Zhang Jimin, Mizoi Takayuki, Harada Nobuhiko, Shiiba Ken-Ichi, Miyagawa Kikuo, Matsuno Seiki, Sasaki Iwao
Division of Biological Regulation and Oncology, Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai 980-8574, Japan.
Anticancer Res. 2003 Jan-Feb;23(1A):323-9.
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.
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.
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.
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.
胸苷磷酸化酶（dThdPase）是5-氟尿嘧啶（5-FU）、5-脱氧-5-氟尿苷（5'-DFUR）和卡培他滨前体药物激活过程中的关键酶。在结直肠癌（CRC）中，已表明表达dThdPase的主要细胞是基质细胞，尤其是巨噬细胞。
本研究旨在阐明在巨噬细胞样细胞系THP-1和U937以及来自人外周血的富含单核细胞的单核细胞（MoMNCs）中表达的dThdPase是否能调节5'-DFUR对CRC细胞的抗肿瘤作用。
通过酶联免疫吸附测定（ELISA）在THP-1和U937中发现了dThdPase蛋白，而在所测试的CRC细胞系中几乎检测不到或未检测到dThdPase。在5-DFUR敏感性试验中，与未处理的5'-DFUR相比，5'-DFUR与巨噬细胞样细胞共孵育显著增强了5'-DFUR的抗肿瘤作用。MoMNCs也显示出类似的效果。当用THP-1或U937细胞处理含有5'-DFUR的培养基时，在处理后的培养基中可检测到5-FU水平。
这些数据表明巨噬细胞将5'-DFUR转化为5-FU并释放转化后的5-FU，从而增强了5'-DFUR的抗肿瘤作用。
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