Y2 RECEPTORS DECREASE HUMAN PANCREATIC-CANCER GROWTH AND INTRACELLULAR CYCLIC ADENOSINE-MONOPHOSPHATE LEVELS

Background, Peptide YY (PYY), a 36 amino acid enteric hormone is known to decrease pancreatic exocrine and endocrine function. Previous stud ies with BIM-43004-1, a modified PYY(22-36) Y2 receptor agonist, have revealed diminished mitochondrial activity in pretreated pancreatic ca ncer cells in vitro. We investigated the effects of both PYY and BIM-4 3004-1 on pancreatic cancer growth in vivo. Methods, The 100,000 to 15 0,000 human pancreatic cancer cells, Mia PaCa-2, were orthotopically t ransplanted into 48 male athymic mice. After 1 week animals were treat ed with either PYY or BIM-43004-1 at 200 pmol/kg/hr via miniosmotic pu mps for 2, 3 or 4 weeks. Paired controls received saline solution. At death tumor size and mass were measured. Receptor binding studies and intracellular cyclic adenosine monophosphate (cAMP) levels were measur ed in vitro. Results, All mice had significant human cancer growth wit hin the pancreas by histologic sections at 2, 3, and 4 weeks. Tumor ma ss was decreased by 60.9% in BIM-43004-1 treated mice and 27.1 % in PY Y treated mice. Receptor binding studies revealed binding of [I-125]-B IM-43004-1 and displacement of ligand on competitive addition of nonra dioactive BIM-43004-1. AK dissociation constant of 4.5 nmol and 27, 00 0 receptors per cell were quantitated by receptor binding studies. In BIM-43004-1 treated pancreatic cells a 52.5 % decrease in intracellula r cAMP levels was noted, whereas a 25.3 % decrease was seen in PW trea ted cells. Conclusions. BIM-43004-1, a novel Y2 synthetic agonist, spe cifically binds to human pancreatic cancer cells, decreases intracellu lar cAMP levels, and suppresses tumor growth in vivo. Adjuvant hormona l treatment with this Y2 receptor analog may be beneficial in the trea tment of patients with pancreatic adenocarcinoma.