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Food, Facts and Fantasies: Can Your Diet Really Reduce Cancer Risk?

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Presentation on theme: "Food, Facts and Fantasies: Can Your Diet Really Reduce Cancer Risk?"— Presentation transcript:

1 Food, Facts and Fantasies: Can Your Diet Really Reduce Cancer Risk?
J. A. Milner Nutrition Science Research Group Division of Cancer Prevention National Cancer Institute Bethesda, MD 20892

2 Unprecedented Opportunities Exist for Expanded Use of Foods and Components to Achieve Genetic Potential, to Increase Productivity and Decrease Risk of Disease 6

3 While we have come a long way since this 1940’s United Kingdom Advertisement, we still can not identify who will and will not benefit from dietary intervention strategies

4 Fruits, Vegetables & Cancer Prevention
Variety or Category % Positive Vegetables 80% (59/74) Fruits 64% (36/56) Raw vegetables 87% (40/46) Cruciferous 69% (38/55) Allium vegetables 77% (27/35) Green vegetables 77% (68/88) Carrots 81% (59/73) Tomatoes 71% (36/51) Citrus Fruit 66% (27/41) WCRF/AICR Expert Committee Conclusions

5 Nutritional Genomics and Proteomics
Epigenomic CH3-DNA Genomic Post-translational DNA mRNA Proteins Enzymes, structural, Transport,signaling caused by phosphorylation, glycosylation, etc. Bioactive Food Components

6 Influence of Caffeine on Bone Mass May Depend on Genes
6 < 300 mg Caffeine > 300 mg D Spine Bone Mass Density (%) -6 BACKGROUND: The role of caffeine as a risk factor for bone loss is controversial. OBJECTIVE: Our goals were 1) to compare in both a cross-sectional study and a 3-y longitudinal study the bone mineral density (BMD) of postmenopausal women consuming high or low amounts of caffeine and 2) to study the interaction between caffeine intake, vitamin D receptor (VDR)polymorphism, and BMD in the longitudinal study. DESIGN: The results are derived from cross-sectional measurements of BMD in 489 elderly women (aged y) and from longitudinal measurements made in 96 of these women who were treatedwith a placebo for 3 y. Changes in BMD were adjusted for confounding factors and were compared between groups with eitherlow (< or =300 mg/d) or high (>300 mg/d) caffeine intakes and between the VDR genotype subgroups of the low- andhigh-caffeine groups. RESULTS: Women with high caffeine intakes had significantly higher rates of bone loss at the spine than did those with low intakes ( /- 0.97% compared with /- 1.08%; P = 0.038). When the data were analyzed according to VDR genotype and caffeine intake, women with the tt genotype had significantly (P = 0.054) higher rates of boneloss at the spine ( /- 2.62%) than did women with the TT genotype ( /- 1.42%) when their caffeine intake was>300 mg/d. CONCLUSIONS: Intakes of caffeine in amounts >300 mg/d ( approximately 514 g, or 18 oz, brewed coffee) accelerate bone loss at the spine in elderly postmenopausal women. Furthermore, women with the tt genetic variant of VDRappear to be at a greater risk for this deleterious effect of caffeine on bone. -12 TT Tt tt TT Tt tt Vitamin D Receptor Genotype Rapuri et al. Am J Clin Nutr 2001 Nov;74(5):

7 Diet-Gene Interactions in Colon Cancer
p21+/+ AIN-76A Diet 100 p21+/- AIN-76A Diet 90 80 p21+/+ Western Diet 70 p21-/- AIN-76A Diet 60 p21+/- Western Diet Percent survival 50 40 p21-/- Western Diet 30 20 10 4 8 12 16 20 24 28 32 36 Weeks Yang et al, Cancer Res. 61, 565, 2001


9 Selenium & Skin Cancer Prevention Trial
Phase III trial with 1,312 skin cancer subjects Se (200 mg) as Brewers Yeast vs. Placebo, follow-up 6.4 yrs Selenium Placebo RR 97% CI Skin Cancer Squamous cell Basal cell Cancer (- Skin) Lung Prostate Colorectal Breast All Sites (- Skin) Clark et al. JAMA 276: 1957, 1996.

