Lipophilization of somatostatin analog RC‐160 with long chain fatty acid improves its antiproliferative and antiangiogenic activity in vitro

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) 129 , 101–109; doi: 10.1038/sj.bjp.0702990