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Food, Facts and Fantasies: Can Your Diet Really Reduce Cancer Risk? Nutrition Science Research Group Division of Cancer Prevention National Cancer Institute.

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Presentation on theme: "Food, Facts and Fantasies: Can Your Diet Really Reduce Cancer Risk? Nutrition Science Research Group Division of Cancer Prevention National Cancer Institute."— Presentation transcript:

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

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

3 While we have come a long way since this 1940s 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 Vegetables80% (59/74) Fruits64% (36/56) Raw vegetables87% (40/46) Cruciferous Vegetables69% (38/55) Allium vegetables77% (27/35) Green vegetables77% (68/88) Carrots81% (59/73) Tomatoes71% (36/51) Citrus Fruit66% (27/41) WCRF/AICR Expert Committee Conclusions

5 DNA Nutritional Genomics and Proteomics Proteins Enzymes, structural, Transport,signaling caused by phosphorylation, glycosylation, etc. mRNA CH 3 -DNA Genomic Post-translational Bioactive Food Components Epigenomic

6 < 300 mgCaffeine> 300 mg 6 -12 0 -6 Vitamin D Receptor Genotype TT Tt tt Spine Bone Mass Density (%) Influence of Caffeine on Bone Mass May Depend on Genes Rapuri et al. Am J Clin Nutr 2001 Nov;74(5):694-700

7 Diet-Gene Interactions in Colon Cancer Yang et al, Cancer Res. 61, 565, 2001 04812162024283236 0 10 20 30 40 50 60 70 80 90 100 Weeks Percent survival p21+/+ AIN-76A Diet p21+/- AIN-76A Diet p21-/- AIN-76A Diet p21+/+ Western Diet p21+/- Western Diet p21-/- Western Diet


9 Selenium PlaceboRR 97% CI Skin Cancer Squamous cell2181901.140.93-1.39 Basal cell3773501.100.95-1.28 Cancer (- Skin) Lung17310.540.30-0.98 Prostate13350.370.18-0.71 Colorectal8190.420.18-0.95 Breast932.880.72-16.5 All Sites (- Skin)771190.630.47-0.85 Selenium & Skin Cancer Prevention Trial Clark et al. JAMA 276: 1957, 1996. Phase III trial with 1,312 skin cancer subjects Se (200 g) as Brewers Yeast vs. Placebo, follow-up 6.4 yrs

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 Vitamin EPlacebo Selenium 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 Hormonal Regulation Carcinogen Metabolism Apoptosis Bioactive Food Components Differentiation Cell Cycle 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 Mariadason et al, Cancer Res. 60, 4561, 2000. Gene Expression in Human Cultured Colon Cells Red - increased Green - decreased Black - unchanged Butyrate Curcumin

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

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

18 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) 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 Dried Tea Leaves Crushed tea leaves Polyphenol oxidase Oxidation, Polymerization O OR 2 HO OH R 1 HO Yang CS. Personal Communication

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

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

22 Recent Epidemiologic Studies of Lycopene and Cancer Risk Cancer Type of Study Reference Breast CohortDorgan et al. Can Cau Cont 9: 89-97, 1998 Colon Case-controlFranceschi et al. Int J Cancer 72:56-61, 1997 Lung Case-controlAgudo et al. Eur J Cancer 33:1256-61, 1997 Prostate CohortGiovannucci et al. J Natl. Cancer Inst. 87:1767-76, 1995

23 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. Steinmetz et al. Amer. J. Epidemiology 139:1, 1994 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

24 Effects of Microwave Heating of Garlic on Total DMBA-Induced DNA Adducts a b b 0 250 500 750 1000 DNA Adducts (nmol Adducts/mol DNA) ControlPeel/ Crushed 30 seconds 60 seconds Microwave/ Peel/ Crushed a Song and Milner J Nutr 1999;129:657-61

25 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). How Much of A Given Food is Needed

26 NameT/C (Ave) p value ALOX5AP--arachidonate 5-lipoxygenase-a0.4510.016 BMP7--bone morphogenetic protein 7 0.3090.017 ERCC6--excision repair cross-complemen0.455.046 ESR1--estrogen receptor 10.4150.001 EXTL3--exostoses (multiple)-like 30.5090.011 GATA3--GATA-binding protein 30.5210.013 HMG2--high-mobility group (nonhistone0.4790.011 Homo sapiens cDNA FLJ14201 fis, clone0.4440.015 Homo sapiens clone 23836 mRNA sequence0.5260.026 KIAA0165--extra spindle poles, S. cere0.5320.003 KRT7--keratin 70.5050.001 LAP18--leukemia-associated phosphoprot0.5280.013 NRCAM--neuronal cell adhesion molecule0.4820.016 SFRP5--secreted frizzled-related prote0.4980.048 TCF3--transcription factor 3 0.5280.034 UGDH--UDP-glucose dehydrogenase0.5360.029 Unknown0.4880.008 Unknown0.4810.015 Unknown0.4790.019 ZXDA--zinc finger, X-linked, duplicate0.3580.021 Top 20 down-regulated genes from 3 microarray analysis from MCF-7 cells ( T: with, C: without 100µM indole-3-carbinol) Wang, Kim and MilnerAACR 2002

27 Cover et al. Cancer Research 59:1244, 1999. Indole 3-Carbinol and Tamoxifen Interactions in Attached MCF-7 Cells M Tamoxifen Integrated Density/Area (pixel value/mm 2 ) 00.5 1 0- 20- 40- 60- 80- 100- 0 50 100 I3C ( M)

28 Soy Intake and Cancer Concerns Growth enhancement of human mammary tumors transplanted into mice that were fed soy or isoflavonids (Hsieh, et al. Cancer Res. 58:3833, 1998). 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)

29 Soymilk Intake & Prostate Cancer Risk Cancer Causes Control 9: 553, 1998 0<11>1 Daily Intake (servings) Relative Risk 1.0 0.9 0.8 0.3*

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: 4411-4413. Strick et al. (2000) Proc. Natl Acad. Sci. 97:4790-4795

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

36 One Size Does Not Fit All!

37 Just when I knew all of lifes answers, They changed all the questions!!

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