Metabolism of pyrimidine analogues and their nucleosides

Non-invasive molecular and functional imaging of cytosine deaminase and uracil phosphoribosyltransferase fused with red fluorescence protein

“…One of the best-characterized suicide gene therapy strategies utilizes cytosine deaminase CD/ UPRT fusion gene, which has been used in clinical gene therapy trials [2,3]. CD is found in bacteria and fungi but not in mammalian cells, and it converts the anti-fungal agent 5-fluorocytosine (5-FC) which has low toxicity in humans, to the potent chemotherapeutic agent 5-fluorouracil (5-FU), which is then catalyzed by cellular enzymes to fluoronucleotides (FNucs), such as 2?-deoxy-5-fluorouridine mono-, di-and tri-phosphates (FdUMP, FdUDP and FdUTP) and 5-fluorouridine-5?-mono-, di-and triphosphates (FUMP, FUDP, FUTP) [4] which subsequently inhibit DNA or RNA synthesis. Certain tumor cells are not sensitive to or become resistant to 5-FU because of the low efficiency in the conversion of 5-FU to its toxic metabolites.…”

Comparison of different methods to assess the cytotoxic effects of cytosine deaminase and thymidine kinase gene therapy

“…4,5 Cellular enzymes subsequently metabolize 5-FU to cytostatic/cytotoxic fluoronucleotides such as FUTP and FdUMP. 6 5-FU acts throughout the cell cycle with emphasis on certain events such as DNA synthesis. When cells were incubated continuously with 5-FU, most of them accumulated in S-phase and remained there.…”

Cytosine deaminase and thymidine kinase gene therapy in a Dunning rat prostate tumour model: absence of bystander effects and characterisation of 5-fluorocytosine metabolism with 19F-NMR spectroscopy

“…14,15 Actually, 5-FU itself is also a prodrug which must be converted intracellularly to cytostatic/cytotoxic fluoronucleotides, such as FUTP and FdUMP. 16 This anabolic activation occurs readily in tumour cells, but also in rapidly proliferating normal cells, resulting in the familiar toxic side-effects of conventional 5-FU therapy. Tumour-selective amplification of the intracellular anabolic activation of 5-FU to FUMP can be achieved by transfection with the E. coli gene for uracil phosphoribosyltransferase (UPRT).…”