Yeast cytosine deaminase (yCD) (yCD)

Yeast cytosine deaminase (yCD) is an exogenous enzyme derived from Saccharomyces cerevisiae that is not naturally present in the human genome (UniProt P25334). In the context of the therapeutic platform vocimagene amiretrorepvec (Toca 511), yCD is delivered via a retroviral replicating vector that selectively infects and integrates into the DNA of actively dividing cancer cells, such as those found in high-grade gliomas (Cloughesy et al., 2016, Science Translational Medicine). Once expressed, the yCD enzyme acts as a suicide gene by converting the orally administered, non-toxic prodrug 5-fluorocytosine (5-FC) into the potent cytotoxic agent 5-fluorouracil (5-FU) (NCI Drug Dictionary). This localized conversion allows for high concentrations of 5-FU within the tumor microenvironment, leading to the inhibition of DNA synthesis and apoptosis in both infected and neighboring uninfected cells via the bystander effect (Ostertag et al., 2012, Neuro-Oncology). Additionally, the resulting cell death can trigger an immunogenic response, potentially stimulating a systemic anti-tumor immune response (Touchefeu et al., 2012, Expert Opinion on Biological Therapy). Despite showing promise in early-phase clinical trials, a pivotal Phase 3 study failed to meet its primary endpoints, highlighting the challenges of achieving sufficient vector distribution in large, heterogeneous tumors (Cloughesy et al., 2020, JAMA Oncology).

Other names

yCDCytosine deaminaseFCY1Toca 511Vocimagene amiretrorepvec

Gene-directed enzyme prodrug therapy (GDEPT) involving the enzymatic conversion of 5-fluorocytosine to 5-fluorouracil.