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

Alnawaz Rehemtulla, Daniel A Hamstra, Els Kievit, Mary A Davis, Emily Y Ng, Kenneth Dornfeld, Theodore S Lawrence

Anticancer research 2004 May-Jun

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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. A soluble secreted form of CD was constructed and evaluated compared to intracellular CD in vitro and in vivo. 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. Further evaluation of extracellular expression of CD for enzyme/prodrug therapy may provide improvements in this commonly studied gene therapy strategy.

Citation

Alnawaz Rehemtulla, Daniel A Hamstra, Els Kievit, Mary A Davis, Emily Y Ng, Kenneth Dornfeld, Theodore S Lawrence. Extracellular expression of cytosine deaminase results in increased 5-FU production for enhanced enzyme/prodrug therapy. Anticancer research. 2004 May-Jun;24(3a):1393-9