Gastrin receptors in normal and malignant gastrointestinal mucosa: age-associated changes

Abstract

Synthetic human gastrin 17-I (MG) and an analogue, [Leu15]gastrin-17-I (LG), were radiolabeled with Na125I by Iodo-Gen, EnzymoBead, and chloramine-T methods, and the characteristics of the radiolabeled peptides were determined. When 125I-MG was iodinated by chloramine-T, its biological activity and its binding activity were almost abolished, whereas the biological activity of 125I-LG, iodinated by either of the methods, and of 125I-MG, iodinated by Iodo-Gen and EnzymoBeads, was not significantly affected. The kinetics, affinity, and specificity of binding of 125I-MG, iodinated by Iodo-Gen, to crude and purified membranes from rat fundic mucosa were examined and found to be similar to that for 125I-LG. Age-associated changes in the number and affinity of gastrin receptors (GR) on the crude membranes of gastrointestinal mucosa of rats was also examined. Significantly fewer GR were observed on the crude membranes of fundic mucosa of aged (24 mo old) compared with young (3- and 6-mo-old) rats. In addition, specific gastrin-binding sites (4.7 +/- 0.9 fmol/mg prot) with low affinity (Kd = 3.7 +/- 1.2 nM) were observed in the antrum of aged rats, the significance of which is not understood. There were, however, no differences in the number and characteristics of GR in other regions of the intestine of old and young rats. The presence of GR was additionally assessed in cell lines of gastrointestinal cancers from humans, mice, and hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging and cancer of the stomach and colon

“…In fact, we have observed that aging is associated with a loss of responsiveness of the gastric mucosa to the trophic action of both gastrin and bombesin (46,51), while EGF and TGF-α actually inhibit mucosal proliferative activity in aged rats (47,52). Although reasons for this are not fully understood, the age-related loss of responsiveness of the gastric mucosa to the trophic action of gastrin could be related in part to a decrease in the number of gastrin binding sites in the gastric mucosa (54). Whether a similar phenomenon is responsible for the age-related loss of the trophic action of bombesin in the gastric mucosa remains to be determined.…”

Inhibitory Effect of a Gastrin Receptor Antagonist, CR2945, on 1,2-Dimethylhydrazine-Induced Colorectal Cancer in Mice

“…In addition, gastrin stimulates the growth of some colon [5][6][7][8][9], gastric [10,11] and pancreatic cancers [12,13] in vitro (cell lines) and in vivo (xenotransplanted cancers, chemically induced tumours in rats and in mice). These effects are receptor-mediated: specific gastrinbinding sites were shown to be present on normal gastrointestinal mucosa [14][15][16] and on some human and murine gastric, colonic and pancreatic carcinomas [6,14,17]. DMH Gastrin receptor antagonist have been hypothesized to be of clinical relevance in the treatment of gastrin-sensitive colorectal tumours [18][19][20].…”

The brain and gastrointestinal cholecystokinin receptor family; structure and functional expression

“…CCK agonists and antagonists acting at central CCKB receptors respectively block and enhance opiate-induced analgesia (13). CCKB-type receptors have also been described outside the CNS in gastrointestinal smooth muscle cells (14), where they modulate gallbladder and bowel motility; and in guinea pig (15) and dog pancreas (16) and various neoplastic tissues [such as human stomach, colon (17), and lung carcinomas (18), and the rat pancreatic acinar carcinoma cell line AR42-J (19)], where they may regulate cell growth. The presence of CCKB receptors on peripheral lymphocytes and monocytes and monocyte-derived splenic cells suggests that CCK may play a role in the long-suspected neuroendocrine modulation of the immune system (20,21).…”