Antioxidants, Carotenoids, and Risk of Rectal Cancer
Maureen A. Murtaugh1 ,
Khe-ni Ma1,
Joan Benson1,
Karen Curtin1,
Bette Caan2 and
Martha L. Slattery1
1 Health Research Center, Department of Family and Preventive Medicine, University of Utah, Salt Lake City, UT.
2 Division of Research, Kaiser Permanente, Oakland, CA.
Received for publication April 2, 2003; accepted for publication July 21, 2003.
 |
ABSTRACT
|
---|
Numerous properties suggest that antioxidants and carotenoids may be valuable chemopreventive agents. A population-based case-control study of 952 rectal cancer cases and 1,205 controls from Northern California and Utah was conducted between September 1997 and February 2002. Detailed diet history, medical history, and lifestyle factors interviews were conducted. Dietary antioxidants were not associated with rectal cancer risk in men. For women, relative to the highest level of intake, low intake of dietary lycopene (odds ratio (OR) = 1.7, 95% confidence interval (CI): 1.0, 2.8) or vitamin E (OR = 2.2, 95% CI: 1.1, 4.3) was associated with an increased risk of rectal cancer. Alpha-, beta-, and gamma-tocopherol were associated with an approximate twofold increased risk of rectal cancer in women. Associations were stronger for women aged
60 years for vitamin E and tocopherols (alpha-tocopherol OR = 3.6, 95% CI: 1.4, 9.4; gamma-tocopherol OR = 5.3, 95% CI: 2.1, 13.2; delta-tocopherol OR = 1.9, 95% CI: 0.9, 4.0), except for beta-tocopherol, for which risk increased twofold for all women. Associations differed by estrogen status for beta-carotene, lycopene, and vitamin E. These results suggest that vitamin E and lycopene may modestly reduce the risk of rectal cancer in women.
antioxidants; carotenoids; diet; rectal neoplasms
 |
INTRODUCTION
|
---|
Antioxidants include a variety of vitamins, carotenoids, minerals, and phytochemicals that deactivate free radicals and thereby prevent damage to cellular membranes or genetic material within the cell. Approximately two dozen of the more than 600 fat-soluble plant pigments called carotenoids are found in human blood and tissue (1). Although it is commonly perceived that vitamin E, beta-carotene, and other carotenoids act similarly to antioxidants, their unique biologic activities distinguish them from each other (2, 3). For example, individual antioxidants and carotenoids act differently in different components of the immune system (2, 4) in addition to contributing to cell-to-cell communication, cellular differentiation, and regulation of cell growth (5) or induction of apoptosis (6). Because of these biologic properties, they have been proposed as being potentially important chemopreventive agents that may alter cancer risk.
Epidemiologic studies examining associations between antioxidants, carotenoids, and cancer have produced far from consistent results. Significant associations have been reported for alpha-carotene and lycopene with breast cancer (7); alpha-carotene, beta-carotene, and lycopene with ovarian cancer (8, 9); lycopene with prostate cancer (10, 11); lycopene with colorectal cancer (9); lutein with proximal colon cancer (12); and vitamin E with colon cancer (1317). On the other hand, some observational studies and clinical trials have shown that beta-carotene supplementation increases the risk of cancer, especially among smokers (18, 19).
In general, it can be concluded that the associations of antioxidants with colorectal cancer are inconsistent, and studies have primarily focused on colon cancer (14, 16, 1925). However, a few studies have reported associations between antioxidants and carotenoids and rectal cancer (15, 26, 27). These studies can be characterized as having limited carotenoid data (15, 26, 28), usually including only beta-carotene, and imprecise estimates of association since most report that few cases of rectal cancer were available for analysis (27).