10 Prostate Cancer Prevention Selenium and Vitamin E
Cancer Prevention Trail (SELECT) ($175M) 32,000 men, age >55 (> 50 for Black Men) Selenium 200 ug/d Vitamin E 400 mg/d Selenium Vitamin E Placebo 7 + Years Treatment Endpoint Prostate Cancer Incidence

11 Early Biomarkers Needed
Ideal Qualities: Readily accessible Easily & reliably assayed Differentially expressed Directly associated with disease progression Modulable Predictive


13 Diet May Influence Genetic & Epigenetic Events Associated with Several Cancer Processes
DNA Repair Carcinogen Metabolism Hormonal Regulation Bioactive Food Components Cell Cycle Differentiation Apoptosis U54 RFA Review Nov

14 Numerous Dietary Components Can Alter Genetic and Epigenetic Events
Essential Nutrients- Ca, Zn, Se, Folate, C, E Non-Essential Phytochemicals- Carotenoids, Flavonoids, Indoles, Isothiocyanates, Allyl Sulfur Zoochemicals - Conjugated linoleic acid, n-3 fatty acids Fungochemicals - Several compounds in mushrooms Bacteriochemical - Those formed from food fermentations and those resulting from intestinal flora

15 Gene Expression in Human Cultured Colon Cells
Butyrate Curcumin Red - increased Green - decreased Black - unchanged . Mariadason et al, Cancer Res . 60, 4561, 2000

16 How Should We Consume Bioactive Food Components?
MARKET STAGE BROCCOLI 3-DAY SPROUTS 3 grams FREEZE-DRIED SPROUT EXTRACT 150 grams 150 mg All preparations contain the same quantity of detoxification enzyme inducer activity, (Glutathione S-transferase and Quinone Reductase)

17 S S OLTIPRAZ Isothiocyanates (OLTIPRAZ) Cytoplasm Nucleus ARE nrf2
HS SH keap-1 keap-1 nrf2 Cytoplasm nrf2 nrf2 small Nucleus maf ARE Gene expression “antioxidant responsive element”

18 isothiocyanates (nutrient) have similar mechanism of action
Effect of Nrf2 genotype on induction of GST and NQO1 activities by oltipraz in mouse liver (Ramos-Gomez et al. Proc Natl Acad Sci U S A 2001;98:3410) Oltipraz (drug) and isothiocyanates (nutrient) have similar mechanism of action

19 Tea (Camellia sinensis)
Crushed tea leaves Polyphenol oxidase Oxidation, Polymerization Dried Tea Leaves O OR 2 HO OH R 1 Green Tea Black Tea 30-40% Catechins 3-6% Caffeine ~310 mg polyphenols per 6 ounces 3-10% Catechins 2-6% Theaflavins > 20% Thearubigens 3-6%  Caffeine ~340 mg polyphenols per 6 ounces Yang CS. Personal Communication

20 Tea and Cancer Prevention
Skin Liver Camellia Sinensis Colon Oral Esophagus Prostate Mammary Stomach Lung Yang CS. Personal Communication

21 Types of Bioactive Compounds May Vary with New Varieties
Tomato Varieties

22 Recent Epidemiologic Studies of Lycopene and Cancer Risk
Cancer Type of Study Reference Breast Cohort Dorgan et al Can Cau Cont 9: 89-97, 1998 Colon Case-control Franceschi et al Int J Cancer 72:56-61, 1997 Lung Case-control Agudo et al Eur J Cancer 33: , 1997 Prostate Cohort Giovannucci et al J Natl. Cancer Inst. 87: ,

23 Prospective cohort study with 41,837 women age 55 to 69, examined 127 food items. “The strongest association in the present study was that for garlic consumption, with an approximate 50% lesser risk associated with high consumption.” Steinmetz et al. Amer. J. Epidemiology 139:1, 1994 Recent meta-analysis of Data from 11 trials concluded The random-effects relative risk (RR) estimate for raw and cooked garlic and colorectal cancer was 0.69 and for stomach was 0.53. Fleischauer, et al. Amer JClin Nutr 72, 1047, 2000.

