title: Comparative in vitro biological evaluation of daunorubicin containing GnRH-I and GnRH-II conjugates developed for tumor targeting.
abstract: Hormone based drug targeting is a promising tool for selective tumor therapy. In this study, synthesis and systematic comparative biological evaluation of novel drug containing analogs of gonadotropin-releasing hormone GnRH-I and GnRH-II is reported demonstrating their suitability for tumor targeting. The cytotoxic conjugates were prepared by the attachment of the chemotherapeutical agent daunorubicin (Dau) to GnRH analogs directly or through an enzyme-labile spacer with oxime linkage. All conjugates were found to be proteolytically stable under circumstances applied in biological assays. Both GnRH-I and GnRH-II were able to bind similarly to high-affinity GnRH-I receptors on human pituitary and human prostate cancer cells. The in vitro long-term cytotoxic effect of the conjugates was comparable with that of the free drug in human breast and colon cancer cell lines. Furthermore, a concentration-dependent cellular uptake profile was observed. The in vitro apoptotic effect of the compounds was evaluated by flow cytometry analysis using annexin-V. Our results show that both the GnRH-I and the GnRH-II based analogs might be applied for targeted tumor therapy.
authors.affiliation: MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, 1117, Budapest, Hungary.
authors.forename: Ildikó
authors.initials: I
authors.lastname: Szabó
authors.forename: Szilvia
authors.initials: S
authors.lastname: Bősze
authors.forename: Erika
authors.initials: E
authors.lastname: Orbán
authors.forename: Éva
authors.initials: É
authors.lastname: Sipos
authors.forename: Gábor
authors.initials: G
authors.lastname: Halmos
authors.forename: Magdolna
authors.initials: M
authors.lastname: Kovács
authors.forename: Gábor
authors.initials: G
authors.lastname: Mező
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003630:Daunorubicin / Q000737:chemistry* / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000737:chemistry; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011966:Receptors, LHRH / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; C484844:GNRHR protein, human; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D003630:Daunorubicin
keywords: apoptotic effect; gonadotropin-releasing hormone; long-term cytotoxic effect; receptor binding affinity; targeted tumor therapy; targeting unit