Gemcitabine, a drug with established efficacy against a number of solid tumors, has
therapeutic limitations due to its rapid metabolic inactivation. The aim of this study
was the development of an innovative strategy to produce a metabolically stable
analogue of gemcitabine that could also be selectively delivered to prostate cancer
(CaP) cells based on cell surface expression of the Gonadotropin Releasing Hormone-
Receptor (GnRH-R). The synthesis and evaluation of conjugated molecules,
consisting of gemcitabine linked to a GnRH agonist, is presented along with results in
androgen-independent prostate cancer models. NMR and ligand binding assays were
employed to verify conservation of microenvironments responsible for binding of
novel GnRH-gemcitabine conjugates to the GnRH-R. In vitro cytotoxicity, cellular
uptake and metabolite formation of the conjugates were examined in CaP cell lines.
Selected conjugates were efficacious in the in vitro assays with one of them, namely
GSG, displaying high antiproliferative activity in CaP cell lines along with significant
metabolic and pharmacokinetic advantages in comparison to gemcitabine. Finally,
treatment of GnRH-R positive xenografted mice with GSG, showed a significant
advantage in tumor growth inhibition when compared to gemcitabine.