GnRH-gemcitabine conjugates for the treatment of androgen-independent prostate cancer : pharmacokinetic enhancements combined with targeted drug delivery

dc.contributor.authorKarampelas, Theodoros
dc.contributor.authorArgyros, Orestis
dc.contributor.authorSayyad, Nisar
dc.contributor.authorSpyridaki, Katerina
dc.contributor.authorPappas, Charalampos
dc.contributor.authorMorgan, Kevin
dc.contributor.authorKolios, George
dc.contributor.authorMillar, Robert P.
dc.contributor.authorLiapakis, George
dc.contributor.authorTzakos, Andreas G.
dc.contributor.authorFokas, Demosthenes
dc.contributor.authorTamvakopoulos, Constantin
dc.date.accessioned2014-09-22T12:15:31Z
dc.date.issued2014-04
dc.description.abstractGemcitabine, 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.en_US
dc.description.embargo2015-02-28
dc.description.librarianhb2014en_US
dc.description.sponsorshipA.G.Leventis foundation and the General Secretariat for Research & Technology of the Greek Ministry of Education (LS7- 1682/17156/6.12.10).MRC and National Research Foundation of South Africa, and the Universities of Pretoria and Cape Townen_US
dc.description.urihttp://pubs.acs.org/bcen_US
dc.identifier.citationKarampelas, T, Argyros, O, Sayyad, N, Spyridaki, K, Pappas, C, Morgan, K, Kolios, G, Millar, RP, Liapakis, G, Tzakos, AG, Fokas, D & Tamvakopoulos, C 2014, 'GnRH-gemcitabine conjugates for the treatment of androgen-independent prostate cancer : pharmacokinetic enhancements combined with targeted drug delivery', Bioconjugate Chemistry, vol. 25, no. 4, pp. 813-823.en_US
dc.identifier.issn1043-1802 (print)
dc.identifier.issn1520-4812 (online)
dc.identifier.other10.1021/bc500081g
dc.identifier.urihttp://hdl.handle.net/2263/42062
dc.language.isoenen_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Bioconjugate Chemistry, © 2014 American Chemical Society after peer review and technical editing by the publisher.en_US
dc.subjectGemcitabineen_US
dc.subjectRapid metabolic inactivationen_US
dc.subjectGonadotropin-releasing hormone-receptor (GnRH-R)en_US
dc.titleGnRH-gemcitabine conjugates for the treatment of androgen-independent prostate cancer : pharmacokinetic enhancements combined with targeted drug deliveryen_US
dc.typePostprint Articleen_US

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