Chemosensitivity of peritoneal micrometastases as evaluated using a green fluorescence protein (GFP)-tagged human gastric cancer cell line

Abstract

The chemosensitivity of micrometastases in the peritoneal cavity to a 5-fluorouracil derivative (TS-1) was examined with a micrometastasis model featuring a human gastric cancer cell line tagged with the green fluorescence protein (GFP) gene in nude mice. Peritoneal metastases on the omentum and mesentery could be specifically visualized even when minute or dormant and also externally monitored noninvasively under illumination with blue light from 1 day after intraperitoneal (i.p.) injection of tumor cells. Metastatic deposits formed after i.p. injection of 2×1O6 tumor cells were significantly reduced by TS-1 in a dose-dependent manner (15-20 mg/kg), when it was orally administered from day 1 post-injection for 4 weeks (early administration . No such inhibition was evident after injection of 1×107 tumor cells. When 2×106 tumor cells given injection, the ascites-free period in TS-1-treated mice was significantly longer than in their untreated counterparts. Survival of TS-1-treated mice (5/15) was also significantly higher than the zero rate in controls (0/15), with 4 out of 5 surviving mice being free from peritoneal metastasis and the exception having only a few dormant metastases. In contrast, when TS-1 was administered starting from day 7 post-injection for 4 weeks (late administration), the survival and ascites-free period of the TS-1-treated mice were not significantly influenced. The results indicate that the chemosensitivity of peritoneal metastases to TS-1 is dependent on the number of i.p. tumor cells and the timing of drug administration. Peritoneal micrometastases at an early stage are most susceptible and can be effectively eliminated by oral administration of an anti-cancer agent, which leads to the longer survival and better quality of life (QOL) of the mice.