HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

N(3)-o-toluyl-fluorouracil inhibits human hepatocellular carcinoma cell growth via sustained release of 5-FU.

AbstractPURPOSE:
N(3)-o-toluyl-fluorouracil (TFU), the prodrug of 5-fluorouracil (5-FU), is the metabolite of N(1)-acetyl-N(3)-o-toluyl-fluorouracil (atofluding). In the present study, we aimed to evaluate the efficacy of TFU on the inhibition of human hepatocellular carcinoma cells via sustained release of 5-FU. The metabolism of TFU underlying the inhibitory effect was also analyzed.
METHODS:
In vitro assays, inhibition of cell growth by TFU was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide method. The levels of TFU and 5-FU in the cell culture supernatant fluid were measured by high-performance liquid chromatography (HPLC). In vivo assays, the efficacy of TFU was evaluated in a human hepatocellular carcinoma xenograft mice model after 3 weeks of oral administration. The distributions of TFU and 5-FU in plasma and homogenate tissues including liver, lung and tumor were determined by HPLC.
RESULTS:
N(3)-o-toluyl-fluorouracil weakly inhibited the proliferation of SMMC-7721 and PLC/PRF/5 cells in the absence of liver microsomal enzymes. In contrast, the inhibition rates were significantly increased in the presence of these enzymes. HPLC results revealed that TFU was metabolized slowly by liver microsomal enzymes and therefore the concentration of 5-FU was gradually increased with a longer retention time in cell culture supernatant fluid. The efficacy of TFU was confirmed in SMMC-7721 xenografts in Balb/c athymic (nu+/nu+) mice model. TFU treatment induced inhibition of SMMC-7721 growth with few side effects. HPLC results showed that high levels of TFU were still in liver 48 h after the end of oral administration, implying that TFU preferentially accumulated in liver with slow conversion to 5-FU by enzymes. This led to a long-lasting concentration of 5-FU in plasma. Further, a high level of 5-FU was found in tumors with a relatively low level in lungs. These results suggest that the metabolite of TFU was preferentially converted or taken up by tumor cells. The distributions of 5-FU may contribute to its high anti-tumor activity and low adverse reactions in vivo.
CONCLUSION:
These results demonstrate that TFU is a promising prodrug of 5-FU for cancer treatment via sustained release of 5-FU in liver.
AuthorsXiaofan Zhang, Julia Li Zhong, Wei Liu, Zuhua Gao, Xia Xue, Pan Yue, Limei Wang, Cuirong Zhao, Wenfang Xu, Xianjun Qu
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 66 Issue 1 Pg. 11-9 (May 2010) ISSN: 1432-0843 [Electronic] Germany
PMID19756602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimetabolites, Antineoplastic
  • N3-o-toluyl-fluorouracil
  • Prodrugs
  • Fluorouracil
Topics
  • Animals
  • Antimetabolites, Antineoplastic (pharmacokinetics, pharmacology)
  • Carcinoma, Hepatocellular (drug therapy)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Drug Screening Assays, Antitumor
  • Fluorouracil (analogs & derivatives, metabolism, pharmacokinetics, pharmacology)
  • Humans
  • Liver Neoplasms (drug therapy)
  • Mice
  • Mice, Inbred BALB C
  • Microsomes, Liver (enzymology)
  • Prodrugs (pharmacokinetics, pharmacology)
  • Time Factors
  • Tissue Distribution
  • Xenograft Model Antitumor Assays

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: