Dietary Chemoprevention of Cancer

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Dietary Chemoprevention of Cancer

• June 27, 2007
• BYU Cancer Research Center Summer Fellows
• 2007 Workshop

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• The incidence of cancer among strict Mormons in
  Utah is only about half that among Americans in
  general.

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Factors contributing to death in the U.S.
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United States, MalesRates age-adjusted to the
U.S. 2000 population
From Jemal, A. et al. CA Cancer J Clin
20075743-66
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United States, FemalesRates age-adjusted to the
U.S. 2000 population
From Jemal, A. et al. CA Cancer J Clin
20075743-66
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United States 2007

• From Jemal, A. et al. CA Cancer J Clin
  20075743-66.

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The Nature of Cancer

• Underlying causes environmental
• DNA damage fundamental
• Occurs only in replicating cells - pattern
  different in children, adults

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Nutrients and cancer roles

• Possibly Protective
• Vitamins A, D, E, C, folate selenium,
  carotenoids, fiber, calcium, omega-3 fatty acids
• Possibly carcinogenic
• fats, alcohol, nitrites, nitrates, aflatoxin,
  benzopyrene

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Multistage process
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Diet and cancer

• Eliminate foods that cause cancer
• Increase consumption of foods that slow
  development of cancer (initiation, promotion,
  progression)
• Increase period of life thats cancer-free

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Human Carcinogenesis

• Exposure to agent
• Metabolism of agent
• Interaction between agent and cell constituent at
  risk (e.g. DNA) initiation
• DNA damage repair, cell death, or replication
• Growth to definable locus of cells promotion
• Growth and spread of tumor progression

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Exposure to Agents

• Tobacco, workplace, diet, alcohol, wider
  environment, viruses, bacteria - procarcinogens
• DNA damage by oxyradicals produced by normal
  metabolism

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Human Carcinogenesis

• Exposure to agent
• Metabolism of agent
• Interaction between agent and cell constituent at
  risk (e.g. DNA) initiation
• DNA damage repair, cell death, or replication
• Growth to definable locus of cells promotion
• Growth and spread of tumor progression

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Enzymes
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Phase I (P450s, mixed function oxidases)

• Phase I Reactions Addition or unmasking of a
  functional polar group. This typically results in
  a relatively small increase in hydrophilicity and
  may cause metabolic activation.
• Incorporate one atom of molecular oxygen into the
  substrate and one atom into water.
• NADPH H O2 RH gt NADP H2O R-OH

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Phase I polymorphisms and risk of lung cancer
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Phase II e.g. GST

• Conjugation with a small hydrophilic endogenous
  substance (e.g. GSH) - often, but not always, to
  a functional group provided by a Phase I reaction
  - thereby significantly increasing hydrophilicity
  and facilitating excretion.

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Role of food and nutrition

• block activation (Phase I)
• increase detoxification (Phase II)
• provide alternate targets

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• Induces Phase II
• Inhibits Phase 1
• Induce cell cycle arrest, apoptosis

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Human Carcinogenesis

• Exposure to agent
• Metabolism of agent
• Interaction between agent and cell constituent at
  risk (e.g. DNA) initiation
• DNA damage repair, cell death, or replication
• Growth to definable locus of cells promotion
• Growth and spread of tumor progression

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Initiation

• Mutations, deletions
• Genetic alteration
• somatic mutation
• DNA repair

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DNA Repair

• Heredity may determine efficiency
• Mutation -gt no mechanic
• Death of damaged cell - apoptosis
• Dietary effectors of apoptosis

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Apoptosis
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X-ray repair cross complementing group 1 (XRCC1)
protein is involved in the base-excision repair
pathway and plays a critical role in repairing
DNA base damage and DNA singlestrand breaks.
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Human Carcinogenesis

• Exposure to agent
• Metabolism of agent
• Interaction between agent and cell constituent at
  risk (e.g. DNA) initiation
• DNA damage repair, cell death, or replication
• Growth to definable locus of cells promotion
• Growth and spread of tumor progression

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Promotion (growth to definable locus of cells)

• Affect cell replication, growth
• Physical activity, energy intake, obesity,
  dietary factors - hormones, growth factors
• Carotenoids, retinol - redifferentiation
• Colon, fiber, volatile fatty acids - apoptosis
• Epigenetic mechanisms - affect behavior but not
  structure of DNA
• Hyper- or hypomethylation of gene - loss or gain
  of function

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Human Carcinogenesis

• Exposure to agent
• Metabolism of agent
• Interaction between agent and cell constituent at
  risk (e.g. DNA) initiation
• DNA damage repair, cell death, or replication
• Growth to definable locus of cells promotion
• Growth and spread of tumor progression

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Progression (growth and spread of tumor)

• Growth and expansion from focal lesion to
  invasive tumor mass
• Metastasis
• Fat, reactive oxygen species (ROS)

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Preventive mechanisms
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The Reductionist Approach

• Identify, isolate compound
• Test in cells
• Test in animals
• Proceed to clinical trials (Phase I, II, III)

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Grape seed extract a case study

• Grape seed extract (GSE) a complex mixture of
  polyphenols
• Which compound in GSE accounts for its
  anti-cancer efffects?

