Thymidine phosphorylase expressed in macrophages enhances antitumor effect of 5'-deoxy-5-fluorouridine on human colorectal carcinoma cells

Background: Thymidine phosphorylase (dThdPase) is a key enzyme in the activation of the pro-drugs of 5-fluorouracil (5-FU), 5'-deoxy-5-fluorouridine (5'-DFUR) and capecitabine. In colorectal carcinoma (CRC), the major cells expressing dThdPase have been shown to be stromal cells, particularly macrophages. Materials and Methods: The present study was designed to clarify whether dThdPase expressed in macrophage-like cell lines, THP-1 and U937, and monocyte-rich mononuclear cells (MoMNCs) from human peripheral blood can modulate the antitumor effect of 5'-DFUR on CRC cells. Results: dThdPase protein was found in THP-1 and U937 by ELISA, while little or no dThdPase could be detected in the CRC cell lines tested. Incubation of 5'-DFUR with the macrophage-like cells significantly enhanced the antitumor effect of 5'-DFUR in a 5-DFUR sensitivity assay compared with untreated 5'-DFUR. MoMNCs also showed a similar effect. When the media containing 5'-DFUR was treated with either THP-1 or U937 cells, detectable levels of 5-FU could be measured in the treated media. Conclusion: These data suggest that macrophages convert 5'-DFUR to 5-FU and release the converted 5-FU, resulting in an enhancement of the antitumor effect of 5'-DFUR.