MAMMARY TUMOR CHEMOPREVENTION BY ANGIOGENIC INHIBITORS

这项研究的目的是确定血管生成抑制剂是否可以作为高危女性乳腺癌的化学预防药物。我们的假设是：导致侵袭性乳腺疾病的遗传和表观遗传事件也导致血管生成表型；进展为高级形式的侵袭性乳房疾病依赖于血管生成；阻断血管生成可以阻止侵袭性前肿瘤的发展，抑制进展到下一阶段，最终防止侵袭性疾病。在这些研究中，我们将使用两种具有良好特征的乳腺肿瘤形成模型，即7，12-二甲基苯并[a]菲(DMBA)和N-亚硝基-N-甲基脲(NMU)诱导的大鼠乳腺肿瘤。我们的具体目标是研究致癌物诱导的侵袭前乳腺肿瘤形成血管的时间框架，抑制血管生成防止致癌物诱导的侵袭前和浸润性乳腺肿瘤的形成和发展，这一过程独立于特定的遗传或表观遗传致癌途径发生，以及抑制血管生成将增强雌激素受体阻滞剂的化学预防作用。两种血管生成抑制剂将在长期给予时进行测试，从致癌物质暴露时开始，并在延迟一个月后，以允许在治疗之前形成侵袭前肿瘤。肿瘤不同发展阶段的组织将被检查表型变化，如组织形态和血管程度。此外，还将在体外和体内的血管生成试验中测试它们的血管生成潜力。最后，将检查他们的基因变化，特别是密码子61的DNA加合物和H-ras突变的数量和类型。这项研究是独一无二的，它考察了血管生成在侵袭前肿瘤中的作用，这是一个在很大程度上尚未被探索的领域。此外，这项研究提出了一种非激素方法来解决高危妇女的化学预防问题。

The goal of this research is to determine whether inhibitors of angiogenesis can serve as chemoprophylactics for breast cancer in high risk women. Our hypothesis is that: the genetic and epigenetic events which lead to pre-invasive breast disease also lead to an angiogenic phenotype; progression to advanced forms of pre-invasive breast disease is dependent upon angiogenesis; and blocking angiogenesis prevents the development of pre-invasive tumors, inhibits progression to the next stage and ultimately prevents invasive disease. For these studies we shall use two well-characterized models for the formation of pre-invasive and invasive mammary tumors, the 7,12-dimethylbenz[a]anthracene (DMBA) and N-nitroso-N-methylurea (NMU) - induced rat mammary tumors. Our specific aims are to investigate the time frame in which carcinogen-induced pre-invasive mammary tumors become angiogenic, that inhibition of angiogenesis prevents the formation and progression of carcinogen-induced pre-invasive and invasive breast tumors, that this occurs independent of the specific genetic or epigenetic pathway of carcinogenesis, and that inhibition of angiogenesis will potentiate the chemopreventive effects of estrogen receptor blocking agents. Two angiogenic inhibitors will be tested when given chronically, beginning at the time of carcinogen exposure, and after a one-month delay, to allow pre-invasive tumors to form prior to treatment. Tissues at different stages of tumor development will be examined for phenotypic changes such as histomorphology and degree of vascularity. In addition, they will be tested for angiogenic potential in angiogenic assays in vitro and in vivo. Finally, they will be examined for genetic changes, specifically the number and type of DNA-adducts and H-ras mutations at codon 61. This study is unique by examining the role of angiogenesis in pre-invasive tumors, an area that is largely unexplored. In addition, this study presents a non-hormonal approach to the problem of chemoprophylaxis in high-risk women.