RIBONUCLEASES IN CANCER CHEMOTHERAPY

描述（来自申请人摘要）：拟议的总体目标 研究的目的是揭示核糖核酸酶A（RNase A）的同源物和变体是如何 促进肿瘤细胞死亡。Onconase是RNase A的一种两栖动物同系物， 目前正在进行III期人体临床试验， 恶性间皮瘤和I/II期试验用于治疗转移性 肾癌与洋葱酶相反，RNA酶A没有细胞毒性。在 在最初的资助期间，RNA酶A的变体被创造出来，像onconase一样， 能够逃避内源性核糖核酸酶抑制蛋白（RI）， 存在于哺乳动物细胞的胞质溶胶中。这些变异体对肿瘤细胞有毒性作用 细胞这一发现预示着一类新癌症的发展 基于RNA酶A的同源物和变体的化学治疗剂。 本研究的具体目标是：（1）确定RNase A 同源物结合到细胞表面，（2）发现RNA酶A所采取的路线 同源细胞质RNA，（3）揭示有关的基本信息， RI的亚细胞定位和细胞内功能，和（4）创建一个 核糖核酸酶A的人类同系物，对肿瘤细胞的毒性比癌康酶大。 RNase A同源物和变体的相关性质将在 与癌蛋白酶（阳性对照）和野生型RNA酶A（阴性）的比较 对照）。这些特性包括细胞毒性、RI逃避、核糖核酸溶解、 活性和构象稳定性。最后，三维 具有显著细胞毒性的RNase A同源物和变体的结构将被 通过X射线衍射分析测定。 拟议的研究旨在揭示新的见解的基础， 核糖核酸酶的细胞毒性，并可能导致新的癌症化疗药物。

DESCRIPTION (from applicant's abstract): The overall goal of the proposed research is to reveal how homologs and variants of ribonuclease A (RNase A) promote tumor cell death. Onconase, which is an amphibian homolog of RNase A, is now undergoing Phase III human clinical trials for the treatment of malignant mesothelioma and Phase I/II trials for the treatment of metastatic renal carcinoma. In contrast to onconase, RNase A is not cytotoxic. In the initial funding period, variants of RNase A were created that, like onconase, were able to evade the endogenous ribonuclease inhibitor protein (RI) that resides in the cytosol of mammalian cells. These variants were toxic to tumor cells. This finding portends the development of a new class of cancer chemotherapeutics based on homologs and variants of RNase A. The specific aims of the proposed research are: (1) to determine how RNase A homologs bind to the cell surface, (2) to discover the route taken by RNase A homologs to cytosolic RNA, (3) to reveal fundamental information about the subcellular localization and intracellular function of RI, and (4) to create a human homolog of RNase A that is more toxic to tumor cells than onconase. Relevant properties of RNase A homologs and variants will be assessed in comparison to onconase (positive control) and wild-type RNase A (negative control). These properties include cytotoxicity, RI evasion, ribonucleolytic activity, and conformational stability. Finally, the three-dimensional structures of RNase A homologs and variants with notable cytotoxicity will be determined by X-ray diffraction analysis. The proposed research is designed to reveal new insights into the basis of ribonuclease cytotoxicity, and could lead to new cancer chemotherapeutics.