Effect of Cholecystokinin-B Gastrin Receptor Blockade on Chemically Induced Colon Carcinogenesis in Mice: Follow-Up at 52 Weeks

Abstract

Background/Aims: The potential role of gastrin and the cholecystokinin-B (CCK-B)/gastrin receptor in the genesis of colon cancer is debated. Aberrant crypt foci (ACF) are considered to be preneoplastic lesions of colon cancer. We aimed to assess whether the CCK-B/gastrin receptor antagonist, CR2945, may prevent the development of ACF and adenocarcinoma in the experimental model of dimethylhydrazine (DMH)-induced colorectal cancer. Materials and Methods: 226 CD1 mice were randomized into 3 groups (sham, control and treated) and received intraperitoneal injections of NaCl 0.9%, DMH, and DMH + CR2945, respectively, for 5 weeks. 168 mice were sacrificed at 15, 38, 45 and 52 weeks after the first injection day. The colon and rectum were investigated for frequency, multiplicity and distribution of ACF as well as for adenocarcinoma at histology. The expression of gastrin was assessed in tumor samples at histology by immunohistochemistry. Results: ACF frequency and multiplicity significantly increased with time in both controls and treated mice with no difference between groups except that at week 45. 38.8% of controls and 14.3% of treated mice developed cancer (p = 0.004). No cancer was positive for gastrin at immunohistochemistry. The mean number of cancers per mouse and the proportion of mice with cancer increased with time with statistically significant difference between controls and treated mice at week 38 only but not afterwards. A significant correlation between cancer and ACF frequency (r = 0.35) and multiplicity (r = 0.25) was observed. Conclusions: Our findings support the preneoplastic significance of ACF and indicate that CR2945 treatment does not interfere with the DMH-induced cancerigenic process.

Selective CCK‐A but not CCK‐B receptor antagonists inhibit HT‐29 cell proliferation: synergism with pharmacological levels of melatonin

“…In summary, our results further support previous data showing that the CCK‐B/gastrin receptors did not interfere with colon carcinogenesis in mice [53]. The pharmacological manipulation of the CCK‐B receptors suggests the presence of CCK‐A but not CCK‐B receptor expression in the HT‐29 cell line used in our experiments.…”

Bioactivity of analogs of the N-terminal region of gastrin-17

“…Recent research has suggested that elevated gastrin levels in the circulation do not play a role in cancer promotion in the colon [8, 15–16, 28, 30, 35], and that CCK 2 receptors, responsible for the mediation of gastric acid secretion and epithelial growth promoting effects of G17, are largely absent from the colon and thus do mediate such effects [5, 12–14, 31–32]. Additionally, it has been found that processing intermediates in the formation of G17 including progastrin and G17-Gly are secreted by colon cancer cells and are more frequently present in the colon than is G17 [9, 20, 27].…”

The Production and Role of Gastrin-17 and Gastrin-17-Gly in Gastrointestinal Cancers

“…Other studies failed to show that hypergastrinemia stimulated the growth of the colonic mucosa [249–251]. Finally, the use of the gastrin receptor antagonist CR2945 to block CCK 2 -R over a period of 52 weeks did not reduce tumor numbers in the colonic mucosa [252–253]. Overall, the studies seem to suggest that, while hypergastrinemic antral mucosa may promote gastric carcinomas, if colorectal carcinomas are stimulated by gastrin or gastrin processing intermediates these would have to be local autocrine or paracrine products [251, 254–255].…”