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Chemical constituents of GSE
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Fractionation
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Fractionation
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Fractionation
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14 Compounds isolated
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Effects on growth, death, apoptosis
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Effects in normal cells
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Mechanism pathway(s), intermediate(s)
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Mechanisms (cont.)

• Cultured cells (appropriateness?)
• Knockdown (siRNA) decreases effect
• Transfection increases effect

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Animal models - xenografts

• Human prostate cancer cells injected
  subcutaneously into nude mice
• Advantages
• Easy to measure tumor development
• Human, rather than mouse tumors
• Disadvantages
• Cant study immunostimulatory effects
• Cant study prevention

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Xenografts in nude mice
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Animal models Transgenic/K.O.

• Cancer-causing gene added, or tumor suppressor
  gene knocked out of mouse genome
• Advantages
• Allows study of chemoprevention
• Allows study of immunomodulation
• Disadvantage
• Tumor formation driven by one or limited nubmer
  of genetic events

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TRAMP Transgenic Adenocarcimoma of Mouse
Prostate
Probasin promoter
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The Reductionist Approach

• The more garlic people consume, the lower is
  their risk of colon cancer.
• Q What is it in garlic thats protective?
• Dissect garlic to identify individual chemical
  compounds.
• Test supplements of each compound individually
  for potency in chemoprevention

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Phytochemicals

• Isoflavones, phytoestrogens soy
• Catechins tea
• Sulfur compounds garlic
• Resveratrol red wine
• Flavonoids fruits and vegetables

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B-carotene, vitamin E and lung cancer

• Observation People with higher blood levels of
  B-carotene and vitamin E had lower rates of lung
  cancer
• Experiment Give smokers (people at high risk of
  lung cancer) B-carotene and vitamin E supplements
  to reduce their risk

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Results (NEJM 19943301029)
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Results (NEJM 19943301029)
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Food synergy (EB2002)

• Results with isolated compounds disappointing
• Chronic disease much more complex than deficiency
  disease
• Apples vitamin C 5.7 mg total antioxidant
  activity of apples 1500 mg vitamin C (Nature
  2000405903)
• Orange, apple, grape, blueberry combination has
  greater effect than sum of individual effects
• Soy concentrate genistein increased colon cancer

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aTwo arrows indicate more consistent evidence.
bCancers of the gastric cardia. cGIglycemic
index GLglycemic load. dEvidence for a
potential benefit from some components of fruits
and vegetables (not necessarily blanket effect).
eIncreased risk limited to smokers
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Breast Cancer

• Energy - rapid growth, obesity
• Alcohol
• Fat jury still out
• Fiber phytoestrogens, hormones
• Physical activity
• Vitamins/minerals

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Breast Cancer (cont.)

• Decrease risk
• Lower BMI
• High fiber
• Physical activity
• Low sex hormone levels
• High F/V intakes

• Increase risk
• Alcohol
• Obesity
• High sex hormone levels
• Dietary fat? jury still out

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Breast Cancer

• No association with fat intake in Nurses Health
  Study (Boston)
• Hunter et al. 1996 - lowest fat intake (lt 15
  kcal) increased RR for BRCA
• Post-menopausal BRCA related to adiposity (?
  circulating estrogen)

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Colon Cancer

• Fuchs 1999. Giovanucci 1994, Platz 1997 - no hint
  of fiber effect
• Two recent intervention trials (high fiber, low
  fat diet) - no effect on polyps
• Michels 2000 - no hint of Fr-Veg effect in
  health-conscious populations
• Terry 2001 Fr-Veg protective in populations
  with low intakes (especially fruits)
• Adiposity - 43 waist circumference ? RR 2.0
  (Giovanucci 1995)
• Calcium, folate may decrease risk

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Modifiable Risk Factors

• BMI lt 25
• Physical activity ? 30/d
• Alcohol lt 15 g/d
• Folate supplement ?100 ?g/d
• Smoking ? 3 pack-years
• Red meat ? 2 servings/wk
• Would eliminate 70 of colon cancer (Platz et al.
  2000)

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Colon Cancer - Tentative Summary

• Previous case-control studies subject to
  selection bias, recall bias
• Cancer clearly related to adiposity - energy
  balance most important
• Folate the most promising nutrient (at present)
  for further investigation
• mutation in THFR gene ? CaCo risk
• hi folate ? BRCA risk due to EtOH

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Prostate Cancer

• Nutritional Science Research Group, Division of
  Cancer Prevention, NCI
• Dietary fat
• Lycopene (tomatoes)
• Vitamin D and Calcium
• Selenium
• Vitamin E
• Soy products (isoflavones)

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Prostate cancer