Characteristics of Cytosine Deaminase-5-Fluorocytosine System

Abstract

The cytosine deaminase gene (CD) is one of the suicide genes used in cancer gene therapy to sensitize tumor cells to certain prodrugs. CD encodes an enzyme, present in bacteria and fungi but absent in mammalian cells, that deaminates cytosine to uracil. CD can also deaminate 5-fluorocytosine (5-FC) to toxic 5-fluorouracil (5-FU) [1], a potent chemoterapeutic and radiosensitizing agent. 5-FC has significant anticancer effect on tumors engineered to express CD and a few percent only of CD-expressing cells is sufficient for regression of experimental tumors [2]. This is because generated 5-FU is able to kill neighboring non-CD-expressing cells (this is the so-called bystander effect). Endogenous enzymes convert 5-FU to nucleosides upon the addition of ribose or deoxyribose. Phosphorylation than leads to the active fluorinated nucleotides: 5-FUTP (5-fluorouridine triphosphate) and 5-FdUMP (5-fluorodeoxyuridine triphosphate). The former can be incorporated into RNA in place of UTP (uridine triphosphate); this leads to inhibition of nuclear processing of RNA. The latter inhibits irreversibly thymidylate synthase, leading to depletion of dTMP (thymidine monophosphate) that is required for DNA synthesis. It seems that 5-FU-mediated radiosensitization depends on DNA-directed effects.