Thus, our primary objective was to explore associations of antioxidants and carotenoids with the risk of rectal cancer in a case-control study of adult men and women residents of Utah and Northern California. We investigated potential modification of these associations by age and estrogen status.
 |
MATERIALS AND METHODS
|
---|
Study population
Participants in the study were from the Kaiser Permanente Medical Care Program of Northern California (KPMCP) and the state of Utah. All eligible cases within these defined populations were identified and recruited for the study. Cases with a first primary tumor in the rectosigmoid junction or rectum were identified between May 1997 and May 2001 by using a rapid-reporting system. Case eligibility was determined in Northern California by using the Surveillance, Epidemiology, and End Results (SEER) Program Cancer Registries and in Utah by using the Utah Cancer Registry. An online pathology reporting system was searched for rapid ascertainment of rectal cancer cases. In California, cases identified were confirmed through linkage to the Kaiser Permanente Northern California Cancer Registry. To be eligible for the study, cases could not have had a previous colorectal tumor. Cases with known (as indicated on the pathology report) familial adenomatous polyposis, ulcerative colitis, or Crohns disease were not eligible. In addition to these criteria, participants were required to be between 30 and 79 years of age at the time of diagnosis, English speaking, and mentally competent to complete the interview.
Controls were categorically matched to cases by sex and by 5-year age groups. At the Kaiser Permanente Medical Care Program of Northern California, controls were randomly selected from membership lists; in Utah; controls aged 65 years or older were randomly selected from social security lists, and controls younger than age 65 years were randomly selected from drivers license lists. A total of 952 rectal cancer cases and 1,205 matched controls were included in the analyses presented. Response rates were 65.2 percent for cases and 65.3 percent for controls; cooperation rates, or the number of people who participated and we were able to contact, was 73.2 percent for cases and 68.8 percent for controls.
Data collection
Data were collected by trained and certified interviewers using laptop computers. The interview lasted approximately 2 hours. Quality control methods used in the study were the same as those used in the colon cancer study and have been described in detail elsewhere (7, 8).
Diet
Dietary intake was ascertained by using an adaptation of the CARDIA diet history to accommodate yearly seasonal variation and changes in food availability, for example, more low-fat choices (8, 12). Participants were asked to recall foods eaten during the calendar year 2 years prior to diagnosis or selection, the frequency with which they were eaten, the serving size, and whether fats were added in the preparation. Nutrient information was obtained by converting food intake data into nutrient data using the University of Minnesota Nutrition Coding Center nutrient database, version 4.04_30. This version of the database has information on alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene (29) as well as complete data on other antioxidants, including alpha-, beta-, gamma-, and delta-tocopherols. Participants were asked whether they used any multivitamins, multivitamins with minerals, single vitamins, single minerals, or other supplements. Participants who responded in the affirmative were asked to report the kind, frequency, and dose of the supplements they used.
Other information
Height was measured at the time of interview, and weight was reported for the 2 and 5 years prior to interview. Body mass index (weight (kg)/height (m)2) was calculated for men and women. Physical activity data were collected by using a detailed physical activity questionnaire (30). "Estrogen status" was determined by a combination of menopausal status and use of hormone replacement therapy. Women who were premenopausal or postmenopausal and reported hormone replacement therapy use within the past 2 years were considered estrogen positive. Postmenopausal women who did not report recent hormone replacement therapy use were considered estrogen negative. Women who reported having a hysterectomy with one ovary removed and were younger than age 57 years were excluded from analysis because menopausal status could not be determined. The estrogen status variable enabled us to use our entire population rather than restrict the analysis to postmenopausal women only. Information also was collected on smoking, reproductive, and medical history.
