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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
GnRH-gemcitabine conjugates for the treatment of androgen-independent prostate cancer: Pharmacokinetic enhancements combined with targeted drug delivery
Bioconjugate Chemistry, Volume 25, No. 4, Year 2014
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Description
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. © 2014 American Chemical Society.
Authors & Co-Authors
Karampelas, Theodoros
Greece, Athens
Biomedical Research Foundation Academy of Athens
Argyros, Orestis
Greece, Athens
Biomedical Research Foundation Academy of Athens
Sayyad, Nisar
United States
Section of Organic Chemistry and Biochemistry
Spyridaki, Katerina
Greece, Rethymnon
University of Crete
Pappas, Charalampos G.
United States
Section of Organic Chemistry and Biochemistry
Morgan, Kevin
United Kingdom, Hull
University of Hull
Kolios, George
Greece, Komotini
Democritus University of Thrace, Medical School
Millar, Robert P.
South Africa, Pretoria
University of Pretoria
South Africa, Cape Town
University of Cape Town
United Kingdom, Edinburgh
The University of Edinburgh
Liapakis, George
Greece, Rethymnon
University of Crete
Tzakos, Andreas G.
United States
Section of Organic Chemistry and Biochemistry
Fokas, Demosthenes
Greece, Ioannina
University of Ioannina
Tamvakopoulos, Constantin S.
Greece, Athens
Biomedical Research Foundation Academy of Athens
Statistics
Citations: 41
Authors: 12
Affiliations: 9
Identifiers
Doi:
10.1021/bc500081g
ISSN:
10431802
e-ISSN:
15204812
Research Areas
Cancer
Noncommunicable Diseases