Tumor-tropic properties of neural stem cells (NSCs) provide a novel approach with which to deliver targeting therapeutic genes to
brain tumors. Previously, we developed a therapeutic strategy against metastatic
brain tumors using a human NSC line (F3) expressing
cytosine deaminase (F3.CD). F3.CD converts systemically administered
5-fluorocytosine (5-FC), a blood-brain barrier permeable nontoxic
prodrug, into the
anticancer agent 5-fluorouracil (5-FU). In this study, we potentiated a therapeutic strategy of treatment with
nucleosides in order to chemically facilitate the endogenous conversion of
5-FU to its toxic metabolite
5-FU ribonucleoside (5-FUR). In vitro, 5-FUR showed superior cytotoxic activity against MDA-MB-435
cancer cells when compared to
5-FU. Although
adenosine had little cytotoxic activity, the addition of
adenosine significantly potentiated the in vitro cytotoxicity of
5-FU. When MDA-MB‑435 cells were co-cultured with F3.CD cells, F3.CD cells and 5-FC inhibited the growth of MDA-MB-435 cells more significantly in the presence of
adenosine. Facilitated 5-FUR production by F3.CD was confirmed by an HPLC analysis of the
conditioned media derived from F3.CD cells treated with 5-FC and
adenosine. In vivo systemic
adenosine treatment also significantly potentiated the
therapeutic effects of F3.CD cells and 5-FC in an MDA-MB-435 metastatic
brain tumor model. Simple
adenosine addition improved the antitumor activity of the NSCs carrying the therapeutic gene. Our results demonstrated an increased therapeutic potential, and thereby, clinical applicability of NSC-based gene therapy.