title: Lipophilization of somatostatin analog RC-160 with long chain fatty acid improves its antiproliferative and antiangiogenic activity in vitro.
abstract: The therapeutic potential of the somatostatin analogue RC-160 having antiproliferative activity, is limited by its short serum half life. To overcome this limitation, fatty acids namely butanoic acid and myristic acid were conjugated to the N-terminal residue of RC-160. The lipophilized derivatives of RC-160 were synthesized, purified by reverse phase HPLC and characterized by ES-mass spectroscopy. The antiproliferative activity of lipophilized derivatives of RC-160 on the growth of MIA-PaCa2 (human pancreatic carcinoma), DU145 (human prostate carcinoma), ECV304 (human umbilical chord endothelioma), as well as their antiangiogenic activity was evaluated in vitro. The relative stability of myristoyl-RC-160 towards degradation by proteases and serum was also determined. Myristoyl-RC-160 exhibited significantly higher antiproliferative efficacy than RC-160, on the above cell lines (P<0.01). Receptor binding assays, demonstrated that the affinity of RC-160 towards somatostatin receptors remains unaltered by myristoylation. Unlike RC-160, the myristoylated derivative was found to have significantly greater resistance to protease and serum degradation (P<0.01). Myristoyl-RC-160 exhibited significantly greater antiproliferative activity on ECV304, than RC-160 (P<0.01). Myristoyl RC-160 could also inhibit capillary tube formation more efficiently than RC-160 in a dose dependent manner, suggesting that it possessed enhanced antiangiogenic activity in vitro (P<0.001). Lipophilization of RC-160 with long chain fatty acids like myristic acid endows it with improved antiproliferative and antiangiogenic activity, stability and therapeutic index. British Journal of Pharmacology (2000) 109, 101 - 109
authors.affiliation: NeuroImmunology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi-110067, India.
authors.forename: P
authors.initials: P
authors.lastname: Dasgupta
authors.forename: R
authors.initials: R
authors.lastname: Mukherjee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000494:pharmacology*; D002197:Capillary Action / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D010450:Endopeptidases / Q000737:chemistry; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005227:Fatty Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006727:Hormone Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D017481:Receptors, Somatostatin / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D005227:Fatty Acids; D006727:Hormone Antagonists; D017481:Receptors, Somatostatin; C051458:vapreotide; D013004:Somatostatin; D010450:Endopeptidases