PROTEASES--TUMOR BIOLOGY

本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育和进展中的作用 并测试抗蛋白酶疗法在抑制癌症中的作用， 这些过程。 在第一个目标中，蛋白酶参与初级 研究上皮肿瘤的生长、侵袭和转移 在体外和体内使用人前列腺癌和结肠癌肿瘤细胞 在免疫缺陷小鼠的异种移植模型中。 我们将确定 丝氨酸、半胱氨酸和金属蛋白酶在人类肿瘤中的表达 前列腺和结肠细胞系衍生自核心B。 在 第二个目的是确定大分子物质在体内的作用， 在项目1和核心C中开发的蛋白酶抑制剂和化学品 蛋白酶抑制剂在项目1中开发。 这些特工要么 通过注射施用或表达为转基因重组体 proteins. 外源性药物的给药将遵循 由Core D进行的药代动力学研究。 蛋白酶和/或 蛋白酶抑制剂将在转基因小鼠中通过遗传调节 互补 我们将使用核心C开发的转基因小鼠 和项目1，其是无效的或过表达特异性蛋白酶，或 蛋白酶抑制剂，并确定是否以及何时这些蛋白酶 参与恶性肿瘤的多阶段进展。 肿瘤系 将被移植到免疫功能低下的小鼠体内 蛋白酶抑制剂转基因对组成性或时间调节 发起人。 在第三个目标中，我们将确定哪些蛋白酶是 在体内由响应血管生成刺激的内皮细胞表达 以及蛋白酶抑制剂对体内生长模型的影响 因子诱导的血管生成。 然后我们将测试这些抑制剂， 对抑制人结肠异种移植模型中血管生成的作用 和前列腺癌。 我们相信，这些研究将带来新的 具有更高特异性和降低毒性的化学治疗剂 比目前用于这些肿瘤的许多药物都要多。

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.