Statistical methods
Unconditional logistic regression models were used to estimate the risk of rectal cancer associated with dietary carotenoids/antioxidants. Dietary data were first assessed by determining risk across quintiles of intake; quintiles were determined by the sex-specific intake distribution in the control population. We assessed associations both with and without inclusion of supplement information; however, since associations were similar, this paper reports associations for dietary intake without supplement use to make these data more comparable to data reported elsewhere (12, 24, 2628, 31). In these models, the following variables were included: age at selection, body mass index, physical activity, energy intake, dietary fiber, dietary calcium, and cigarette smoking status. Linear trend was determined by evaluating significance of linear association across the categorized variable. Interaction or effect modification between dietary intake and estrogen status was evaluated as the relative excess risk from interaction on the additive scale (32).
 |
RESULTS
|
---|
Approximately 1418 percent of the population were under age 50 years (table 1). Compared with cases, controls had slightly more education, reported more physical activity, had slightly lower body mass index levels, and were more likely to report never having smoked cigarettes. Cases reported higher mean levels of energy intake, while controls reported higher mean levels of calcium intake. Among women, over half of the population reported multivitamin use, while about 40 percent of men reported multivitamin use. In addition, roughly 25 percent of the population reported using vitamin E and vitamin C as a single supplement during the referent year.
View this table:
[in this window]
[in a new window]
|
TABLE 1. Description of the population studied to assess associations of antioxidants and carotenoids with risk of rectal cancer, Northern California and Utah, 19972002
|
|
After adjustment for covariates, low intakes of lycopene (odds ratio = 1.7, 95 percent confidence interval: 1.0, 2.8; p for linear trend = 0.01) and vitamin E (odds ratio = 2.2, 95 percent confidence interval: 1.1, 4.3; p for linear trend = 0.04) were associated with an increased risk of rectal cancer in women. No association of lutein, beta-carotene, vitamin C, or selenium from dietary sources with risk of rectal cancer was found for either men or women (table 2). Vitamin supplement use was not associated significantly with rectal cancer in women or men (data not shown).
View this table:
[in this window]
[in a new window]
|
TABLE 2. Associations between intake of dietary carotenoids and antioxidants and rectal cancer risk, Northern California and Utah, 19972002
|
|
The association between vitamin E and rectal cancer was stronger for women aged 60 years or older than for younger women (quintile 5 vs. quintile 1 odds ratio = 3.5, 95 percent confidence interval: 1.5, 8.5; p for interaction = 0.05 (table 3)). Associations with lycopene, beta-carotene, vitamin C, and selenium did not vary by age for men or women.
View this table:
[in this window]
[in a new window]
|
TABLE 3. Association of levels of intake of antioxidants and carotenoids with rectal cancer risk,* by womens age, Northern California and Utah, 19972002
|
|
Further assessment of types of vitamin E showed that all forms except delta-tocopherol were associated with a decreased risk of rectal cancer in women (table 4), but not men (data not shown in table). Assessment of tocopherols by age showed that beta-tocopherol was associated with rectal cancer in both younger and older women, while other forms of tocopherols were associated with rectal cancer in older women only. At the lowest level of intake, alpha-tocopherol was associated with a 3.6-fold (95 percent confidence interval: 1.4, 9.4) increased risk, gamma-tocopherol was associated with a 5.3-fold (95 percent confidence interval: 2.1, 13.2) increased risk, and delta-tocopherol was associated with a 1.9-fold (95 percent confidence interval: 0.9, 4.0) increased risk.
View this table:
[in this window]
[in a new window]
|
TABLE 4. Associations between forms of tocopherols and rectal cancer in women, Northern California and Utah, 19972002
|
|
Given the gender-specific associations observed with some antioxidants and carotenoids, we evaluated the associations for women by estrogen status. We found no differences in the associations of lutein, vitamin C, and selenium by estrogen status. However, estrogen status appeared to modify the associations of beta-carotene, lycopene, and vitamin E with rectal cancer in women (table 5). The combined effect of being estrogen negative and having low intakes of lycopene, beta-carotene, and vitamin E was greater than any of these factors independently. For lycopene and vitamin E, lower dietary intakes were associated with approximately a threefold increase in risk of rectal cancer in estrogen-negative women relative to estrogen-positive women with high intakes; for beta-carotene, there was an approximate twofold increase in risk of rectal cancer in estrogen-negative women.
