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

University Of California, San Francisco, San Francisco CA

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Abstract

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.