Cholecystokinin 길항제인 L-364,718이 시험관내 췌장암세포 성장에 미치는 영향

Abstract

Background/Aims: It has been reported that some gastrointestinal regulatory peptides including cholecystokinin(CCK) may ac: as growth modulators of pancreatic cancer and CCK antagonists have antitumor effect. However, there have been still debates on the role of CCK antagonists. This study was done to answer the guestions: Does L-364,7 l8 inhibit the growth of cultured pancreatic cancer cells?", What is the growth inhibitory mechanism and is it cell-cycle specific?, and finally, Does the combinatior with L-364,718 and 5-fluorouracil(5-FU) have a synergistic effect on the growth inhibition?" Methods: Using Panc-1 and Capan-2 cells, the effects of caerulein, I -364,718 and 5-FU were evaluated, respectively and combined effect of L-364,718 and 5-FU measured. To evaluate the effect of L-364,718 on DNA synthesis and cell cycles, [3H]-thymidine uptake and flow cytometric analysis were performed. The in vitro cytotoxicity was measured by MTT assay and an isobologram model used to analyze the synergism. Results: The both cells, especially Capan-2 cells, grev faster in a medium of CCK supplementation. Dose-dependent powth inhibition o, both cell.', was noted by L-364,718. The IC50 of Panc-1 and Capan-2 cells were 2.43x10-5 M/L and 3.25:cl0-5 M/L, respectively. The IC50 of 5-FU on Panc-I and Capan-2 cells were 13.83 pg/ml and 2.19 pg/ml, respectively. ['H]-thymidine uptake of both cells decreased dose-dependently by L-364,715. The proportion of S phase cells decreased and that of G0/G1 phase cells increased dose-dependently by L-364,718. When L-364,718 was combined with 5-FU, a synergistic effect was observed in 62.5% in Capan-2 cells, however 14.3% in Panc-1 cells. Conclusions: L-364,718 has a antitumor effect on pancreatic cancer cells cultured in vitro and its synergistic effect with certain anticancer agent can be expected. The antiproliferative effect of L-364,718 is considered as the inhibition of DNA synthesis, which cause the blockage of GO/Gl phase of cell cycle.