MATRIX-ATTACHMENT THERAPY: A STRATEGY TO DELIVER 5-FLUOROURACIL TO TUMOR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 透明质酸是一种广泛存在于脊椎动物所有组织和体液中的糖胺聚糖。透明质酸在正常组织中的基础水平很低，但在各种恶性肿瘤中都发现了高水平的透明质酸，包括黑色素瘤、卵巢、乳腺、胶质母细胞瘤和膀胱癌细胞。CD44和TSG-6是两个透明质酸结合蛋白，在功能和结构上都有很好的特征。我们正在创造包含来自CD44或TSG-6的透明质酸结合结构域(也称为链接结构域)和酵母胞嘧啶脱氨酶(YCD)的融合蛋白。我们的假设是，融合蛋白Link-yCD将与细胞外基质中的透明质酸结合，并将口服的5-氟胞嘧啶(5-FC)转化为5-氟尿嘧啶(5-FU)。我们相信，这将在肿瘤周围建立一道化疗围栏，并改善抗肿瘤治疗。目前，我们使用计算机图形实验室提供的各种序列分析工具，并计划使用嵌合体来可视化修饰融合蛋白的功能结构域的结构。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hyaluronan is a ubiquitous glycosaminoglycan found in all tissues and body fluids of vertebrates. The basal levels of HA is low in normal tissues, but elevated levels of hyaluronan are found in various malignant tumors, including melanoma, ovaries, breast, glioblastoma, and bladder cancer cells. CD44 and TSG-6 are two hyaluronan binding proteins that are well characterized, both functionally and structurally. We are creating fusion proteins that contain the hyaluronan binding domain (also known as the Link domain) from either CD44 or TSG-6 and yeast cytosine deaminase (yCD). Our hypothesis is that the fusion protein Link-yCD will bind to hyaluronan in the extracellular matrix and covert the orally available 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU). We believe this will create a chemotherapeutic fence around the tumor and improve antitumor therapy. Currently, we use various sequence analysis tools that are available from the Computer Graphics Laboratory and we plan to use Chimera to visualize the structures of functional domains for modified fusion proteins.