Roberd M. Bostick

DIETARY ANTIOXIDANT VITAMINS AND DEATH FROM CORONARY HEART DISEASE IN POSTMENOPAUSAL WOMEN

Background. The role of dietary antioxidant vitamins in preventing coronary heart disease has aroused considerable interest because of the knowledge that ox- idative modification of low-density lipoprotein may pro- mote atherosclerosis. Methods. We studied 34,486 postmenopausal wom- en with no cardiovascular disease who in early 1986 com- pleted a questionnaire that assessed, among other fac- tors, their intake of vitamins A, E, and C from food sources and supplements. During approximately seven years of follow-up (ending December 31, 1992), 242 of the women died of coronary heart disease. Results. In analyses adjusted for age and dietary en- ergy intake, vitamin E consumption appeared to be in- versely associated with the risk of death from coronary heart disease. This association was particularly striking in the subgroup of 21,809 women who did not consume vitamin supplements (relative risks from lowest to highest quintile of vitamin E intake, 1.0, 0.68, 0.71, 0.42, and 0.42; P for trend � 0.008). After adjustment for possible con- founding variables, this inverse association remained (rel- ative risks from lowest to highest quintile, 1.0, 0.70, 0.76, 0.32, and 0.38; P for trend � 0.004). There was little evi- dence that the intake of vitamin E from supplements was associated with a decreased risk of death from coronary heart disease, but the effects of high-dose supplementa- tion and the duration of supplement use could not be de- finitively addressed. Intake of vitamins A and C did not appear to be associated with the risk of death from cor- onary heart disease. Conclusions. These results suggest that in postmeno- pausal women the intake of vitamin E from food is inverse- ly associated with the risk of death from coronary heart disease and that such women can lower their risk without using vitamin supplements. By contrast, the intake of vita- mins A and C was not associated with lower risks of dying from coronary disease. (N Engl J Med 1996;334:1156-62.)

Sugar, meat, and fat intake, and non-dietary risk factors for colon cancer incidence in Iowa women (United States)

To investigate the relation of dietary intakes of sucrose, meat, and fat, and anthropometric, lifestyle, hormonal, and reproductive factors to colon cancer incidence, data were analyzed from a prospective cohort study of 35,215 Iowa (United States) women, aged 55–69 years and without a history of cancer, who completed mailed dietary and other questionnaires in 1986. Through 1990, 212 incident cases of colon cancer were documented. Proportional hazards regression was used to adjust for age and other risk factors. Risk factors found to be associated significantly with colon cancer included: (i) sucrose-containing foods and beverages other than ice cream/milk; relative risks (RR) across the quintiles=1.00, 1.73, 1.56, 1.54, and 2.00 (95% confidence intervals [CI] for quintiles two and five exclude 1.0); (ii) sucrose; RR across the quintiles=1.00, 1.70, 1.81, 1.82, and 1.45 (CI for quintiles two through four exclude 1.0); (iii) height; RR=1.23 for highest to lowest quintile (P for trend-0.02); (iv) body mass index; RR=1.41 for highest to lowest quintile (P for trend=0.03); and (v) number of livebirths, RR=1.59 for having had one to two livebirths and 1.80 for having had three or more livebirths compared with having had none (P for trend=0.04). These data support hypotheses that sucrose intake or being tall or obese increases colon cancer risk; run contrary to the hypothesis that increased parity decreases risk; support previous findings of no association with demographic factors other than age, cigarette smoking, or use of oral contraceptives or estrogen replacement therapy; and raise questions regarding previous associations with meat, fat, protein, and physical activity.Cancer Causes and Control 1994, 5, 38–52.

Association of menstrual and reproductive factors with breast cancer risk: Results from the Shanghai breast cancer study

The incidence of breast cancer among women in Shanghai, a traditionally low‐risk population, has increased substantially over the past 20 years. To evaluate the association of menstrual and reproductive factors with breast cancer risk and the influence of these factors on the temporal trend of breast cancer incidence, we analyzed data from the Shanghai Breast Cancer Study, a population‐based case‐control study of breast cancer recently completed among Chinese women in urban Shanghai. In‐person interviews were completed for 1,459 women newly diagnosed with breast cancer between ages 25 and 64 and for 1,556 controls frequency‐matched to cases by age. Unconditional logistic regression was employed to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) related to menstrual and reproductive factors. Earlier menarcheal age, nulliparity, and later age at first live birth were associated with increased risk of breast cancer among both pre‐ and post‐menopausal women, while never having breast‐fed and later age at menopause were associated with elevated risk only among post‐menopausal women. Among controls, 32% of younger women (≤40 years) and 24% of older women (>40 years) reported starting menarche at age of 13 or younger, and this factor contributed to 44% of cases diagnosed among younger women and 26% to 28% of cases in older women. Older age at first live birth or at menopause explained a considerable portion of cases diagnosed in older, but not younger, women. Our study suggests that the changes in menstrual and reproductive patterns among women in Shanghai have contributed to the recent increase in breast cancer incidence, particularly among younger women. Int. J. Cancer 87:295–300, 2000.

