Harold L. Newmark

Calcium inhibits the damaging and compensatory proliferative effects of fatty acids on mouse colon epithelium.

Intrarectal instillations of the fatty acids (FA), lauric, linoleic or oleic acids induce inflammation and superficial lysis of the colon epithelium. This reaction is followed by increases in colonic mitotic activity and the number of cells engaged in DNA synthesis in compensatory regeneration for the cells that were lost. This explains, in part, the promotional effect of dietary fat in carcinogenesis. Concomitant oral administration of calcium salts, as CaCO3, largely reduced the mitogenic effects of fatty acids on colon epithelium, presumably by forming biologically inert calcium soaps. Calcium soap formation of dietary fatty acids may be one natural mechanism by which colon epithelium cells are protected hence reducing the impact of dietary fat on carcinogenesis for this organ.

Butyrate as a differentiating agent: pharmacokinetics, analogues and current status.

The field of butyrate-induced differentiation of neoplastic and non-neoplastic cells is reviewed and possible clinical correlations considered with regard to butyrate, butyrate prodrugs and butyrate analogues. These topics are discussed from the point of view of the concentrations required in vitro for biologic effect, and likely pharmacokinetic behavior in vivo.

Determinants and consequences of colonic luminal pH: implications for colon cancer.

Epidemiological data suggest that increased risk of colon cancer is correlated with a higher fecal pH. Although some experimental studies have shown a protective effect against experimentally induced colon cancer by acidifying colonic contents, others have shown that a more acidified colonic content is associated with increased cell proliferation and enhanced tumorigenesis. It is now clear that simply acidifying colonic contents will not consistently result in decreased tumorigenesis. Perhaps the key is how colonic contents are acidified--a decrease in base production or an increase in acid production. Or, more important than luminal pH itself, may be a factor affected by changes in hydrogen ion concentration. This paper reviews the determinants of colonic luminal pH and their dietary sources and discusses important physiological consequences of modifying the pH of colonic contents.

Colonic hyperproliferation induced in rats and mice by nutritional-stress diets containing four components of a human Western-style diet (series 2)

In a previous study colonic hyperplasia and hyperproliferation were induced in mice and rats by a nutritional-stress diet, based on the AIN-76A semisynthetic diet modified to contain four suggested high-risk components of the human Western-style diet: increased fat and phosphate and decreased calcium and vitamin D contents. In this study the effect of raising calcium alone to near the median level (0.22 mg/kcal) and to a high level (1.3 mg/kcal), comparable to adult human dietary intake, was tested in mice and rats while retaining the three other high-risk components. With median calcium intake the nutritional-stress diet induced hyperproliferation of epithelial cells in colonic crypts, with increased numbers of proliferating cells in crypt columns in sigmoid colon of mice (P less than 0.001) and rats (P = 0.02) and in the ascending colon of mice (P = 0.01). With high calcium intake, hyperproliferation was reduced almost to control amounts in the presence of unchanged fat, phosphate, and vitamin D.

Model of mouse mammary gland hyperproliferation and hyperplasia induced by a western-style diet.

Mammary glands of female C57BL/6J mice were analyzed after they were fed a Western-style diet or control AIN-76A diet. The Western-style diet contained several risk factors found in human diets in geographic regions having increased risk for breast cancer: high fat and phosphate and low calcium and vitamin D. After they were fed these diets for 8, 14, and 20 weeks, mice were sacrificed, and mammary glands were removed for morphometric and radioautographic measurements. Although after the animals were fed the Western-style diet for 8 weeks the number of terminal ducts per mouse mammary gland (NTDMG) was similar in the Western-style and control diet groups, after they were fed the Western-style diet for 14 weeks (p < 0.05) and 20 weeks (p < 0.01) the NTDMG significantly increased compared with the control group. Moreover, there was a significant increase (p < 0.01) in the tritiated thymidine labeling index of mammary terminal ductal epithelial cells after 14 and 20 weeks of Western-style diet administration. Thus the Western-style diet induced increased epithelial cell proliferation and increased NTDMG in female mice when fed during young adult growth and development. The findings raise the possibility that the ingestion of a diet with Western-style fat and phosphate content and with low calcium and vitamin D may induce similar changes during the early development of the human mammary gland.

The role of micronutrient deficiency in carcinogenesis

Nutritional deficiencies are suspected to be contributing factors to several types of human cancers. Studies with laboratory animals have demonstrated that deficiencies in certain nutrients can enhance chemically induced carcinogenesis. In this review, we discuss several possible mechanisms for the involvement of nutritional deficiencies in carcinogenic processes, and note that different severities of deficiency may have varied effects on these processes. The relationship between results from studies with animals and the genesis of human cancer is discussed, and the application of the concept of nutrient density in relating experimental animal diets to human dietary conditions is emphasized. We also discuss in detail several recent studies that potentially may have a great impact on the prevention of human cancer. These include (1) the possible involvement of micronutrient deficiencies in carcinogenesis of the esophagus; (2) the effects of choline/methionine deprivation and calcium supplementation on liver carcinogenesis; and (3) the roles of low-calcium and high-fat intake on development of colon cancer. The possible mechanistic link between teratogenesis and carcinogenic processes is noted.