Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators

Anticancer Drugs. 1996 Jul;7(5):548-57. doi: 10.1097/00001813-199607000-00010.


We have focused our attention on the development of a novel form of a tegafur-based [FT; a prodrug of 5-fluorouracil (5-FU)] antitumor agent. We have used two biochemical and pharmacological modulators of 5-FU to improve its overall activity. To potentiate the antitumor activity of FT, 5-chloro-2,4-dihydroxypyridine (CDHP) was used as a potent reversible inhibitor of 5-FU degradation. The reduction of gastrointestinal (GI) toxicity, induced in the host by 5-FU, was modulated by potassium oxonate (Oxo), an inhibitor of orotate phosphoribosyltransferase that catalyzes the phosphorylation of 5-FU, a process believed to be responsible for the toxic effects of 5-FU. When CDHP and FT were simultaneously given orally to Yoshida sarcoma-bearing rats in various molar ratios, the antitumor effect of FT was significantly potentiated by the combination consisting of at least a 0.2 versus 1 molar ratio of CDHP to FT, respectively. This augmentation of an antitumor activity was supported by potent and prolonged inhibition of dihydrouracil dehydrogenase activity (5-FU degrading activities) in the liver of tumor-bearing rats after oral CDHP (0.2:0.8 molar ratio) and furthermore by elevation and over 12 h retention of 5-FU levels in the tumors following combined administration of FT and CDHP at a molar ratio of 1:0.4, respectively. Moreover, to reduce the severe GI injury and subsequent loss of body weight, observed in parallel with an increased antitumor efficacy, Oxo was given orally to Yoshida sarcoma-bearing rats and nude rats xenografted with H-81 human gastric carcinoma, during consecutive administration of the FT-CDHP mixture. Combined treatment with Oxo and FT (1:2 molar ratio) supplemented with 0.4 molar CDHP resulted in protection of body weight loss without affecting the high antitumor efficacy of the FT-CDHP mixture. When [2-14C]FT plus CDHP was administered with Oxo, the 14C-labeled fluoronucleotide content was objectively decreased in the GI tract of the tumor-bearing rats but not in the tumor and bone marrow, which supports our initial hypothesis. Based on these promising data, we propose a suitable formulation of a FT-based anticancer drug, called S-1, and consisting of FT, CDHP and Oxo at a 1:0.4:1 molar ratio and showing tumor-selective cytotoxicity of 5-FU.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Dihydrouracil Dehydrogenase (NADP)
  • Drug Synergism
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects
  • Fluorouracil / therapeutic use*
  • Gastrointestinal Diseases / chemically induced
  • Gastrointestinal Diseases / prevention & control
  • Liver / drug effects
  • Liver / enzymology
  • Male
  • Oxidoreductases / antagonists & inhibitors
  • Oxonic Acid / administration & dosage
  • Oxonic Acid / therapeutic use*
  • Prodrugs / administration & dosage
  • Prodrugs / therapeutic use*
  • Pyridines / administration & dosage
  • Pyridines / therapeutic use*
  • Rats
  • Rats, Nude
  • Sarcoma, Experimental / drug therapy*
  • Sarcoma, Experimental / pathology
  • Tumor Cells, Cultured


  • Prodrugs
  • Pyridines
  • Oxonic Acid
  • Oxidoreductases
  • Dihydrouracil Dehydrogenase (NADP)
  • Fluorouracil
  • gimeracil