The Challenge of Cancer Chemoprevention Research In South Carolina

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The Challenge of Cancer ChemopreventionResearch
In South Carolina

• Michael J. Wargovich, Ph.D.
• Professor and Director
• Chemoprevention Program,
• South Carolina Cancer Center
• University of South Carolina School of Medicine

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In 2006 the American Cancer Society Estimated
That

• 1,399,970 Americans will learn that they have
  cancer including 21,500 in South Carolina
• 564, 830 Americans will lose their lives to
  cancer including 8,860 in South Carolina
• In South Carolina, risk for cancer is higher than
  the national average

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Incidence of All Cancers in SC 1996-2001
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What Is Chemoprevention?

• The science of trying to apply natural and
  synthetic compounds to interfere with the
  earliest stages of carcinogenesis, before
  invasive cancer appears

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The Ideal Chemopreventive Agent

• Is effective
• Easily administered
• Preferably once/twice day
• Little or ideally no toxicity
• Affordable

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Mechanisms of Chemoprevention

• Antioxidants defense against radicals
• Phase 1 enzyme inducers
• Phase 2 enzyme inducers
• Anti-proliferative agents
• Anti-hormonal compounds
• Disruption of mutational gain or loss of function

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Fruit and Vegetable Consumption and Cancer Risk
Fraction of studies showing cancer
protection Relative riskCancer site (p lt
.05) (low vs. high quartile) Epithelial Pancreas
9/11 2.8 Stomach 17/19 2.5 Lung 24/25 2.
2 Esophagus 15/16 2.0 Cervix 7/8 2.0 Color
ectal 20/35 1.9 Hormone Dependent Ovary/endomet
rium 3/4 1.8 Breast 8/14 1.3 Prostate
4/14 1.3
(Ames and Gold, Drug Metabolism Reviews
30201-223, 1998)
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Surh et al Nat Reviews 32003
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Antioxidants

• Oxygen is actually a very toxic substance
• Antioxidants are the first line defense mechanism
  against oxidative damage in plants
• Fruits and vegetables are loaded with antioxidant
  chemicals

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Smoking and Oxidative Damage

• Smokers have 50 more damaged DNA bases in their
  urine than non-smokers
• ß carotene tablets do not reduce this damage
• Eating 300g of Brussels sprouts does markedly
  reduce DNA damage

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Green Tea
Camellia sinensis

• Epidemiologic studies support a protective effect
  for green tea but not black tea in prevention of
  several cancers
• Animal studies are highly supportive of a
  preventive effect of green tea, GTP, and purified
  polyphenols, especially EGCG against several
  cancers

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Evidence for Tea Drinking and Prevention of
Colorectal Cancer

• Ecological Studies
• Cohort Studies
• Case-Control Studies

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Bioflavonoids

• Naturally occurring chemicals present in many
  fruits and vegetables
• Major flavonoids in onion are quercetin and its
  glycoside, rutin
• Can reach appreciable levels in onions but tea
  also is a major source

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Inhibitory Effect of EGCG on COX-2 expression
EGCG
COX-2 protein
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Effect of EGCG on MAPKs and PI3K pathways
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Intestinal Medium RXR alpha negative Foci
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Methylation of RXRa gene
DNA Methyltransferase
RXRa
APC Protein
Accumulation of ß-Catenin in the cytoplasm then
its nuclear translocation
Activation of down stream targets Such as cyclin
D1 and c-myc
Uncontrolled cell proliferation
Tumor Formation