死。肿瘤内皮细胞的最新组织化学染色 细胞支持这一假设。血管内皮细胞染色也 指示刺激血管内皮细胞生长的边界 肿瘤细胞坏死区和活跃区。这些边界毛细血管 似乎表现出高渗透性在T1加权，动态， 对比度增强的MR图像。鉴于这一系列事件，我们 建议将重点放在以下三个领域，预计 揭示肿瘤对抗雌激素的反应： 1.大体组织病理学特征(例如，坏死， 高空间分辨率的MRI在生长和发育过程中获得的 治疗的疗程。这一部分需要与 组织病理学检查结果。 2.研究肿瘤的分布、功能和完整性 生长和后续治疗期间的血管系统。本部分将包括 动态增强磁共振成像在高时空分辨率成像中的应用 分辨率以及与免疫组织化学研究的相关性 微血管和内皮细胞。 3.监测葡萄糖的输送和代谢，以及 生长和治疗期间乳酸的产生和清除。在这些 我们计划利用13C标记的葡萄糖并在空间上应用 定义了高时间分辨率的~(13)C-MRS和~(13)C-1H检测方法。 为了建立时间相关性，在 抗雌激素及其产品及对其作用的反应 我们建议在这个项目中包括19F药代动力学研究 他莫昔芬和ICI 182780的氟化衍生物。

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.