Gemcitabine Based Peptide Conjugate with Improved Metabolic Properties and Dual Mode of Efficacy

• DOI: 10.1021/acs.molpharmaceut.6b00961
• Publication Date: 2017-01-18T23:12:55Z
• Authors: Theodoros Karampelas; Eleni Skavatsou; Orestis Argyros; Demosthenes Fokas; Constantin Tamvak...
• Keywords: Male; Deoxycytidine; Gemcitabine; 3. Good health; Mice, Inbred C57BL; Mice; Prostatic Neoplasms, Castration-Resistant; 03 medical and health sciences; 0302 clinical medicine; Tumor Cells, Cultured; Animals; Humans; Female; Prodrugs; Tissue Distribution; Rats, Wistar; Peptides; Receptors, LHRH

Gemcitabine is a clinically established anticancer agent potent in various solid tumors but limited by its rapid metabolic inactivation and off-target toxicity. We have previously generated metabolically superior to gemcitabine molecule (GSG) conjugating gonadotropin releasing hormone receptor (GnRH-R) ligand peptide showed that GSG was efficacious castration resistant prostate cancer (CRPC) animal model. The current article provides an in-depth mechanistic study of GSG, coupled with toxicity assays strengthen the potential role clinic. LC-MS/MS based approaches were employed delineate metabolism cellular uptake, release quantitate intracellular levels metabolites (active dFdCTP inactive dFdU) resulting from GSG. GnRH-R agonistic investigated quantifying testosterone animals dosed daily while vitro colony forming assay together vivo whole blood measurements performed elucidate hematotoxicity profile Stability major metabolite more stable nonapeptide could prolong gemcitabine's bioavailability. acted as prodrug offered advantage compared generating higher steadier dFdCTP/dFdU ratio, DU145 CRPC cells depended on nucleoside transporters. Daily administrations mice agonist can also cause ablation without any observed hematotoxicity. In summary, offer powerful unique pharmacological approach treatment: single nontoxic be used reach tumor site selectively metabolism, biodistribution, safety agonistically ablating levels.