View this table:
[in this window]
[in a new window]
|
TABLE 5. Interaction between estrogen status and levels of intake of lycopene, beta-carotene, and vitamin E, Northern California and Utah, 19972002
|
|
 |
DISCUSSION
|
---|
High intakes of dietary lycopene and vitamin E were associated with a modest reduction in risk of rectal cancer in women, but not men. The association between vitamin E and rectal cancer varied by the type of tocopherol being assessed. Age and estrogen status appeared to modify the relations of antioxidants and carotenoids with rectal cancer in women.
These results add to those from previous studies that point to a modest reduction in risk of rectal cancer associated with high dietary and supplemental sources of vitamin E (15, 26, 33). We found that the highest dietary intakes of vitamin E were associated with a decreased risk of rectal cancer in women. Bostick et al. (16) reported significant associations between colon cancer and total vitamin E intake (diet and supplements in a cohort of older women), but associations were stronger for women aged 5559 versus 6064 years. A study of incident rectal cancer found no association with dietary vitamin E for men or women (26). Many explanations are possible for the differences observed, including different levels of vitamin E reported, different sources of vitamin E in the diet, and type of tocopherol being eaten; differences in the proportion of the population using supplements and the dosage of supplements could exist as well as differences in other factors that could modify associations, including age and estrogen status of the population being studied.
Assessment of various forms of tocopherols was informative. Low levels of beta-tocopherol were associated with an increased risk for both younger and older women, while low levels of alpha- and gamma-tocopherol were associated with a strong increased risk for older women. Delta-tocopherol had a much weaker effect than other forms of tocopherols on the risk for older women. In a review of tocopherols and colon cancer (34), it was suggested that alpha- and gamma-tocopherols both may be important in the prevention of colon cancer, although alpha-tocopherol is usually studied. Alpha-tocopherol, present in relatively high concentrations in plasma compared with other forms of tocopherol, may reduce lipid peroxidation in cellular membranes. Gamma-tocopherol, on the other hand, is high in Western diets and is preferentially secreted into the intestine and fecal material. Antioxidants in fecal material may be effective in preventing DNA damage in epithelial cells lining the colon (34). It has long been hypothesized that fecal bacteria contribute to colon cancer risk by producing carcinogens or procarcinogens (35). It is possible that gamma-tocopherol is involved in reducing the risk of rectal cancer via this mechanism.
Although we found no previous reports of the association of lycopene with the risk of rectal cancer, dietary lycopene has been associated with other cancers whose etiology is thought to have a hormonal basis, including breast, ovarian, and prostate cancer (7, 8, 10, 11). Cramer et al. (8) reported an inverse association of lycopene with the risk of ovarian cancer, predominantly among postmenopausal women. Similarly, in the present study, the highest intakes of lycopene were associated with a decreased risk of rectal cancer in women only, and the association was stronger for estrogen-negative women. It has been suggested that the actions of higher levels of prooxidant catechol estrogens prior to menopause could be countered by the free-radical-quenching activity of lycopene (7). Differences in associations detected for studies including serum and dietary lycopene could be explained by their poor correlation (36) and by variability in the bioavailability of lycopene (1) and interactions among carotenoids and other nutrients (37). Other possibilities for the detected association include up-regulation of the cytochrome P450 enzyme system (38) and of the proteins that enable cell-to-cell communication at high levels of lycopene intake (39, 40).
Findings from the present study conflict with previous reports of an inverse association of beta-carotene with rectal cancer (15, 27); with the highest intake of beta-carotene, a 46 percent reduction in risk was reported for Chinese (27) and a 68 percent reduction in risk was reported for Italians (15). Our findings are more consistent with those from the Australian case-control study in which no significant associations were detected (28). To our knowledge, others have not examined the associations between rectal cancer and beta-carotene by hormone replacement therapy use or estrogen status. However, in our study, for estrogen-negative women versus estrogen-positive women, the lowest intakes of beta-carotene were associated with a twofold greater risk of rectal cancer. Beta-carotene exposure has been linked to production of reactive oxygen species in the colon that may act in either a prooxidant or antioxidant capacity, depending on the cellular environment (5). It is also possible that the association of beta-carotene with rectal cancer is through regulation of cell growth. Availability of beta-carotene as a precursor to vitamin A and the maintenance of cell integrity may be more important for estrogen-positive women, since estrogen may increase cell proliferation.
