Cytosine deaminase / Uracil phosphoribosyltransferase (CD/UPRT)

Cytosine deaminase / Uracil phosphoribosyltransferase (CD/UPRT) is a bifunctional fusion protein primarily utilized in suicide gene therapy, also known as gene-directed enzyme prodrug therapy (GDEPT) [1, 2]. This chimeric enzyme combines the activities of cytosine deaminase, which deaminates the non-toxic antifungal prodrug 5-fluorocytosine (5-FC) into the potent antimetabolite 5-fluorouracil (5-FU), and uracil phosphoribosyltransferase, which further converts 5-FU into toxic fluoronucleotides like 5-fluorouridine monophosphate (5-FUMP) [2, 6]. By integrating these two steps, the CD/UPRT system significantly increases the local concentration of toxic metabolites within the tumor microenvironment, bypassing common resistance mechanisms to 5-FU [3, 16]. The therapeutic strategy typically involves delivering the CD/UPRT gene to cancer cells using viral or non-viral vectors, followed by systemic administration of 5-FC [7, 13]. A key advantage of this system is the 'bystander effect,' where the small, diffusible 5-FU molecules spread from gene-modified cells to neighboring untransduced tumor cells, enhancing the overall anti-tumor efficacy [5, 17]. CD/UPRT is currently being investigated for the treatment of various solid tumors, including prostate, lung, and brain cancers, as well as for the selective elimination of T cells in graft-versus-host disease [1, 4].

Other names

FCU1CD-UPRTyCD-UPRTyCD-yUPRTCytosine deaminase-uracil phosphoribosyltransferase

The fusion protein catalyzes the conversion of the non-toxic prodrug 5-fluorocytosine (5-FC) into 5-fluorouracil (5-FU) via its cytosine deaminase activity, followed by the conversion of 5-FU into 5-fluorouridine monophosphate (5-FUMP) via its uracil phosphoribosyltransferase activity [1, 2]. These metabolites inhibit thymidylate synthase and are incorporated into RNA and DNA, resulting in cell death [3, 8].