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Lorglumide and Loxiglumide Inhibit Gastrin-stimulated DNA Synthesis in a Rat Tumoral Acinar Pancreatic Cell Line (AR42J)¹

Institut National de la Santé et de la Recherche Medicale, Unité 151, C.H.U. Rangueil, Bat. L3, 31054 Toulouse Cedex, France

Many reports emphasized the role of gastrin as growth factor on normal gastrointestinal mucosa and pancreas. In the present study, we analyzed the proliferative effects of cholecystokinin (CCK) and gastrin peptides on a rat tumoral pancreatic cell line, AR42J, which possesses both CCK_A and CCK_B receptor subtypes.

The results showed a good correlation between the binding of gastrin to CCK_B receptor [K_d 1.125 ± 0.3 (SD) nM] and its ability to either induce ornithine decarboxylase activity [50% effective concentration, 0.6 ± 0.3 nM] and [³H]-thymidine incorporation [50% effective concentration, 2 ± 0.4 nM]. Furthermore, the ability of different cholecystokinin and gastrin antagonists such as proglumide and asperlicin derivatives (respectively, CR1409, CR1505, and L364,718) were tested. We found that all antagonists displaced ¹²⁵I-labeled gastrin binding, with the following order of potencies: L364,718 > CR1409 > CR1505 > proglumide. Furthermore, the 50% inhibitory concentration of CR1409 and CR1505 to inhibit gastrin stimulated ornithine decarboxylase activity (an early event involved in cell proliferation) and [³H]thymidine incorporation were in agreement with their constants of inhibition (K₁) on gastrin binding. The L364,718 compound, at a concentration which fully occupied the CCK_A without affecting the CCK_B, had no effect on gastrin stimulated ornithine decarboxylase activity and [³H]thymidine incorporation. In addition, this compound appeared to be a full agonist on CCK_B receptor.

These results confirm the implication of the CCK_B receptor in the proliferative response of AR42J cells to gastrin.

¹ The present work was supported by grants from the Association pour la Recherche sur le Cancer (6414), EEC (ST₂ J00 1-3F), and Région Midi-Pyrénées (8700777).

² To whom requests for reprints should be addressed, at INSERM U 151, C.H.U. Rangueil, Bat. L3, 31054 Toulouse, France.

Received 3/ 6/90. Accepted 6/ 4/90.

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