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

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.

journal_name

Anticancer Res

journal_title

Anticancer research

authors

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

subject

Has Abstract

pub_date

2004-05-01 00:00:00

pages

1393-9

issue

3a

eissn

0250-7005

issn

1791-7530

journal_volume

24

pub_type

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