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.


METHODS
The present study was designed to clarify whether dThdPase expressed in macrophage-like cell lines, THP-1 and U937, and monocyte-rich mono-nuclear 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.


CONCLUSIONS
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.
Zhang
Jimin
J
Division of Biological Regulation and Oncology, Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai 980-8574, Japan.
Mizoi
Takayuki
T
Harada
Nobuhiko
N
Shiiba
Ken-Ichi
K
Miyagawa
Kikuo
K
Matsuno
Seiki
S
Sasaki
Iwao
I
D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D003470:Culture Media; D005467:Floxuridine / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000201:enzymology*; D013939:Thymidine Phosphorylase / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D000964:Antimetabolites, Antineoplastic; D003470:Culture Media; D005467:Floxuridine; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; C025034:doxifluridine