Affiliations of authors: H. L. Newmark, Laboratory of Cancer Research, Rutgers University, Piscataway, NJ; S. J. Shiff, The Cancer Institute of New Jersey, New Brunswick, NJ.
Correspondence to: Harold L. Newmark, D.Sci. (Hon.), Laboratory of Cancer Research, Rutgers University, Piscataway, NJ 088548020 (e-mail: p.newmark{at}worldnet.att.net).
In a recent article, Wu et al. (1) reported findings from two large-scale, prospective studies in women (Nurses Health Study) and men (Health Professionals Follow-up Study) showing that higher calcium intake was associated with a statistically significantly reduced risk of distal colon cancer, but not of proximal colon cancer. The authors found a 40%50% lower risk of distal colon cancer among subjects with a calcium intake of 700800 mg/day or higher than in subjects with a calcium intake of less than or equal to 500 mg/day. The authors also cited the results of other studies that indicate a potential protective effect of higher dietary calcium intake, primarily on distal colon cancer. In the United States today, the incidence of colon cancer in the left-sided or distal colon (descending or sigmoid colon, as used by Wu et al.) is about two-thirds of all colon cancers (2). Thus, net total reduction of colon cancer by higher dietary calcium intake as shown in this study can be estimated at approximately 30% (i.e., a 40%50% reduction of two-thirds of all colon cancer cases).
One possible explanation for the difference in the effect of higher calcium intake on the risk of distal and proximal colon cancer is the variability of pH in different regions of the colon. Probably the most reliable measurements of intraluminal pH were made using a pH-sensitive radiotelemetry capsule, which passes freely through the gastrointestinal tract and is monitored for position in the gut of healthy, free-living volunteers (3). The results of that study showed that the pH of the intestinal contents of the cecum has a mean of 6.4 ± 0.4 (P<.001) and rises progressively from the right (i.e., proximal) colon to the left (i.e., distal) colon to a final mean pH value of 7.0 ± 0.7 (P<.001). This rise in pH increases the ionization of fatty acids and free unconjugated bile acids by approximately fivefold, with accompanying increases in solubility (4, 5). Increased ionization and solubilization of long-chain fatty acids and free unconjugated bile acids due to increased pH is deleterious to the colonic mucosa in the rat (4), and the mechanism of this has been discussed (5). Thus, the lower pH of the proximal colon might be expected to aid in the protection of the colon mucosa from fatty acid and bile acid damage by decreasing ionization and solubilization of these lipid acids.
Fatty acids bind to calcium more tightly than to any other component of the normal colon contents (6). Therefore, we suggest that lower dietary intake of calcium, resulting in lower "delivery" of calcium to the distal colon, would result in a larger proportion of tightly bound calcium (primarily to free fatty acids) in the proximal colon. This would result in proportionately less calcium available for binding to fatty acids and bile acids in the distal colon. Increased dietary intake of calcium could prevent this effect by supplying additional calcium to the distal colon, where the concentration of ionized lipids (as free fatty and unconjugated bile acids) increases due to the rise in pH and where they are free to exert their deleterious effect (4, 6).
Regardless of the postulated mechanisms, the results of Wu et al. (1) suggest that an approximately 30% total reduction in colon cancer incidence may be achieved with a moderate increase in dietary calcium intake of 300400 mg/day. With colon cancer deaths currently numbering about 55 000 per year in the United States (7), the addition of this amount of dietary calcium intake could effect a reduction of approximately 16 000 colon cancer deaths annually.
REFERENCES
1 Wu K, Willett WC, Fuchs CS, Colditz GA, Giovannucci EL. Calcium intake and risk of colon cancer in women and men. J Natl Cancer Inst 2002;94:43746.
2 Winawer SJ, Fletcher RM, Miller L, Godlee F, Stolar MH, Mulrow CD, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112:594642.[Medline]
3 Evan DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut 1998;29:103541.[Abstract]
4 Rafter JJ, Eng VW, Furrer R, Medline A, Bruce WR. Effects of calcium and pH on the mucosal damage produced by deoxycholic acid in the rat colon. Gut 1986;27:13209.[Abstract]
5 Newmark HL, Lupton JR. Determinants and consequences of colonic luminal pH: implications for colon cancer. Nutr Cancer 1990;14:16172.[Medline]
6 Newmark HL, Wargovich MH, Bruce WR. Colon cancer and dietary fat, phosphates and calcium: a hypothesis. J Natl Cancer Inst 1984;72:13235.[Medline]
7 American Cancer Society. Cancer facts and figures. Atlanta (GA): American Cancer Society; 2001.
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