Cross-Competition between Vasoactive Intestinal Peptide and Somatostatin for Binding to Tumor Cell Membrane Receptors¹

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide with a wide range of biological activities. Recent data suggest that functional VIP receptors are expressed on various tumor cells. Somatostatin (SST) and its long-acting analogue octreotide (OCT) are potent inhibitors of tumor cell growth and secretion. In the present study, the interactions between VIP and SST/OCT on primary tumors (insulinomas, n = 3; VIPomas, n = 2; intestinal adenocarcinomas, n = 5; neuroblastomas, n = 5; papillary thyroid cancers, n = 7; carcinoids, n = 5; ductal breast cancers, n = 8; small cell lung cancers, n = 3; ACTH-producing hypophyseal adenomas, n = 5; pheochromocytomas, n = 5) as well as on tumor cell lines (A431, HT29, PANC1, COLO320, HMC1, and KU812 cells) were analyzed by use of ¹²³I-labeled VIP and ¹²³I-labeled Tyr-3-OCT. Cross-competition between VIP and SST/OCT for binding to tumor cells was observed. The rank-order of potency for displacement of ¹²³I-labeled VIP binding to intact A431 cells was VIP $$\rm [concentration\;causing\;half-maximal\;inhibition\;(IC_{50}) = 2.9\;\pm\;1.9 (SD)\;nM] > OCT\;(IC_{50} = 9.3\;\pm\;1.7\;nM) = SST > substance\; P = secretin\;(IC_{50} = 1 \mu M)$$⁠. Binding of ¹²³I-labeled Tyr-3-OCT to A431 cells, in turn, was inhibited by $$\rm OTC = Tyr-3-OCT\;(IC_{50} = 1.5 \pm 0.3\;nM) = SST > VIP\;(IC_{50} = 4.9 \pm 1.1\;nM)$$⁠. This rank-order of potency was also obtained for primary tumors and tumor cell lines. Furthermore, SST and OCT inhibited VIP-induced [³H]thymidine incorporation, cyclic AMP formation, and tyrosine kinase activity with IC₅₀ values <10 nm. Together, these data provide evidence for functional interactions between SST and VIP on various tumor cells. These interactions may involve peptide cross-competition at cellular binding sites and may have implications for the biology and pathophysiology of respective cells and disease states.