【摘要】  Approximately 20C30% of Americans consume multivitamin supplements daily, indicating high public interest in the prevention of cancer and other chronic diseases through a nutrition-based approach. Although several bioactive food components, including vitamins and minerals, have been investigated for their ability to affect cancer risk, few large, randomized, placebo-controlled clinical trials of multivitamins with cancer as the primary endpoint have been performed. The results of most large-scale trials of multivitamin supplements (combinations of 2 vitamins and minerals) to prevent cancer have been mixed. The Linxian General Population and Dysplasia trials found a decreased risk of cancer, particularly stomach cancer, for participants taking a multivitamin supplement, but this was in a borderline-deficient population in China. Two trials, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study and the ??-Carotene and Retinol Efficacy Trial, found an increased risk of lung cancer among male cigarette smokers or asbestos-exposed persons taking ??-carotene?a surprising result, considering that most epidemiologic studies have suggested that consumption of fruit and vegetables appears to lower cancer risk. To clarify the effects of multivitamin supplements, several large randomized clinical trials are underway, including the Physicians' Health Study II, the Selenium and Vitamin E Cancer Prevention Trial, and a European study, Suppl?mentation en Vitamines et Min?raux Antioxydants (SU.VI. MAX). Because epidemiologic studies generally evaluate foods rather than specific bioactive food components, a systematic approach to determining how combinations of vitamins and minerals may interact to ameliorate cancer risk is necessary to further our understanding of the potential benefits and risks of supplement use.

【关键词】  multivitamin supplements randomized clinical trials cancer prevention bioactive food components nutrition

INTRODUCTION

For the past 3 decades, cancer prevention clinical trials have been based on rationales developed from laboratory and epidemiologic research that identified numerous natural and synthetic agents for further testing in people. The premise is that medical interventions that aim to prevent, arrest, or reverse either the initiation phase of carcinogenesis or the progression of premalignant cells are an important research aim for cancer prevention. Much of this effort focused on the identification of bioactive food components (BFCs) in the diet that appeared to decrease or increase the risk of cancer. Among the BFCs, investigations of vitamins and minerals produced the most intriguing results, especially in observational epidemiologic studies (1). Based largely on the results of these studies, clinical trials of vitamin and mineral supplements have been designed and conducted to establish their benefit or lack of benefit for cancer prevention. The public is likely to support cancer prevention clinical trials of multivitamins?defined as preparations with 2 vitamins or minerals, regardless of the form of consumption?because 20C30% of the population already consumes these supplements daily (2). However, only a few large, randomized, placebo-controlled clinical trials have been conducted of multivitamins with specific cancer sites as the primary endpoint. Selected larger trials are reviewed below; results from the first generation of these trials form the basis for the clinical trials now underway, which should report results within the next few years.

THE LINXIAN TRIALS

The Nutrition Intervention Trials (ie, the Linxian Trials) were conducted by the US National Cancer Institute (NCI) in collaboration with the Chinese Institute of the Chinese Academy of Medical Sciences. The Linxian Trials were based on epidemiologic evidence that the people of Linxian, China, had low intakes of numerous nutrients and the world's highest rate of esophageal cancer. The results of the 2 Linxian Trials, which were randomized, double-blind, placebo-controlled chemoprevention trials, were the first human experimental studies to show that multivitamin supplementation in a nutritionally marginal population reduced rates of cancer at any site. The Linxian General Population Trial began in 1986 and randomly assigned 29 594 adults aged 40C69 y to receive 1 of 4 combinations of multivitamin supplements containing retinal and zinc, riboflavin and niacin, vitamin C and molybdenum, or ??-carotene, vitamin E, and selenium each day for 5.25 y. Doses were equivalent to 1 to 2 times the US Recommended Dietary Allowances (RDAs) (3). A second trial, the Linxian Dysplasia Trial, enrolled 3318 adults aged 40C69 y with esophageal dysplasia, a precursor to esophageal cancer. Trial participants were randomly assigned to receive either a placebo or a daily supplement of 14 vitamins and 12 minerals at 2 to 3 times the US RDA for 6 y (3).

Results from the General Population Trial showed that those who received the ??-caroteneCvitamin ECselenium combination had a 13% reduction in cancer mortality, including a 21% decrease in stomach cancer mortality, a 41% decrease in gastric noncardia cancer mortality, and a 4% decrease in deaths from esophageal cancer (4). Results from the Dysplasia Trial showed that supplementation reduced the likelihood of having esophageal dysplasia after both 30 and 72 mo of intervention (4). Adding to these important findings, postintervention follow-up indicated that the beneficial effects of the ??-caroteneCvitamin ECselenium combination in the General Population Trial remained evident up to 10 y after the intervention. These benefits were consistently greater in participants who were younger (<55 y) at the beginning of the intervention.

THE ??-CAROTENE AND RETINOL EFFICACY TRIAL AND THE ALPHA-TOCOPHEROL, BETA-CAROTENE CANCER PREVENTION STUDY

Other clinical trials of multivitamin supplement use and cancer prevention have produced null or possibly harmful results for the primary endpoints regarding supplement use. The FinnishCNCI collaborative trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) of 29 133 male smokers aged 50C69 y did not observe a reduction in lung cancer with intervention as hypothesized before the trial (5). Participants were randomly assigned to 1 of 4 supplementation regimens, including -tocopherol (50 mg) and ??-carotene (20 mg) together, individually, or placebo. Contrary to expectation, men who took ??-carotene had a 16% increase in lung cancer incidence; results for -tocopherol indicated a statistically insignificant 2% decrease in lung cancer incidence (5). Interestingly, prostate cancer, a secondary endpoint, was reduced by one-third during the intervention, although the benefit diminished after supplementation concluded (6). The ??-Carotene and Retinol Efficacy Trial (CARET) reported a 39% increase in lung cancer incidence among male smokers who received a combination of ??-carotene and retinyl palmitate (7). These results were surprising because observational and epidemiologic studies had suggested that individuals who consumed high dietary amounts of ??-carotene, generally from high vegetable and fruit intake, had a lower risk of cancer (8). Since the results of ATBC and CARET were reported, the causes for these negative results have been much discussed (9).

