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 toxicity 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 tumors in the liver of nude mice. The human
colorectal cancer cell line C170HM2 readily forms liver
metastases in vivo.
Oral administration of 1500 mg/kg/day
OGT 719 inhibited liver
tumor burden by 95% compared with vehicle control, without any observable signs of toxicity. When the
tumor burden was increased and the same
OGT 719 treatment was compared with a standard clinical 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 days earlier. In contrast to
5-FU,
OGT 719 is p.o. bioavailable and has a plasma half-life between 1.5 and 3 h. Several
colorectal cancer cell lines express 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. Flux through
thymidylate synthase, as measured by 3H release from [3H]dUrd, was inhibited by
OGT 719 at 4 h. The notable difference in the potency of
OGT 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 significantly inhibit growth of metastatic
colorectal tumors in the liver in vivo. This hypothesis is presently being explored in clinical trials for primary
hepatocellular carcinoma and colorectal liver
metastases.