title: Investigation on chemotactic drug targeting (chemotaxis and adhesion) inducer effect of GnRH-III derivatives in Tetrahymena and human leukemia cell line.
abstract: GnRH-III has been shown to exert a cytotoxic effect on the GnRH-R positive tumor cells. The chemotactic drug targeting (CDT) represents a new way for drug delivery approach based on selective chemoattractant guided targeting. The major goal of the present work was to develop and investigate various GnRH-III derivatives as potential targeting moieties for CDT. The cell physiological effects (chemotaxis, adhesion, and signaling) induced by three native GnRHs (hGnRH-I, cGnRH-II, and lGnRH-III) and nine GnRH-III derivatives were evaluated in two model cells (Tetrahymena pyriformis and Mono Mac 6 human monocytes). According to our results, the native GnRH-III elicited the highest chemoattractant and adhesion inducer activities of all synthesized peptides in micromolar concentrations in monocytes. With respect to chemoattraction, dimeric derivatives linked by a disulfide bridge ([GnRH-III(C)](2) ) proved to be efficient in both model cells; furthermore, acetylation of the linker region ([GnRH-III(Ac-C)](2) ) could slightly improve the chemotactic and adhesion effects in monocytes. The length of the peptide and the type of N-terminal amino acid could also determine the chemotactic and adhesion modulation potency of each fragment. The application of the chemoattractant GnRH-III derivatives was accompanied by a significant activation of phosphatidylinositol 3-kinase in both model cells. In summary, our work on low-level differentiated model cells of tumors has proved that GnRH-III and some of its synthetic derivatives are promising candidates to be applied in CDT: these compounds might act both as carrier, delivery unit, and antitumor agents.
authors.affiliation: Department of Genetics Cell and Immunobiology, Semmelweis University, Nagyvárad tér. 4, H-1089, Budapest, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Lajkó
authors.forename: Ildikó
authors.initials: I
authors.lastname: Szabó
authors.forename: Katalin
authors.initials: K
authors.lastname: Andódy
authors.forename: András
authors.initials: A
authors.lastname: Pungor
authors.forename: Gábor
authors.initials: G
authors.lastname: Mező
authors.forename: László
authors.initials: L
authors.lastname: Kőhidai
mesh_terms: D000595:Amino Acid Sequence; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002633:Chemotaxis; D002851:Chromatography, High Pressure Liquid; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D008969:Molecular Sequence Data; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D021241:Spectrometry, Mass, Electrospray Ionization; D013769:Tetrahymena pyriformis / Q000378:metabolism*
chemical_list: C448022:gonadotropin-releasing hormone-III; D007987:Gonadotropin-Releasing Hormone; D011761:Pyrrolidonecarboxylic Acid