Effect of cholecystokinin-B gastrin receptor blockade on chemically induced colon carcinogenesis in mice: follow-up at 52 weeks.
OBJECTIVE
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.


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 carcinogenic process.
Fontana
M G
MG
Department of Surgery, University of Brescia and Spedali Civili, Brescia, Italy.
Moneghini
D
D
Villanacci
V
V
Donato
F
F
Rindi
G
G
D000230:Adenocarcinoma / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013997:Time Factors
C116183:CR 2945; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines