Cytosine deaminase-uracil phosphoribosyltransferase fusion enzyme (CD-UPRT) (CD-UPRT)

The Cytosine deaminase-uracil phosphoribosyltransferase (CD-UPRT) fusion enzyme is a synthetic chimeric protein used in Gene-Directed Enzyme Prodrug Therapy (GDEPT) for cancer (Erbs et al., 1999). It combines the activity of cytosine deaminase (CD), which converts 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU), with uracil phosphoribosyltransferase (UPRT), which converts 5-FU to 5-fluorouridine monophosphate (5-FUMP) (Aboody et al., 2000). This fusion significantly enhances the chemosensitivity of cells to 5-FC by bypassing the rate-limiting steps of 5-FU activation in human cells. When expressed in iPS-derived neural stem cells (iNSCs), the enzyme is delivered to invasive brain tumors like glioblastoma due to the innate tumor-tropic properties of the stem cells (Namba et al., 2014). The localized conversion of 5-FC to 5-FU at the tumor site creates a high concentration of cytotoxic metabolites while minimizing systemic side effects. These metabolites, such as 5-FdUMP, inhibit thymidylate synthase, thereby disrupting DNA synthesis and inducing apoptosis (Zhao et al., 2012). The therapy also benefits from a bystander effect, where the produced 5-FU diffuses to and kills neighboring non-engineered tumor cells. This approach is particularly promising for treating disseminated or deep-seated tumors that are difficult to reach with conventional therapies. Safety concerns include the potential for off-target migration of the iNSCs and the immunogenicity of the non-human fusion enzyme. Overall, the CD-UPRT system in iNSCs represents a sophisticated targeted delivery platform for potent antimetabolite chemotherapy.

Other names

CDy-UPRTFCY1-FUR1 fusion proteinYeast cytosine deaminase-uracil phosphoribosyltransferaseSuicide gene CD-UPRT

The CD-UPRT fusion enzyme converts the prodrug 5-fluorocytosine into 5-fluorouracil and subsequently into 5-fluorouridine monophosphate, leading to the inhibition of DNA synthesis and induction of apoptosis.