24 Effects of Microwave Heating of Garlic on Total DMBA-Induced DNA Adducts
1000 30 seconds a 60 seconds a 750 (nmol Adducts/mol DNA) DNA Adducts 500 b b 250 Control Peel/ Crushed Microwave/ Peel/ Crushed Song and Milner J Nutr 1999;129:657-61

25 How Much of A Given Food is Needed
Indole 3-carbinol changes site of hydroxylation of estradiol (>2 and <16 OH). Causes depression in tumor growth and apoptosis. (Telang, et al. PSEBM 216: 246: 1997).

26 Wang, Kim and MilnerAACR 2002
Top 20 down-regulated genes from 3 microarray analysis from MCF-7 cells (T: with, C: without 100µM indole-3-carbinol) Name T/C (Ave) p value ALOX5AP--arachidonate 5-lipoxygenase-a BMP7--bone morphogenetic protein ERCC6--excision repair cross-complemen ESR1--estrogen receptor EXTL3--exostoses (multiple)-like GATA3--GATA-binding protein HMG2--high-mobility group (nonhistone Homo sapiens cDNA FLJ14201 fis, clone Homo sapiens clone mRNA sequence KIAA0165--extra spindle poles, S. cere KRT7--keratin LAP18--leukemia-associated phosphoprot NRCAM--neuronal cell adhesion molecule SFRP5--secreted frizzled-related prote TCF3--transcription factor UGDH--UDP-glucose dehydrogenase Unknown Unknown Unknown ZXDA--zinc finger, X-linked, duplicate Wang, Kim and MilnerAACR 2002

27 Indole 3-Carbinol and Tamoxifen Interactions in Attached MCF-7 Cells
100- I3C (mM) 80- 50 60- Integrated Density/Area (pixel value/mm2) 100 40- 20- 0- 0.5 1 mM Tamoxifen Cover et al. Cancer Research 59:1244, 1999.

28 Soy Intake and Cancer Concerns
17 of 26 animal studies reveal soy or soybean isoflavones reduce tumor tumor development 19 or 21 human epidemiological studies provide evidence of protection against cancer, especially rectal and stomach cancers (1 study reported increase) Concerns Growth enhancement of human mammary tumors transplanted into mice that were fed soy or isoflavonids (Hsieh, et al. Cancer Res. 58:3833, 1998). 13

29 Soymilk Intake & Prostate Cancer Risk
1.0 0.9 0.8 Relative Risk 0.3* <1 1 >1 Daily Intake (servings) Cancer Causes Control 9: 553, 1998

30 More is Not Always Better: Energy Intakes and Expenditures Are Linked to Health!

31 Caloric Restriction in Yeast causes silencing of genes and extended life span (Guarente and Kenyon Nature 2000; 408:255

32 Colon Cancer and Exercise

33 Is it Possible that Bioactive Compounds might be beneficial in some circumstances and detrimental in other?

34 Some Women Appear Susceptible to Flavonoids
Several flavonoids found to cause change in MLL gene on chromosome band 11q23 Associated with increased risk of infant leukemia linked to MLL gene Some cancer patients treated with drugs that modify topoisomerase develop leukemia involving MLL gene. Ross (2000) Proc. Natl Acad. Sci. 97: Strick et al. (2000) Proc. Natl Acad. Sci. 97:

35 Antioxidant reduces efficacy of cisplatin
Vitamin E Inhibits Cisplatin-Induced Apoptosis in MCF-7 Breast Cancer Cells. 6 - Antioxidant reduces efficacy of cisplatin 4 - % Apoptosis + ** 2 - * 0 - Control E CP CP+E Salganik, et al. Carcinogenesis 21: 909, 2000.

36 One Size Does Not Fit All!

37 Just when I knew all of life’s answers,
They changed all the questions!!

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