title: Paclitaxel conjugation with the analog of the gonadotropin-releasing hormone as a targeting moiety.
abstract: A new targeted conjugates in which paclitaxel was used as a cytostatic compound and an analog of the gonadotropin-releasing hormone (GnRH) as a targeting moiety were synthesized. The molecule of the peptide hormone GnRH was modified to allow its connection to paclitaxel via spacer. The conjugates were prepared as prodrugs using 2'-hydroxyl group of paclitaxel. 4-Maleimidobutyric acid and chloroacetic acid served as spacers. The structures of the prepared derivatives were analysed by NMR and HR-MS. The conjugates MP264 and MP265 were chosen and their antiproliferative effect was tested in the breast cancer cell line MCF-7 using the MTT test of cell viability and neutral red uptake test. In MCF-7 cells, conjugate MP265 showed higher antiproliferative effect than paclitaxel alone. Receptor saturation tests showed that the unconjugated peptide analog of GnRH decreased efficacy of conjugate MP265 in concentration- and time-dependent manner. In conclusion, the paclitaxel conjugate with the analog of GnRH exhibited targeted antiproliferative effect for which its further testing will be implemented.
authors.affiliation: Laboratory of Plant Biotechnologies, Joint Laboratory of Institute of Experimental Botany AS CR, v.v.i. and Research Institute of Crop Production, v.v.i., Rozvojová 263, 165 02 Prague 6, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Pribylova
authors.forename: Marcela
authors.initials: M
authors.lastname: Dvorakova
authors.forename: Veronika
authors.initials: V
authors.lastname: Hanusova
authors.forename: Ingrid
authors.initials: I
authors.lastname: Nemethova
authors.forename: Lenka
authors.initials: L
authors.lastname: Skalova
authors.forename: Tomas
authors.initials: T
authors.lastname: Vanek
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011966:Receptors, LHRH / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C484844:GNRHR protein, human; C567982:MP 264; C568100:MP 265; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D017239:Paclitaxel