Extracellular expression of cytosine deaminase results in increased 5-FU production for enhanced enzyme/prodrug therapy.

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Rehemtulla A, Hamstra DA, Kievit E, Davis MA, Ng EY, Dornfeld K, Lawrence TS

Extracellular expression of cytosine deaminase results in increased 5-FU production for enhanced enzyme/prodrug therapy.

Anticancer Res. 2004 May-Jun;24(3a):1393-9.

PubMed ID

15274300 [ View in PubMed

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Abstract

BACKGROUND: The cytosine deaminase/5-fluorocytosine (CD/5-FC), strategy for cancer gene therapy shows considerable promise in experimental models but, because CD is a cytosolic enzyme, intracellular production of 5-fluorouracil (5-FU) causes the demise of the transduced cells before cytotoxic concentrations of' 5-FU can be achieved within the extracellular milieu. MATERIALS AND METHODS: A soluble secreted form of CD was constructed and evaluated compared to intracellular CD in vitro and in vivo. RESULTS: The secreted form of CD temporarily spared transduced cells and enhanced accumulation of extracellular 5-FU. Cytosolic CD produced rapid inhibition of thymidylate synthase and cell death before significant extracellular concentrations of 5-FU developed. Finally, tumors expressing the secreted form of CD had an improved response to 5-FC treatment compared to tumors expressing intracellular CD. CONCLUSION: Further evaluation of extracellular expression of CD for enzyme/prodrug therapy may provide improvements in this commonly studied gene therapy strategy.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Flucytosine	Thymidylate synthase	Protein	Yeast	Unknown	Inhibitor	Details