Investigations into the multistep process of colon carcinogenesis as affected by dietary calcium
Lafave, Lynne M. Z.
The main objective of this dissertation was to explore the growth modulating effect of dietary calcium (Ca) on the azoxymethane induced multistep process of colon carcinogenesis in Sprague Dawley rats. Number and growth features of microscopic aberrant crypt foci (ACF) and colonic tumors were used as the biological end points. Risk markers such as proliferative indices, protein kinase C (PKC) and lipid composition were also investigated. The diets containing low (0.1%), normal (0.5%) or high (1.0 and 2.0%) Ca and low (5%) or high (20%) fat were fed one week after azoxymethane or saline administration. There were significant fat * Ca interactions for the number of ACF with advanced growth characteristics (p = 0.006), PKC activity (p = 0.0001), and the content of polyunsaturated fatty acids in phosphatidylcholine (p = 0.0001), phosphatidylethanolamine (p = 0.0001), phosphatidylserine (p = 0.001), and phosphatidylinositol (p = 0.0006). Dietary intervention was carried out in a group of rats, 12 weeks after azoxymethane treatments, harboring preneoplastic lesions in their colons. Diets varying in Ca were fed for 12 weeks and both ACF and tumors were evaluated. The growth restrictive effect of increasing the level of Ca was more evident on primal ACF (p = 0.05) than their advanced counterparts. Analyses of tumor outcome by region revealed a growth restrictive effect of 2.0% Ca in the distal region and a permissive effect in the proximal region. Dietary Ca affected the lipid composition of neutrophils (p = 0.05) and their ability to produce leukotrienes (p = 0.05). These findings attest to the multiple and complex effect of dietary Ca on cellular responses. The novel and important findings of this dissertation are: (1) dietary Ca, at varying levels, elicits different responses in the presence of a low or high fat diet; (2) a positive correlation was found between alteration in PKC activity and ACF with advanced growth features under the same dietary regime; (3) preneoplastic lesions at different developmental stages respond differently to dietary Ca in different colonic regions; and (4) the ability of Ca to modulate the lipid composition and leukotriene production of neutrophils suggests that Ca mitigates, in part, its biological effect by a systemic route.