PREVENTION OF MAMMARY CANCER IN HER-2NEU TRANSGENIC MICE

通过耐受性良好的口服化合物对肿瘤生长的长期控制在老年人和癌症高风险的无症状个体中是期望的。 血管生成被认为是肿瘤发生和发展的重要决定因素，在正常组织中并不突出。 在植入肿瘤的动物模型中，铜消耗已被证明会导致较小的、大部分无血管的肿瘤。 然而，在以前的研究中使用的植入肿瘤的大尺寸可能已经阻止了由于铜耗尽而检测到任何生存益处。我们假设，口服四硫代钼酸盐（TM），已知的最有效和最安全的血铜抑制剂（用于患有威尔逊氏病的人类），将通过抗血管生成机制延缓癌症易感Her 2/neu+转基因小鼠乳腺肿瘤的发病和/或减缓其生长。 我们实验室的初步数据表明，长期给予TM在Her 2/neu转基因小鼠中完全预防临床显著肿瘤的出现是安全有效的。在本申请中，我们提出在3种体内模型中研究TM对血管生成的影响：Her 2/neu转基因小鼠、Dunning大鼠前列腺癌模型和SCID小鼠中的移植性肺癌异种移植物。 来自这些模型的细胞将用于体外实验以检验TM干扰VEGF分泌和作用以及血管生成趋化因子IL-6和IL-8功能的假设。 这项工作将有助于揭示TM影响癌症血管生成开关信号传导的分子事件。 通过定义TM抑制血管生成的分子基础，这项工作将有助于定制TM在癌症中的临床应用。

The chronic control of tumor growth by a well-tolerated, oral compound would be desirable in the elderly and in asymptomatic individuals at high risk for cancer. Angiogenesis is recognized as an important determinant in tumor development and progression which is not prominent in normal tissues. Copper depletion has been shown to lead to smaller, largely avascular tumors, in animal models of implanted tumors. However, the large size of the implanted tumors used in previous studies may have prevented the detection of any survival benefit due to copper depletion. We hypothesize that oral Tetrathiomolybdate (TM) , the most potent and safest inhibitor of blood copper known (used in humans with Wilson's disease), will retard the onset and/or slow down the growth of mammary tumors in cancer prone Her2/neu+ transgenic mice by an anti-angiogenic mechanism. Preliminary data from our laboratory indicate that long-term administration of TM is safe and effective in the Her2/neu transgenic mouse in completely preventing the appearance of clinically significant tumors. In this application we propose to study TM's effect on angiogenesis in 3 in vivo models: the Her2/neu transgenic mice, the Dunning's rat prostate cancer model, and implanted lung cancer xenografts in SCID mice. The cells from these models will be used in in vitro experiments to test the hypothesis that TM interferes with VEGF secretion and action and angiogenic chemokine IL-6 and IL-8 function. This work will help uncover the molecular events whereby TM affects signaling of the angiogenic switch in cancer. By defining the molecular basis of TM's inhibition of angiogenesis, this work will help tailor the clinical application of TM in cancer.