MRI & MRS OF HORMONAL INDUCED CHANGES IN BREAST CANCER

描述(摘自申请者摘要)：远景目标 这项建议是为了开发无创性的MRI和MRS方法用于早期 评价乳腺癌对激素治疗的反应并提供帮助 提高乳腺癌内分泌治疗水平。建议的实验是 旨在检验一种假说，即亚型的表达 血管内皮生长因子(VEGF)受激素调节，在 反过来，以一种特定的方式改变肿瘤的血管和灌注量， 决定着治疗的结果。分子生物学与核磁共振的结合 研究将涉及人体乳腺癌细胞和裸体肿瘤的研究。 雌激素、三苯氧胺和新药对不同激素水平的小鼠 三苯氧胺-三苯氧胺甲碘衍生物(TMI)。具体目标是 旨在验证上述假设并在分子水平上进行表征， 细胞和整个肿瘤水平抗雌激素的作用，特别是 他莫昔芬和TMI，对不同的血管内皮生长因子亚型和密度， 乳腺癌血管的通透性和灌注量。这些目标 包括使用分子生物学方法来确定 体外培养的血管内皮生长因子异构体的mRNA水平和蛋白水平 不同激素处理下血管内皮生长因子在体内的表达。此外, 他们计划继续开发和应用MRI和MRS方法来 在体内监测荷尔蒙引起的血管系统和其他方面的变化 病理生理特征。最后，这项提议还旨在 测定TMI的药代动力学、药效及作用机制。这部作品 将增加对乳腺癌血管生成的基本了解，还可能 帮助设计和改进新的乳房抗雌激素和抗血管生成疗法 癌症。动物模型的核磁共振研究结果将作为基础 开发非侵入性和早期监测的临床方案 对激素治疗的反应。

DESCRIPTION (Adapted from applicant's abstract): The long range objectives of this proposal are to develop non-invasive MRI and MRS methods for the early evaluation of the response of breast cancer to hormonal therapy and to help improve endocrine therapy of breast cancer. The proposed experiments were designed to test out hypothesis that the expressions of the isoforms of vascular endothelial growth factor (VEGF) are hormonally regulated and this, in turn, modifies tumor vascularity and perfusion in a specific manner which determines the results of therapy. The integration of molecular Biology and MRI studies will involve studies in human breast cancer cells and tumors in nude mice under varying hormonal manipulations with estrogen, tamoxifen and the new derivative of tamoxifen-tamoxifen methiodide (TMI). The specific aims are designed to test the above hypothesis and to characterize at the molecular, cellular and whole tumor levels the effects of anti-estrogens, particularly tamoxifen and TMI, on the various VEGF isoforms and on the density, permeability and perfusion capacity of breast cancer vasculature. These aims include the use of molecular biology methods that will be used to establish the mRNA levels and protein levels of VEGF isoforms in vitro and to map the expression of VEGF in vivo, under varying hormonal treatments. In addition, they plan to continue the development and application of MRI and MRS methods to monitor in vivo the hormonal induced changes in the vasculature and other pathophysiologic characteristics. Finally, this proposal is also designed to test the pharmacokinetics, potency and mechanism of activity of TMI. This work will add to the basic understanding of breast cancer angiogenesis and may also help design and improve new anti-estrogen and anti-angiogenic therapy of breast cancer. The results of the MRI studies in animal models will serve as a basis for developing clinical protocols for non-invasive and early monitoring of response to hormonal therapy.