As in other studies (27, 33), we observed no association between dietary or supplemental vitamin C and rectal cancer. However, inverse associations between vitamin C and rectal cancer have been reported for New York women (26) and Italian men and women (15).
Of interest is the gender-specific associations we noted. Among women, the strongest associations were found for older women, who could, on the surface, appear to be hormonally more similar to men. However, in assessing other risk factors and gender differences in colon cancer, we observed that associations with body mass index were more similar for premenopausal women and men than for postmenopausal women and men (41). We hypothesize that androgens function similarly to estrogen in some disease pathways. Our observation of gender-specific associations between carotenoids and colorectal cancer have some support in the literature. Differences in associations between antioxidants and risk of colon cancer (17), rectal cancer (26, 28), and colorectal cancer (15) between men and women have been noted before. Furthermore, associations of retinol and rectal cancer for men and women reported by Potter and McMichael (28), although not significant, were in opposite directions. Other studies of smaller size (27) have not examined gender-specific associations, but failure to examine them does not preclude their existence.
Both age and estrogen appeared to modify the associations of lycopene and vitamin E with risk of rectal cancer. However, age and estrogen status are tightly related, making it difficult to evaluate whether their influences are independent or whether estrogen status influences the relation of age to risk of rectal cancer. Inadequate power hampered our efforts to clearly distinguish this issue; however, the association of lycopene with hormone-sensitive cancers (7, 8, 10, 11) certainly points to the plausibility of an independent influence of estrogens, as do the gender-specific associations.
Strengths of the study include the large number of cases of rectal cancer, comprehensive assessment of diet using a quantitated diet history, a comprehensive carotenoid database (29) used to calculate carotenoid exposure, and the quality control procedures we used to collect data. Classification of women according to estrogen status enabled us to study both pre- and postmenopausal women. However, despite the large sample size, we were limited in our ability to conduct statistical tests for significant interactions when stratifying by estrogen status or to further stratify by supplement use in gender-specific associations. The CARDIA dietary history has previously been shown to be a valid measure of vitamin A use in White men and women (11). Recall bias cannot be ruled out as a contributor to the present findings. However, since our referent period for dietary data was the calendar year 2 years prior to diagnosis or selection and we noted significant associations, the referent period appears to be appropriate for vitamin E, lycopene, and beta-carotene. If other antioxidants or carotenoids operate at a different stage in the carcinogenic process, we could have missed other potentially important associations.
In summary, this study supports the hypothesis that some antioxidants and carotenoids are modestly associated with a reduction in the risk of rectal cancer. However, the most important associations appear to be restricted to women and, in some instances, are further modified by age. Of interest is the observed effect modification by estrogen status. Further investigation into how estrogens might influence lycopene and vitamin E is needed. Given previously reported associations by others that lycopene is associated with hormonal cancers such as prostate, ovarian, and breast cancer, this could be an informative area of research into diet and cancer etiology.
 |
ACKNOWLEDGMENTS
|
---|
This study was funded by National Cancer Institute grant CA48998 to Dr. Slattery. This research also was supported by the Utah Cancer Registry, which is funded by contract N01-PC-67000 from the National Cancer Institute, with additional support from the State of Utah Department of Health, the Northern California Cancer Registry, and the Sacramento Tumor Registry.
 |
NOTES
|
---|
Correspondence to Dr. Maureen A. Murtaugh, Health Research Center, Department of Family and Preventive Medicine, University of Utah, 375 Chipeta Way, Suite A, Salt Lake City, UT 84108 (e-mail: mmurtaugh{at}hrc.utah.edu). 
