Structure-activity relationship studies of novel somatostatin analogs with antitumor activity.

A series of new somatostatin analogs were synthesized in order to study the relative importance of specific substitutions in relation to selectivity between their endocrine and antitumor effects. Substitutions were carried out in all positions, except for Lys in position 5. Peptides were tested for their ability to inhibit in vitro and in vivo GH release, proliferation of the MCF 7 breast carcinoma cell line and tyrosine kinase activity in the HT 29 human colon carcinoma cell line. Selective biological activity was achieved in GH release and antitumor activity by the different amino acid substitutions. One of the analogs, with a five-residue ring (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2, TT-232), was unique. It had no GH release inhibitory activity, but did have strong tyrosine kinase inhibitory and antiproliferative effects.