Diet and risk of colon cancer in a large prospective study of older women: An analysis stratified on family history (Iowa, United States)

Objective: The purpose was to investigate whether dietary associations with risk of colon cancer in women differ by family history of the disease.Methods: Data were analyzed from a prospective cohort study of 35,216 Iowa (United States) women aged 55 to 69 years at baseline. Through 31 December 1995, 241 colon cancers were identified through record linkage with the State Health Registry. The cohort was stratified on family history of colon cancer in first-degree relatives; nutrient intakes were divided into tertiles.Results: Analyses using Cox regression revealed that the association of most dietary components with colon cancer incidence were similar for individuals with and without a family history. However, total calcium intake was associated inversely with colon cancer among women with a negative family history (relative risk [RR]=0.50 for upper cf lower tertile, P < 0.001), but was unrelated to incidence for women with a positive family history (RR=1.1 for upper cf lower tertile, P=0.69). Similarly, total vitamin E intake was associated with lower risk among women with a negative family history (RR=0.67 for upper cf lower tertile, P=0.04), but not among women with a positive family history (RR=0.87 for upper cf lower tertile, P=0.67). High intakes of fiber, fruits, and vegetables were each weakly inversely associated with risk among family-history negative women, but not among family-history positive women.Conclusions: These data, if corroborated, suggest that dietary factors typically associated with lower risk may be less effective risk-reduction interventions against colon cancer for individuals with a family history of colon cancer.

Clinical trials of antioxidants as cancer prevention agents: Past, present, and future

The purpose of this review is to summarize the most important human clinical trials of antioxidants as cancer prevention agents conducted to date, provide an overview of currently ongoing studies, and discuss future steps needed to advance research in this field. To date there have been several large (at least 7000 participants) trials testing the efficacy of antioxidant supplements in preventing cancer. The specific agents (diet-derived direct antioxidants and essential components of antioxidant enzymes) tested in those trials included β-carotene, vitamin E, vitamin C, selenium, retinol, zinc, riboflavin, and molybdenum. None of the completed trials produced convincing evidence to justify the use of traditional antioxidant-related vitamins or minerals for cancer prevention. Our search of ongoing trials identified six projects at various stages of completion. Five of those six trials use selenium as the intervention of interest delivered either alone or in combination with other agents. The lack of success to date can be explained by a variety of factors that need to be considered in the next generation research. These factors include lack of good biological rationale for selecting specific agents of interest; limited number of agents tested to date; use of pharmacological, rather than dietary, doses; and insufficient duration of intervention and follow-up. The latter consideration underscores the need for alternative endpoints that are associated with increased risk of neoplasia (i.e., biomarkers of risk), but are detectable prior to tumor occurrence. Although dietary antioxidants are a large and diverse group of compounds, only a small proportion of candidate agents have been tested. In summary, the strategy of focusing on large high-budget studies using cancer incidence as the endpoint and testing a relatively limited number of antioxidant agents has been largely unsuccessful. This lack of success in previous trials should not preclude us from seeking novel ways of preventing cancer by modulating oxidative balance. On the contrary, the well demonstrated mechanistic link between excessive oxidative stress and carcinogenesis underscores the need for new studies. It appears that future large-scale projects should be preceded by smaller, shorter, less expensive biomarker-based studies that can serve as a link from mechanistic and observational research to human cancer prevention trials. These relatively inexpensive studies would provide human experimental evidence for the likely efficacy, optimum dose, and long-term safety of the intervention of interest that would then guide the design of safe, more definitive large-scale trials.

Vitamin D gene pathway polymorphisms and risk of colorectal, breast, and prostate cancer.

Higher vitamin D exposure is hypothesized to prevent several cancers, possibly through genomic effects modulated by the vitamin D receptor (VDR), and autocrine/paracrine metabolism of the VDRs ligand, 1alpha,25-(OH)(2)-vitamin D. Herein we review the background and evidence to date on associations between polymorphisms in VDR and selected genes in the vitamin D pathway in relation to colorectal, breast, and prostate cancer. Although most studies to date have examined only a few VDR polymorphisms, more are beginning to comprehensively investigate polymorphisms in the VDR as well as in other vitamin D pathway genes, such as the vitamin D-binding protein gene (Gc) and CYP27B1 and CYP24A1, which code for enzymes that, respectively, synthesize and degrade 1alpha,25-(OH)(2)-vitamin D. Currently, there is no strong, consistent epidemiologic evidence for substantial influences of single variants in vitamin D pathway genes on risk for colorectal, breast, or prostate cancer, but promising leads are developing.

