PROTEASES--TUMOR BIOLOGY

这个项目的目标是确定丝氨酸、半胱氨酸和 金属蛋白酶在上皮细胞发生发展中的作用 并检测抗蛋白酶治疗对肿瘤的抑制作用 这些过程。在第一个目的中，蛋白水解酶参与了原发性 将研究上皮性肿瘤的生长、侵袭和转移。 利用人前列腺癌和结肠癌细胞的体内外实验 在免疫受损小鼠的异种移植模型中。我们将决定 丝氨酸、半胱氨酸和金属蛋白酶在人类肿瘤中的表达 由它们衍生的带有核心B的前列腺和结肠细胞系。 第二个目的，我们将检测大分子在体内的作用。 在项目1和核心C中开发的蛋白酶抑制剂和化学 项目1中的蛋白酶抑制剂DevEd。这些试剂将是 注射或以转基因重组表达 蛋白质。外源性药物的给药将由以下人员指导 由Core D.Protease和/或 蛋白水解酶抑制物在转基因小鼠中的调节作用 互补性。我们将使用Core C开发的转基因小鼠 和项目1是空的或过度表达特定的蛋白酶或 并确定这些蛋白酶是否以及何时使用 参与了恶性肿瘤的多阶段进展。肿瘤细胞系 将被移植到免疫功能低下的小鼠体内 结构性或时间性调节的蛋白酶抑制因子转基因 推动者。在第三个目标中，我们将确定哪些蛋白酶 内皮细胞在体内对血管生成刺激的反应 蛋白水解酶抑制剂对体内生长模型有什么影响 因子诱导的血管生成。然后我们将测试这些抑制剂的 抑制人结肠异种移植模型血管生成的实验研究 和前列腺癌。我们相信，这些研究将导致小说的产生 特异性更强、毒性更低的化疗药物 比许多目前使用的治疗这些肿瘤的药物更多。

The goal of this project is to determine the role of serine, cysteine and metallo-proteases in the development and progression of epithelial cancers and to test the effects of anti-protease therapy in inhibiting these processes. In the first aim protease involvement in primary epithelial tumor growth, invasion and metastasis will be investigated using human prostate and colon cancer tumor cells in vitro and in vivo in xenograft models in immunocompromised mice. We will determine the serine, cysteine and metallo-proteases expressed in human tumors of prostate and colon cell lines derived from them with Core B. In the second aim, we will detrmin the effect in vivo of macromolecular protease inhibitors developed in Project 1 and Core C and chemical protease inhibitors deved in Project 1. These agents will either be administered by injection or expressed as transgenic recombinant proteins. Administration of exogenous agents will be guided by pharmakokinetic studies carried out by Core D. Protease and/or protease inhibitors will be modulated in transgenic mice by genetic complementation. We will use transgenic mice developed by Core C and Project 1 that are null or overexpress specific proteases or protease inhibitors and determine whether and when these proteases are involved in the multistage progression of malignancy. Tumor lines will be transplanted into immunocompromised mice that overexpress proteaseinhibitor transgenes on constitutive or temporally regulated promoters. In the third aim we will determine which proteases are expressed by endothelial cells responding to angiogenic stimuli in vivo and what effect protease inhibitors have on an in vivo model of growth factor-induced angiogenesis. We will then test these inhibitors for effects on inhibiting angiogenesis in xenograft models of human colon and prostate cancer. We believe that these studies will lead to novel chemotherapeutic agents with greater specificity and reduced toxicity than many currently used agents for these tumors.