# Presentation: 020356

## Diet and Functional Foods:  Inhibitors of the Cancer Process ? 

**Harold Seifried, PhD, CIH, DABT**

**Nutrition Science Research Group**
**Division of Cancer Prevention, **
**National Cancer Institute**
**Bethesda, MD 20892**

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

## Factors Promoting Interest in Foods Based Health Care in the U.S.

** ****Health Care Cost**
**1.****	****14% GNP**
**2.****	****Aging population**
**      ****In 1997 more visited alternative therapist ****	****than primary care physician**
** ****Changing Regulatory Environment**
**	****1. Nutrition Labeling and Education Act  ****	****	****	****(NLEA) of 1990**
**	****2.Dietary Supplement Health and Education ****	****	****Act  (DSHEA) of 1994**
** ****Scientific Advances**

## Diet and Health Risk

**people with higher intakes of ****fruit and Vegetables**** or ****blood antioxidant concentrations**** have**
**lower risk of some cancers, coronary heart disease and stroke.**

**Zino, et al. BMJ 314:1787, 1997.**

**Diet and Health Risk**

## Dietary Components with Potential Health Benefits

- Essential Nutrients
- Phytochemicals or allelochemicals (bioactive secondary compounds) in plants.  Thousands!! Carotenoids, Flavonoids, Indoles, Isothiocyanates, Allyl  Sulfur
- Zoochemicals- Peptides, Conjugated linoleic acid, n-3 fatty acids

## Functional Foods

**Functional Foods**
**to “encompass potentially healthful products,”**
** ****including “any modified food or food**
**ingredient that may **
**provide a health benefit beyond the traditional**
**nutrients it contains.  **

## Herbal and Botanical U.S. Consumer Sales ($mil)

- Sales (Million $)

- Nutrition Business Journal, Dec. 1999. Data for 1999 projected sales.

- *

## Functional Foods and Health

**	****Apples, Barley, Blackberry,  Blueberry, Carrots, Chili peppers, Currants,  Eggplant, Flax, Fish, Garlic, Ginger,  Ginseng, Mushrooms, Oats, Oranges, Onions, Plum, Strawberry, Soybeans, Tea**
**II.  Maintain Normal Drug Detoxification:****  **
**	****Apples,  Beets, Broccoli, Brussel Sprouts, Cabbage, Carrots, Cucumber, Garlic, Grapefruit, Lemons, Limes, Onions, Parsley, Peaches, Squash**** ****	**

**Functional Foods and Health**

## Functional Foods and Health

**III.  Anti-Inflammatory:****  **
**	****Ginseng, Licorice, Melon, Mushrooms, Parsley**
**IV.  Antibacterial/Antifungal**
**	****Chocolate, Garlic, Onions, Cranberry, Green tea, Black tea**
**V.   Block Cell Division:**** **
**	****Apples, Cucumber, Garlic, Lemons, Limes, Soybean**
**VI.  Anti-estrogenic:****  **
**	**** ****Anise, Carrots, Soybean, Fennel,**

## High intake of tomatoes and tomato products associated with a reduction in prostate cancer risk (Giovannucci, et al. JNCI 87: 1767, 1995).

## Chemoprotection by Cruciferous Vegetables

**Cohen et al. J. Natl. Cancer Inst.  92:61-68, 2000   Fruit and Vegetable Intakes and Prostate Cancer.**
**Olsen et al. Cancer Causes & Control 2: 291, 1991    In Asians , a diet high in crucifers protected against pancreatic cancer.**
**Lee et al. Int. J. Cancer 434:1007, 1989  In Asians, a diet high in crucifers protected against colorectal cancer.**

**Notes:**
Possibility of protection against cancer by fruits & veg is really, & specifically by cruciferous veg, is exciting.
Numerous expt and epi studies showing lower cancer rates in individuals eating diet high in fruits & veg generally, and cruciferous veg  in particular.
It would be fair to say that at the moment we know of a number of non-nutritive components in crucifers that protect rats & mice from chemical carcinogens.