Effects of Vitamin D and Calcium Supplementation on Markers of Apoptosis in Normal Colon Mucosa: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

To further clarify and/or develop calcium and vitamin D as chemopreventive agents against colorectal cancer in humans, understand the mechanisms by which these agents reduce risk for the disease, and develop “treatable” biomarkers of risk for colorectal cancer, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial to test the effects of calcium and vitamin D3, alone and in combination on markers of apoptosis, in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2.0 g/d calcium or 800 IU/d vitamin D3, alone or in combination, versus placebo over 6 months. Overall expression and colorectal crypt distributions of Bcl-2 (an apoptosis inhibitor) and Bax (an apoptosis promoter) in biopsies of normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, Bax expression along the full lengths of crypts increased 56% (P = 0.02) in the vitamin D group and 33% in both the calcium (P = 0.31) and calcium plus vitamin D (P = 0.36) groups relative to the placebo group. The vitamin D treatment effect was more pronounced in the upper 40%, or differentiation zone, of crypts (80%; P = 0.01). There were no statistically significant treatment effects on Bcl-2 expression. Overall, these preliminary results suggest that calcium and vitamin D, individually or together, may enhance apoptosis in the normal human colorectal epithelium, and the strongest treatment effects may be vitamin D related and in the upper sections of the colorectal crypts.

A trial of calcium and Vitamin D for the prevention of colorectal adenomas

BACKGROUND Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. METHODS We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. We randomly assigned 2259 participants to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither in a partial 2×2 factorial design. Women could elect to receive calcium plus random assignment to vitamin D or placebo. Follow-up colonoscopy was anticipated to be performed 3 or 5 years after the baseline examinations, according to the endoscopists recommendation. The primary end point was adenomas diagnosed in the interval from randomization through the anticipated surveillance colonoscopy. RESULTS Participants who were randomly assigned to receive vitamin D had a mean net increase in serum 25-hydroxyvitamin D levels of 7.83 ng per milliliter, relative to participants given placebo. Overall, 43% of participants had one or more adenomas diagnosed during follow-up. The adjusted risk ratios for recurrent adenomas were 0.99 (95% confidence interval [CI], 0.89 to 1.09) with vitamin D versus no vitamin D, 0.95 (95% CI, 0.85 to 1.06) with calcium versus no calcium, and 0.93 (95% CI, 0.80 to 1.08) with both agents versus neither agent. The findings for advanced adenomas were similar. There were few serious adverse events. CONCLUSIONS Daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00153816.).

Effects of supplemental vitamin D and calcium on oxidative DNA damage marker in normal colorectal mucosa: a randomized clinical trial.

The exact antineoplastic effects of calcium and vitamin D3 in the human colon are unclear. Animal and in vitro studies show that these two agents reduce oxidative stress; however, these findings have never been investigated in humans. To address this, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial to test the effects of calcium and vitamin D3 on a marker of oxidative DNA damage, 8-hydroxy-2′-deoxyguanosine (8-OH-dG), in the normal colorectal mucosa. Patients (N = 92) with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d calcium and/or 800 IU/d vitamin D3 versus placebo over 6 months. Overall labeling and colorectal crypt distribution of 8-OH-dG in biopsies of normal-appearing rectal mucosa were detected by standardized automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, 8-OH-dG labeling along the full lengths of colorectal crypts decreased by 22% (P = 0.15) and 25% (P = 0.10) in the calcium and vitamin D3 groups, respectively, but not in the calcium plus vitamin D3 group. The estimated treatment effects were strongest among participants with higher baseline colon crypt vitamin D receptor expression (P = 0.05). Overall, these preliminary results indicate that calcium and vitamin D3 may decrease oxidative DNA damage in the normal human colorectal mucosa, support the hypothesis that 8-OH-dG labeling in colorectal crypts is a treatable oxidative DNA damage biomarker of risk for colorectal neoplasms, and provide support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms. Cancer Epidemiol Biomarkers Prev; 19(1); 280–91

Vitamin E and breast cancer : A review

Breast cancer is a major health problem in America, accounting for almost one-third of cancer-related deaths in women. The prevention of breast cancer through dietary modification is an active area of clinical and epidemiologic research. It has been proposed that the dietary supplementation of vitamin E, a lipid-soluble antioxidant, may reduce a womans risk of developing breast cancer. In animal models, vitamin E has decreased the incidence of carcinogen-induced mammary tumors. Intake and serum levels of vitamin E and their relation to breast cancer have been evaluated in epidemiologic studies. Results of epidemiologic studies, however, have been conflicting. In this review, we examine the evidence that is available pertaining to the relationship between vitamin E and breast cancer. Although epidemiologic study results have been inconsistent, further study of this nontoxic vitamin is warranted. Particular attention should be paid to the interactions of other antioxidants with vitamin E and to the duration and timing (pre- vs. postmenopausal) of vitamin E use in determining its preventive utility in breast cancer.