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乳腺癌高危女性的化学预防药物。我们的假设是：导致侵袭前乳腺疾病的遗传和表观遗传事件也导致血管生成表型；进展到侵袭前乳腺疾病的晚期形式依赖于血管生成；阻断血管生成可以防止侵袭性肿瘤的发展，抑制下一阶段的发展，最终防止侵袭性疾病的发生。在这些研究中，我们将使用两种具有良好特征的模型来形成侵袭前和侵袭性乳腺肿瘤，即7,12-二甲基苯[a]蒽（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癌物诱导的浸润前乳腺肿瘤发生血管生成的时间框架，抑制血管生成可阻止癌物诱导的浸润前和浸润性乳腺肿瘤的形成和进展，这一过程独立于癌变的特定遗传或表观遗传途径，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服用时进行测试，从致癌物质暴露时开始，延迟一个月，以便在治疗前形成侵袭前肿瘤。在肿瘤发展的不同阶段的组织将检查表型变化，如组织形态学和血管的程度。此外，他们将在体外和体内血管生成试验中进行血管生成潜力测试。最后，将检查它们的遗传变化，特别是dna加合物的数量和类型以及密码子61上的H-ras突变。这项研究的独特之处在于研究了血管生成在侵袭前肿瘤中的作用，这是一个很大程度上未被探索的领域。此外，本研究提出了一种非激素的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.