Antiproliferative Effect of a Novel Cholecystokinin‐B/Gastrin Receptor Antagonist, YM022

Cholecystokinin (CCK)‐B and gastrin receptors are expressed on a variety of human tumor cells. Recently, we have demonstrated that the human brain CCK‐B receptors are identical to the gastrin receptors derived from the stomach mucosa, and that the brain‐gut peptides, CCK‐8 and gastrin I are mitogenic for mouse NIH 3T3 fibroblasts expressing human CCK‐B/gastrin receptors (N‐hCCKBR). In this report, we evaluated the antiproliferative potency of CCK‐B/gastrin receptor antagonists by using N‐hCCKBR cells. Among several antagonists, a benzodiazepine derivative, YM022 had the most potent activities in competing with [(125)I]CCK‐8 or [(125)I]gastrin I binding, inhibition of CCK‐8‐ or gastrin I‐induced phosphoinositide hydrolysis and increasing cytoplasmic free calcium. Interestingly, a potent antagonist for rat CCK‐B/gastrin receptors did not have such activities in N‐hCCKBR cells. YM022 inhibited the CCK‐8‐ or gastrin I‐induced [methyl‐(3)H]thymidine incorporation of N‐hCCKBR cells in a dose‐dependent manner. In the absence of exogenous peptide ligands, YM022 also inhibited the proliferation of several human cancer cell lines expressing the genes for both gastrin and its receptor. These results suggest that YM022 could intervene in the autocrine stimulation of human tumor cell lines through CCK‐B/gastrin receptors. N‐hCCKBR cells are an excellent tool to screen for novel human CCK‐B/gastrin receptor antagonists possessing antiproliferative activity for human cancer cells.