title: Inhibition of human gastric carcinoma cell growth by treatment of N(3)-o-toluyl-fluorouracil as a precursor of 5-fluorouracil.
abstract: N(3)-o-toluyl-fluorouracil (TFU), the pro-drug of 5-fluorouracil (5-FU), is the metabolite of N(1)-acetyl-N(3)-o-toluyl-fluorouracil (atofluding). We aimed to evaluate the efficacy of TFU as a precursor of 5-FU on the growth inhibition of human gastric carcinoma cell lines SGC-7901 and MKN-45. Growth of SGC-7901 and MKN-45 cells was remarkably suppressed by treatment with TFU in the presence of liver microsomal enzymes in vitro, suggesting that TFU may be converted to 5-FU by the enzymes. Similar treatment of TFU induced apoptosis of the cells, which was deduced from typical apoptotic features such as morphology, the formation of characteristic ladder pattern of DNA migration and the accumulation of sub-G1 phase. Cancer cells xenografts in nude mice were employed to evaluate the efficacy of TFU in vivo. Growth of human gastric carcinoma cells was significantly delayed by oral administration of TFU with low side effects. Apoptosis in xenografts was also observed by means of TUNEL staining method. These results suggest that the treatment of TFU in the presence of liver microsomal enzymes and the oral administration of TFU in mice induced anti-proliferation and apoptosis in gastric carcinoma cells. This suggests that TFU may be a promising pro-drug of 5-FU for cancer treatments.
authors: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors: Jian
authors: J
authors: Liu
authors: Xun
authors: X
authors: Li
authors: Yan-na
authors: YN
authors: Cheng
authors: Shu-xiang
authors: SX
authors: Cui
authors: Ming-hui
authors: MH
authors: Chen
authors: Wen-fang
authors: WF
authors: Xu
authors: Zhi-gang
authors: ZG
authors: Tian
authors: Masatoshi
authors: M
authors: Makuuchi
authors: Wei
authors: W
authors: Tang
authors: Xian-jun
authors: XJ
authors: Qu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000201:enzymology; D011355:Prodrugs / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C517181:N3-o-toluyl-fluorouracil; D011355:Prodrugs; C475762:atofluding; D005472:Fluorouracil