THE SELENIUM AND VITAMIN E CANCER PREVENTION TRIAL

Selenium inhibits the growth of prostate carcinoma cells in vitro through proposed mechanisms such as antioxidant effects, enhancement of immune function, induction of apoptosis, and inhibition of cell proliferation. Vitamin E inhibits lipid peroxidation, which contributes to carcinogen-induced DNA damage (10). The Selenium and Vitamin E Cancer Prevention Trial (SELECT), sponsored by the NCI, is a randomized, double-blind, placebo-controlled, population-based trial. Previous studies such as the Nutritional Prevention of Cancer Trial (NPCT) and the ATBC suggested that selenium and vitamin E could be effective in preventing certain cancers, including prostate cancer (5, 11). In the ATBC, there was a reduction in prostate cancer incidence in men receiving vitamin E (6); in the NPCT, men receiving selenium also had a reduced prostate cancer incidence as a secondary endpoint. The NPCT found that prevention apparently was more effective in men with the lowest baseline plasma selenium status (11).

SELECT began in 2001 and is investigating the efficacy of selenium (200 g L-selenomethionine) and vitamin E (400 IU dl--tocopherol acetate), alone and in combination, for the prevention of prostate cancer in 35 534 healthy men (10). Study participants include white (78%), African American (14%), Hispanic (6%), and other (2%) men aged 55 y (because of their increased prostate cancer rates, African American men aged 50 y were enrolled). The trial is being conducted at 435 SELECT sites in the United States, Puerto Rico, and Canada and will last 12 y, including 7 y of intervention plus follow-up, with a primary endpoint being the clinical incidence of prostate cancer. Secondary goals of SELECT are to assess the effect of selenium and vitamin E on the incidence of other cancers, including lung, colorectal, and all cancers combined, and on overall mortality rates. In addition, SELECT will assess the effect of selenium and vitamin E on health-related quality-of-life, will evaluate associations of biological and molecular markers as well as diet with cancer risk, and will explore the potential modification of supplements on cancer risk by genetic factors and dietary intake. Three special ancillary studies also have been added to SELECT: the Prevention of Alzheimer's Disease with Vitamin E and Selenium (PREADVISE) will define the effect of selenium and vitamin E on the incidence of Alzheimer disease, the Prevention of Cataract and Age-Related Macular Degeneration with Vitamin E and Selenium?SELECT Eye Endpoints (SEE)?will test whether these supplements reduce age-related macular degeneration or cataracts, and the Prevention of Lung Function Decline with Vitamin E and Selenium?Respiratory Ancillary Study (RAS) will investigate whether these supplements prevent pulmonary function decrease. A fourth ancillary study evaluating the effect of the supplements on colon polyps is anticipated. An important feature of SELECT is the collection and preservation of blood samples that will permit the evaluation of a wide variety of biochemical and molecular hypotheses, particularly those that are prominent in prostate carcinogenesis (ie, polymorphisms in hormone-related genes such as AR, CYP17, SRD5A2, and HSD3??2) (12). This study will provide a better understanding of response to vitamin E and selenium and potentially will identify markers useful in future studies of prostate and other cancers.

THE PHYSICIANS' HEALTH STUDY

The first Physicians' Health Study (PHS) was a 12-y (1982C1995) randomized, double-blind, placebo-controlled trial with a 2 x 2 factorial design that tested aspirin and ??-carotene (50 mg on alternate days) for the prevention of cardiovascular disease (CVD) and cancer in 22 000 male US physicians (13, 14). ??-Carotene recipients showed no benefit or harm for either CVD or cancer in this predominantly nonsmoking population; the aspirin component was stopped in 1987 after the data indicated a 44% reduction in the risk of a first heart attack with aspirin use. PHS II, a follow-on, randomized, double-blind, placebo-controlled trial to the PHS, is in progress and is expected to be completed in 2008 (13). PHS II includes 15 000 male US physicians, about one-half of whom also participated in PHS I. PHS II is investigating vitamin E, vitamin C, and multivitamin supplementation, alone or in combination, on cancer, CVD, and eye disease. This is the only randomized trial to test a multivitamin pill rather than selected vitamins or minerals in the primary prevention of cancer.

THE WOMENS HEALTH INITIATIVE

Observational studies suggest that increased intake of calcium and vitamin D is associated with decreased risk of colorectal cancer and polyps. Vitamin D also has been observed to modify the effect of calcium supplementation on adenoma risk in a clinical trial in which the supplements lowered risk only among subjects with vitamin D intake above the median (15). The calcium plus vitamin D component of the Women's Health Initiative was designed to test the ability of calcium and vitamin D supplementation to lower the risk of hip fracture; the effect of these supplements on colorectal cancer risk was included as a secondary endpoint. Women (36 282 participants) were assigned to receive either placebo or a tablet consisting of 500 mg elemental calcium as calcium carbonate and 200 IU vitamin D3 twice daily for 7 y (16). In contrast with previous studies, results from this trial found that daily calcium and vitamin D supplementation had no effect on colorectal cancer incidence among postmenopausal women (17). The differences between these results and observational studies remain to be explained, although the women's relatively high intakes at baseline (mean calcium intake of 1151 mg, mean vitamin D intake of 367 IU) may have hindered the ability to see a protective effect (17).

SUPPL

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