Growth of colorectal carcinoma cells: regulation in vitro by gastrin, pentagastrin and the gastrin-receptor antagonist proglumide

Abstract

The growth-regulating effects of pentagastrin, gastrin and the gastrin-receptor antagonist proglumide were investigated in three established cell lines derived from human colorectal carcinomas in vitro and after transplantation into nude mice. In vitro a significant increase of cell growth in the SW 403 cell line incubated with pentagastrin or gastrin was observed. In the Lovo cell line this effect was only detected after synchronization of cell growth. Pentagastrin and gastrin had no effect on the growth of the Ls 174 T cell line. Proglumide reduced cell proliferation in all three cell lines as well as in the L929S cell line derived from fibroblasts, which served as control. After transplantation into nude mice all tumor cell lines increased, Lovo and Ls 174 T as undifferentiated tumor, SW 403 as differentiated. Pentagastrin increased and proglumide decreased growth in SW 403 tumors, whereas no effect was observed on Ls 174 T and Lovo tumors. We therefore conclude that growth of some colorectal carcinomas is regulated by gastrin, but that the effect of proglumide is unspecific rather than related to blockage of gastrin receptors. The growth-regulating effect of gastrin could be due to tumor differentiation.

Autocrine stimulation of growth of AR4-2J rat pancreatic tumour cells by gastrin

“…It has been suggested by some investigators that proglumide-inhibition of cellular proliferation may be a result of non-specific effects rather than its ability to interact with gastrin receptors (Imdahl et al, 1989;Singh et al, 1987;Guo et al, 1990). The concentrations of proglumide, benzotript, lorglumide and loxiglumide required for half maximal inhibition of AR4-2J cell growth were directly related to the concentrations required to displace 50% of specific 1251-hGl7-1 binding to gastrin/CCK-B receptors, consistent with growth inhibitory actions mediated through gastrin/CCK-B receptor antagonism.…”

“…Proglumide, a non-specific gastrin/CCK receptor antagonist, inhibited the growth stimulatory effects of gastrin on mouse colon cancer in vivo and prolonged the survival of tumour-bearing mice (Singh et al, 1987;Beauchamp et al, 1985). Direct trophic effects of gastrin and CCK on gastrointestinal and pancreatic tumour cells in vitro are widely reported (Sirinek et al, 1985;Kusyk et al, 1986;Watson et al, 1988Watson et al, , 1989Imdahl et al, 1989;Guo et al, 1990;Smith et al, 1991). Inhibition of gastrointestinal and pancreatic tumour cell growth by gastrin/CCK receptor antagonists has also been shown by several workers (Hoosein et al, 1988;Imdahl et al, 1989;Guo et al, 1990;Smith et al, 1990a).…”

“…Direct trophic effects of gastrin and CCK on gastrointestinal and pancreatic tumour cells in vitro are widely reported (Sirinek et al, 1985;Kusyk et al, 1986;Watson et al, 1988Watson et al, , 1989Imdahl et al, 1989;Guo et al, 1990;Smith et al, 1991). Inhibition of gastrointestinal and pancreatic tumour cell growth by gastrin/CCK receptor antagonists has also been shown by several workers (Hoosein et al, 1988;Imdahl et al, 1989;Guo et al, 1990;Smith et al, 1990a). These data provide strong evidence for a role for gastrin in gastrointestinal and pancreatic tumour cell growth, and suggest that gastrin antagonists may provide a novel pharmacological approach to anti-cancer therapy.…”

“…However, several groups have suggested that a proportion of the inhibition of tumour cell growth by proglumide, the most commonly used gastrin antagonist for such studies, is unrelated to interaction with gastrin receptors (Singh et al, 1987;Imdahl et al, 1989;Guo et al, 1990). Moreover, a recent report has suggested that the growth inhibitory effects of a potent CCK-A receptor antagonist, devazepide (L-364,718), is also independent of its interaction with gastrin or CCK receptors, while a potent CCK-B receptor antagonist, L-365,260 was unable to inhibit proliferation of several colonic cell lines in vitro (Thumwood et al, 1991).…”

Attenuation of Peroxisome Proliferator-activated Receptor γ (PPARγ) Mediates Gastrin-stimulated Colorectal Cancer Cell Proliferation

“…Gastrin has been implicated as a trophic factor for various neoplasms of GI origin, including CRC and those of pancreatic, gastric, and esophageal origin (52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62). Gastrin and gastrin receptors are expressed aberrantly in colorectal adenomas and malignant tumors and have been implicated in malignant progression (17,18).…”