## Broccoli Sprouts

**3 d old sprouts contain 10 to 100 times more glucoraphanin (the glucosinolate of sulforaphane) than do mature plants**
**Sprouts are more effect in reducing enzymes that older plants.**

- Fahey et al. PNAS 94:10367, 1997

## Isothiocyanates

**Formed in plants when glucosinolates are cleaved by myrosinase**
**Glucosinolates yield isothiocyanates, hydrogen sulfate, and glucose ****(****Zhang and Talalay, Cancer Res 54:1976S, 1994)**

## 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).**

## Personal Opinion

**The Science of Nutrition**
**Must move beyond observations to probing studies to determine who will benefit from dietary intervention and identify those individuals who might experience adverse consequences.**

## 1

## Folate in Nucleic Acid Metabolism

***Methylation***
*** ******of DNA/RNA***

- Methionine

- Proteins

- THF

- Homocysteine

- B6

***Purine Synthesis***

- DHF

***Thymidylate***
***Synthesis***

- Formyl
- THF

- Methylenyl
- THF

- Methylene
- THF

- Cystathionine

- Choline

- Betaine

- Dimethylglycine

- Methyl THF

*MTHFR*

## MTHFR Genotype

- Odds Ratio
- of Colorectal
- Cancer

- Folate
- Deficiency

- Ma et al. Cancer Res. 57: 1098, 1997.

## Soy and Cancer Risk

**17  of 26 animal studies reveal soy or soybean isoflavones reduce tumor tumor development**
**10 of 21 human epidemiological studies provide evidence of protection against cancer, especially rectal and stomach cancers (1 study found increase)**

## Potential Mechanisms for Soy isoflavones in Prostate Cancer

**Potential Mechanisms for Soy isoflavones in Prostate Cancer**

- Inhibition of TGFa/EFG-induced proliferation
- Inhibition of TNFa pathways
- Integrin-mediated pathways
- Effects on gene transcription
- Estrogen-mediated processes
- Effect on steroid biosynthesis
- Other targets yet to be discovered

## WARNING

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

## Flavanone

- Citrus

- Celery
- Parsley

- Soy Milk
- Tofu

- Broccoli
- Garlic
- Onions

- Blueberries
- Cherries
- Wine

**Flavone**

**Flavonol**

**Anthocyanin**

## Dietary Flavonoids and Infant Leukemia

- Risk of infant leukemia linked to MLL gene
- Some cancer patients treated with drugs that modify topoisomerase develop leukemia involving MLL gene.
- Several flavonoids found to cause change in MLL gene  on chromosome band 11q23
- Ross (2000) Proc. Natl Acad. Sci. 97: 4411-4413.
- Strick et al. (2000) Proc. Natl Acad. Sci. 97:4790-4795

## Slide 24

## Garlic Intake and 

**Gastric Cancer Mortality**

**Garlic Intake**

**Gastric Cancer Mortality**

**County**

**Gastric Cancer Mortality**

**        ****(per 100,000)**

**Garlic Intake (g/day)**

## Steinmetz et al. Amer. J. Epidemiology139:1, 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.”

## Garlic & N-Nitrosoproline Formation in Humans

- 0

- 20

- 40

- 60

- 80

- 1-3

- 4-6

- 6-9

- Experimental Period

- Nitrosopoline (ng)

- N=9 male subjects.  Day 1 - 3: Control period. Day 4 - 6: 300 mg NaNO3   + 500 mg proline , Day 7 - 9: 300 mg + 500 mg proline + 5 g garlic

- Mei, X., X. Lin, J.Z. Liu, X.Y. Lin, P.J. Song, J.F. Hu, and X.J. Liang (1989) The blocking effect of garlic on the formation of N-nitrosoproline in humans, Acta Nutrimenta Sinica, 11(2), 141-146.

## Garlic and Constituents Modify Chemical Carcinogenesis

**	****Carcinogen****	****	****	****	****	****Tumor Site**
**7,12 dimethylbenz(a)anthracene (DMBA)****	****	****Mammary**
**N-methyl-N-mitrosourea (NMU)****	****	****	****Mammary**
**Dimethylhydrazine (_x0008_DMH)****	****	****	****Colon****	**
**	****(PhIP)****	****	****	****	****	****	**
**Benzo[a]pyrene  (BP)****	****	****	****	****Lung**
**4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone**
**	****(NNK)****	****	****	****	****	****	****Lung**
**Aflatoxin B1  (AFL)****	****	****	****	****	****Liver**
**N-nitrosodiethylamine (ND_x0008_EA)****	****	****	****Liver**
**N-nitrosomethylbenzylamine****	****	****	****Esophagus****	****	**

## 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)**

**Control**

**Peel/**
**Crushed**

**30 seconds**

**60 seconds**

**Microwave/ Peel/**
**Crushed**

**a**

- Song and Milner** **J Nutr 1999;129:657-61

## “A token will get you on the subway, but garlic will get you a seat.”

**Old New York Yiddish Saying**

## Slide 31