title: GnRH-Gemcitabine conjugates for the treatment of androgen-independent prostate cancer: pharmacokinetic enhancements combined with targeted drug delivery.
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.
authors.affiliation: Division of Pharmacology-Pharmacotechnology, Biomedical Research Foundation of the Academy of Athens, Soranou Ephessiou Street 4, Athens GR-11527, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Karampelas
authors.forename: Orestis
authors.initials: O
authors.lastname: Argyros
authors.forename: Nisar
authors.initials: N
authors.lastname: Sayyad
authors.forename: Katerina
authors.initials: K
authors.lastname: Spyridaki
authors.forename: Charalampos
authors.initials: C
authors.lastname: Pappas
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.forename: George
authors.initials: G
authors.lastname: Kolios
authors.forename: Robert P
authors.initials: RP
authors.lastname: Millar
authors.forename: George
authors.initials: G
authors.lastname: Liapakis
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Tzakos
authors.forename: Demosthenes
authors.initials: D
authors.lastname: Fokas
authors.forename: Constantin
authors.initials: C
authors.lastname: Tamvakopoulos
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015394:Molecular Structure; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011966:Receptors, LHRH / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D011966:Receptors, LHRH; D003841:Deoxycytidine; D007987:Gonadotropin-Releasing Hormone; D000093542:Gemcitabine