MAMMARY TUMOR CHEMOPREVENTION BY ANGIOGENIC INHIBITORS

血管生成抑制剂对乳腺肿瘤的化学预防

• 批准号: 6174149
• 负责人: SUE C HEFFELFINGER
• 金额: $ 33.34万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6174149
• 关键词: adduct; angiogenesis; angiogenesis inhibitors; animal genetic material tag; antineoplastics; breast neoplasms; carcinogenesis; carcinogens; cell proliferation; chemical carcinogenesis; chemical related neoplasm /cancer; chemoprevention; disease /disorder model; gene mutation; histopathology; immunocytochemistry; laboratory rat; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic process; pharmacokinetics; phenotype; tamoxifen; vascular endothelium

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.

这项研究的目的是确定血管生成的抑制剂是否可以作为高风险女性乳腺癌的化学预防症。 我们的假设是：导致前侵入性乳房疾病的遗传和表观遗传事件也导致了血管生成表型；侵入前乳腺疾病的晚期形式的进展取决于血管生成。阻止血管生成可防止侵入前肿瘤的发展，抑制向下阶段的进展，并最终阻止侵入性疾病。 在这些研究中，我们将使用两个良好的模型来形成侵入性和侵入性乳腺肿瘤，分别是7,12-二甲基苯甲酸[A]蒽（DMBA）（DMBA）和N-硝基N-硝基N-甲基脲（NMU） - 诱导的大鼠乳腺肿瘤。 我们的具体目的是研究致癌原诱导的浸润性乳腺肿瘤的时间范围，使血管生成抑制血管生成可以阻止致癌物诱导的侵入性和侵入性乳腺肿瘤的形成和进展，从而独立于特定的遗传学或表观生成的术中，并且是依赖于特定的遗传学途径，并构成了吻合式途径。雌激素受体阻断剂的影响。长期进行时，从致癌物暴露开始，然后在一个月的延迟后开始，将测试两种血管生成抑制剂，以使侵入前肿瘤在治疗前形成。 将检查肿瘤发育不同阶段的组织，以进行表型变化，例如组织形态和血管程度。 此外，将测试它们在体外和体内的血管生成测定中的血管生成潜力。最后，将检查它们的遗传变化，特别是密码子61上DNA-添加剂和H-RAS突变的数量和类型。这项研究是独一无二的，它通过检查血管生成在侵入前肿瘤中的作用，该区域在很大程度上没有解释。 此外，这项研究为高危女性化学预防问题提出了一种非激素方法。