1. GnRH-Gemcitabine conjugates for the treatment of androgen-independent prostate cancer: pharmacokinetic enhancements combined with targeted drug delivery.
- Author
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Karampelas T, Argyros O, Sayyad N, Spyridaki K, Pappas C, Morgan K, Kolios G, Millar RP, Liapakis G, Tzakos AG, Fokas D, and Tamvakopoulos C
- Subjects
- Animals, Cell Proliferation drug effects, Deoxycytidine chemistry, Deoxycytidine metabolism, Deoxycytidine pharmacokinetics, Deoxycytidine pharmacology, Gonadotropin-Releasing Hormone pharmacokinetics, Gonadotropin-Releasing Hormone pharmacology, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Molecular Structure, Prostatic Neoplasms, Castration-Resistant metabolism, Prostatic Neoplasms, Castration-Resistant pathology, Receptors, LHRH metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Gemcitabine, Deoxycytidine analogs & derivatives, Drug Delivery Systems, Gonadotropin-Releasing Hormone chemistry, Gonadotropin-Releasing Hormone metabolism, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
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.
- Published
- 2014
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