A novel, orally administered nucleoside analogue, OGT 719, inhibits the liver invasive growth of a human colorectal tumor, C170HM2

OGT 719 is a novel p.o. bioavailable nucleoside analogue in which galactose is incorporated onto the fluoropyrimidine moiety of the cytotoxic agent 5- fluorouracil (5-FU). OGT 719 has been designed to reduce the systemic toxic ity normally associated with 5-FU while retaining activity against disease localized in the liver, in which it may be preferentially localized through the asialoglycoprotein receptor (ASGP-R). We report studies confirming the activity of OGT 719 in inhibiting growth of metastatic human colorectal tu mors in the liver of nude mice. The human colorectal cancer cell line C170H M2 readily forms liver metastases in vivo, Oral administration of 1500 mg/k g/day OGT 719 inhibited liver tumor burden by 95% compared with vehicle con trol, without any observable signs of toxicity, When the tumor burden was I ncreased and the same OGT 719 treatment was compared with a standard clinic al dose regimen of 25 mg/kg/day 5-FU/leucovorin given i.v., both treatments were equally efficacious, although 5-FU/leucovorin treatment started 7 day s earlier. In contrast to 5-FU, OGT 719 is p.o. bioavailable and has a plas ma half-life between 1.5 and 3 h. Several colorectal cancer cell lines expr ess the asialoglycoprotein receptor, although no significant levels can be detected in C170HM2 cells, consistent with the observation that OGT 719 is approximately 3 log orders of magnitude less potent in vitro than 5-FU. Flu x through thymidylate synthase, as measured by H-3 release from [H-3]dUrd, was inhibited by OGT 719 at 4 h. The notable difference in the potency of O GT 719 efficacy on C170HM2 cells in vitro and in vivo supports our model of liver-specific activation of OGT 719. As our data suggest, OGT 719 may sig nificantly inhibit growth of metastatic colorectal tumors in the liver in v ivo. This hypothesis is presently being explored in clinical trials for pri mary hepatocellular carcinoma and colorectal liver metastases.