Potent antitumor effect of 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine on peritoneal dissemination models of gastrointestinal cancers

Abstract

We investigated the antitumor activity of the nucleoside analog 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosine (4'-thio-FAC) in peritoneal dissemination models of gastrointestinal cancers. Oral administration of 4'-thio-FAC showed a marked effect on the development of ascites and on the survival of nude mice implanted with the highly metastatic MKN-45-P gastric cancer cells into the peritoneal cavity. The toxic effect was observed at a dose of 15 mg/kg, however, no toxicity was observed at a dose of 10 mg/kg with excellent antitumor activity. We established another highly metastatic cell line HCT-15-P by serial intraperitoneal passage of the colon cancer cell line HCT-15. In the HCT-15-P model, 4'-thio-FAC showed an inhibitory effect of peritoneal dissemination and an increase in the life span at a dose of 10 mg/kg. On the other hand, oral administration of 5-fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-DFUR) did not show an increase in the life span of mice at a dose of 10 mg/kg. In conclusion, 4'-thio-FAC is a promising therapeutic agent for use against peritoneal dissemination of gastrointestinal cancers.