PREVENTION OF MAMMARY CANCER IN HER-2NEU TRANSGENIC MICE

通过一种耐受性良好的口服化合物来长期控制肿瘤生长，对于老年人和癌症高危无症状的人来说是可取的。血管生成被认为是肿瘤发生和发展的重要决定因素，在正常组织中并不明显。在植入性肿瘤的动物模型中，铜耗竭已被证明会导致较小的、主要是无血管的肿瘤。然而，先前研究中使用的植入性肿瘤的大尺寸可能阻止了由于铜耗尽而检测到的任何生存益处。我们推测，口服四硫钼酸(TM)是已知的最有效和最安全的血铜抑制剂(用于患有威尔逊病的人类)，将通过抗血管生成机制延缓和/或减缓易患癌症的Her2/neu+转基因小鼠的乳腺肿瘤的发生和/或生长。我们实验室的初步数据表明，在Her2/neu转基因小鼠中长期给予TM是安全有效的，可以完全防止临床上有意义的肿瘤的出现。在这项应用中，我们建议在3个体内模型中研究TM对血管生成的影响：Her2/neu转基因小鼠，Dunning‘s大鼠前列腺癌模型，以及SCID小鼠移植的肺癌。来自这些模型的细胞将用于体外实验，以验证TM干扰血管生成趋化因子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的分子事件。通过确定TM抑制血管生成的分子基础，这项工作将有助于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.