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Interaction of endothelial progenitor cells expressing cytosine deaminase in tumor tissues and 5‐fluorocytosine administration suppresses growth of 5‐fluorouracil‐sensitive liver cancer in mice

The drug delivery system to tumors is a critical factor in upregulating the effect of anticancer drugs and reducing adverse events. Recent studies indicated selective migration of bone marrow‐derived endothelial progenitor cells (EPC) into tumor tissues. Cytosine deaminase (CD) transforms nontoxic 5‐fluorocytosine (5‐FC) into the highly toxic 5‐fluorouracil (5‐FU). We investigated the antitumor effect of a new CD/5‐FC system with CD cDNA transfected EPC for hepatocellular carcinoma (HCC) in mice. We used human hepatoma cell lines (HuH‐7, HLF, HAK1‐B, KYN‐2, KIM‐1) and a rat EPC cell line (TR‐BME‐2). Escherichia coli CD cDNA was transfected into TR‐BME‐2 (CD‐TR‐BME). The inhibitory effect of 5‐FU on the proliferation of hepatoma cell lines and the inhibitory effect of 5‐FU secreted by CD‐TR‐BME and 5‐FC on the proliferation of co‐cultured hepatoma cells were evaluated by a tetrazolium‐based assay. In mouse subcutaneous xenograft models of KYN‐2 and HuH‐7, CD‐TR‐BME was transplanted intravenously followed by 5‐FC injection intraperitoneally. HuH‐7 cells were the most sensitive to 5‐FU and KYN‐2 cells were the most resistant. CD‐TR‐BME secreted 5‐FU and inhibited HuH‐7 proliferation in a 5‐FC dose‐dependent manner. CD‐TR‐BME were recruited into the tumor tissues and some were incorporated into tumor vessels. Tumor growth of HuH‐7 was significantly suppressed during 5‐FC administration. No bodyweight loss, ALT abnormality or bone marrow suppression was observed. These findings suggest that our new CD/5‐FC system with CD cDNA transfected EPC could be an effective and safe treatment for suppression of 5‐FU‐sensitive HCC growth. (Cancer Sci 2012; 103: 542–548)