Calcium regulation of colonic crypt cell kinetics: evidence for a direct effect in mice.
OBJECTIVE
Oral calcium supplementation is believed to decrease colonic hyperproliferation through neutralization of fatty acids and bile acids. In the present study, the effect of oral calcium, given with low-fat diets, in the early stages of colorectal carcinogenesis is evaluated.


METHODS
In experiment A, mice received normal or low-calcium diets and were killed at 25 weeks. In experiment B, mice were fed the same diets but were submitted to six weekly injections of dimethylhydrazine and were killed at 10, 16, and 21 weeks. Cell proliferation was evaluated using bromodeoxyuridine immunohistochemistry.


RESULTS
In experiment A, mice fed low-calcium diets showed a significant upward shift of the proliferative compartment (P = 0.04) (phase 2 defect) in the absence of hyperproliferation. In experiment B, besides a phase 2 defect, dimethylhydrazine-induced hyperproliferation was also significantly enhanced in animals fed low-calcium diets (phase 1 defect) as shown by an increased number of labeled cells per column and total labeling index (P = 0.01).


CONCLUSIONS
Low-calcium diets induce an upward shift of the main proliferative compartment, which reflects an increased risk for malignant transformation. This effect was observed with a low-fat diet, suggesting a direct mechanism, rather than the usual indirect one, documented with high-fat diets.
Nobre-Leitão
C
C
Department of Gastroenterology, Instituto Português de Oncologia Francisco Gentil, Lisbon.
Chaves
P
P
Fidalgo
P
P
Cravo
M
M
Gouveia-Oliveira
A
A
Ferra
M A
MA
Mira
F C
FC
D019813:1,2-Dimethylhydrazine; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D003106:Colon / Q000166:cytology / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000473:pathology*; D018752:Diet, Fat-Restricted; D004127:Dimethylhydrazines; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains
D002273:Carcinogens; D004127:Dimethylhydrazines; D019813:1,2-Dimethylhydrazine; D002118:Calcium