 |
REFERENCES
|
---|
- Johnson EJ. The role of carotenoids in human health. Nutr Clin Care 2002;5:5665.[CrossRef][Medline]
- Hughes DA, Wright AJ, Finglas PM, et al. Effects of lycopene and lutein supplementation on the expression of functionally associated surface molecules on blood monocytes from healthy male nonsmokers. J Infect Dis 2000;182(suppl 1):S1115.[CrossRef]
- Hughes DA, Wright AJ, Finglas PM, et al. The effect of beta-carotene supplementation on the immune function of blood monocytes from healthy male nonsmokers. J Lab Clin Med 1997;129:30917.[ISI][Medline]
- Moriguchi S, Muraga M. Vitamin E and immunity. Vitam Horm 2000;59:30536.[Medline]
- Palozza P, Calviello G, Serini S, et al. Beta-carotene at high concentrations induces apoptosis by enhancing oxy-radical production in human adenocarcinoma cells. Free Radic Biol Med 2001;30:10007.[CrossRef][ISI][Medline]
- Turley JM, Funakoshi S, Ruscetti FW, et al. Growth inhibition and apoptosis of RL human B lymphoma cells by vitamin E succinate and retinoic acid: role for transforming growth factor beta. Cell Growth Differer 1995;6:65563.[Abstract]
- Hulten K, Van Kappel AL, Winkvist A, et al. Carotenoids, alpha-tocopherols, and retinol in plasma and breast cancer risk in northern Sweden. Cancer Causes Control 2001;12:52937.[CrossRef][ISI][Medline]
- Cramer DW, Kuper H, Harlow BL, et al. Carotenoids, antioxidants and ovarian cancer risk in pre- and postmenopausal women. Int J Cancer 2001;94:12834.[CrossRef][ISI][Medline]
- La Vecchia C. Tomatoes, lycopene intake, and digestive tract and female hormone-related neoplasms. Exp Biol Med 2002;227:8603.[Abstract/Free Full Text]
- Vogt TM, Mayne ST, Graubard BI, et al. Serum lycopene, other serum carotenoids, and risk of prostate cancer in US Blacks and Whites. Am J Epidemiol 2002;155:102332.[Abstract/Free Full Text]
- Giovannucci E, Rimm EB, Liu Y, et al. A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst 2002;94:3918.[Abstract/Free Full Text]
- Slattery ML, Benson J, Curtin K, et al. Carotenoids and colon cancer. Am J Clin Nutr 2000;71:57582.[Abstract/Free Full Text]
- Slattery ML, Edwards SL, Anderson K, et al. Vitamin E and colon cancer: is there an association? Nutr Cancer 1998;30:2016.[ISI][Medline]
- Wu K, Willett WC, Chan JM, et al. A prospective study on supplemental vitamin E intake and risk of colon cancer in women and men. Cancer Epidemiol Biomarkers Prev 2002;11:1298304.[Abstract/Free Full Text]
- Ferraroni M, La Vecchia C, DAvanzo B, et al. Selected micronutrient intake and the risk of colorectal cancer. Br J Cancer 1994;70:11505.[ISI][Medline]
- Bostick RM, Potter JD, McKenzie DR, et al. Reduced risk of colon cancer with high intake of vitamin E: the Iowa Womens Health Study. Cancer Res 1993;53:42307.[Abstract]
- Ghadirian P, Lacroix A, Maisonneuve P, et al. Nutritional factors and colon carcinoma: a case-control study involving French Canadians in Montreal, Quebec, Canada. Cancer 1997;80:85864.[CrossRef][ISI][Medline]
- Albanes D, Heinonen OP, Taylor PR, et al. Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 1996;88:156070.[Abstract/Free Full Text]
- Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 1996;88:15509.[Abstract/Free Full Text]
- The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994;330:102935.[Abstract/Free Full Text]
- Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:11459.[Abstract/Free Full Text]
- Shibata A, Paganini-Hill A, Ross RK, et al. Intake of vegetables, fruits, beta-carotene, vitamin C and vitamin supplements and cancer incidence among the elderly: a prospective study. Br J Cancer 1992;66:6739.[ISI][Medline]
- Albanes D, Malila N, Taylor PR, et al. Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland). Cancer Causes Control 2000;11:197205.[CrossRef][ISI][Medline]
- Franceschi S. Nutrients and food groups and large bowel cancer in Europe. Eur J Cancer Prev 1999;8(suppl 1):S4952.[Medline]
- Terry P, Jain M, Miller AB, et al. Dietary carotenoid intake and colorectal cancer risk. Nutr Cancer 2002;42:16772.[ISI][Medline]
- Freudenheim JL, Graham S, Marshall JR, et al. A case-control study of diet and rectal cancer in western New York. Am J Epidemiol 1990;131:61224.[Abstract]
- Lee HP, Gourley L, Duffy SW, et al. Colorectal cancer and diet in an Asian populationa case-control study among Singapore Chinese. Int J Cancer 1989;43:100716.[ISI][Medline]
- Potter JD, McMichael AJ. Diet and cancer of the colon and rectum: a case-control study. J Natl Cancer Inst 1986;76:55769.[ISI][Medline]
- Holden JA, Eldridge AL, Beecher G, et al. Carotenoid content of U.S. foods: an update of the database. J Food Comp Anal 1999;12:16996.[CrossRef]
- Slattery ML, Abd-Elghany N, Kerber R, et al. Physical activity and colon cancer: a comparison of various indicators of physical activity to evaluate the association. Epidemiology 1990;1:4815.[Medline]
- Slattery ML, Berry TD, Potter J, et al. Diet diversity, diet composition, and risk of colon cancer (United States). Cancer Causes Control 1997;8:87282.[CrossRef][ISI][Medline]
- Hosmer D, Lemeshow S. Confidence interval estimation of interaction. Epidemiology 1992;3:4526.[ISI][Medline]
- Jacobs EJ, Connell CJ, Patel AV, et al. Vitamin C and vitamin E supplement use and colorectal cancer mortality in a large American Cancer Society cohort. Cancer Epidemiol Biomarkers Prev 2001;10:1723.[Abstract/Free Full Text]
- Stone WL, Papas AM. Tocopherols and the etiology of colon cancer. J Natl Cancer Inst 1997;89:100614.[Abstract/Free Full Text]
- Guarner F, Malagelada JR. Gut flora in health and disease. Lancet 2003;361:51219.[CrossRef][ISI][Medline]
- Feskanich D, Rimm EB, Giovannucci EL, et al. Reproducibility and validity of food intake measurements from a semiquantitative food frequency questionnaire. J Am Diet Assoc 1993;93:7906.[ISI][Medline]
- Castenmiller JJ, West CE. Bioavailability and bioconversion of carotenoids. Annu Rev Nutr 1998;18:1938.[CrossRef][ISI][Medline]
- Bendich A. Recent advances in clinical research involving carotenoids. Pure Appl Chem 1994;66:101724.[ISI]
- Zhang LX, Cooney RV, Bertram JS. Carotenoids enhance gap junctional communication and inhibit lipid peroxidation in C3H/10T1/2 cells: relationship to their cancer chemopreventive action. Carcinogenesis 1991;12:210914.[Abstract]
- Zhang LX, Cooney RV, Bertram JS. Carotenoids up-regulate connexin43 gene expression independent of their provitamin A or antioxidant properties. Cancer Res 1992;52:570712.[Abstract]
- Slattery ML, Ballard-Barbash R, Edwards S, et al. Body mass index and colon cancer: an evaluation of the modifying effects of estrogen (United States). Cancer Causes Control 2003;14:7584.[CrossRef][ISI][Medline]