GTI-2501 is a 20-mer
oligonucleotide that is complementary to a coding region in the
mRNA of R1, the large subunit of
ribonucleotide reductase (RNR). In vitro studies, have demonstrated that
GTI-2501 decreases
mRNA and
protein levels of R1 in a sequence-specific and dose-dependent manner. Furthermore,
GTI-2501 inhibits the growth of human lung, liver, ovary, brain,
melanoma, breast and pancreatic
tumor cells in colony forming assays. In vivo studies have shown that
GTI-2501 significantly inhibits growth of human colon, pancreas, lung, breast, renal, ovarian,
melanoma, brain
glioblastoma-
astrocytoma, and prostatic
tumors in CD-1 nude, Balb/c nude and/or SCID mice.
GTI-2501 treatment caused total regression of human breast and renal
tumor xenografts in mice. These effects are not observed with a scrambled control
oligonucleotide containing the same base content but not complementary to R1.
GTI-2501 specifically inhibits
metastasis of human
melanoma cells to the lungs in CD-1 athymic nude mice and prolongs the survival of mice bearing human
lymphoma. Taken together these results suggest that an antisense mechanism of action is responsible for growth inhibition in vitro and in vivo and that
GTI-2501 can act as a selective and specific anti-
tumor agent.