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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
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
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
The Ideal Chemopreventive Agent • Is effective • Easily administered • Preferably once/twice day • Little or ideally no toxicity • Affordable
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
Fruit and Vegetable Consumption and Cancer Risk Fraction of studies showing cancer protection Relative riskCancer site (p < .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 Colorectal 20/35 1.9 Hormone Dependent Ovary/endometrium 3/4 1.8 Breast 8/14 1.3 Prostate 4/14 1.3 (Ames and Gold, Drug Metabolism Reviews30:201-223, 1998)
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
Smoking and Oxidative Damage • Smokers have 50% more damaged DNA bases in their urine than non-smokers • βcarotene tablets do not reduce this damage • Eating 300g of Brussels sprouts does markedly reduce DNA damage
Green Tea • 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 Camellia sinensis
Evidence for Tea Drinking and Prevention of Colorectal Cancer • Ecological Studies • Cohort Studies • Case-Control Studies
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
EGCG 0 10 50 125 200 250 0 10 50 125 200 250 (M) Western Blot Analysis COX-2 (72 kDa) -actin (47 kDa) 1.00 0.87 0.93 0.54 0.43 0.86 1.00 0.80 0.95 0.70 0.56 0.37 HT-29 HCA-7 Inhibitory Effect of EGCG on COX-2 expression EGCG COX-2 protein
Dose: 0 10 50 125 200 250 (M) Phospho-ERK1/2 Decrease of ERK activation 44kDa 42kDa ERK1/2 Phospho- p38 Increase of p38 activation 43kDa p38 Phospho- Akt Decrease of Akt activation 60kDa Akt Effect of EGCG on MAPKs and PI3K pathways
Methylation of RXRα gene DNA Methyltransferase RXRα APC Protein Accumulation of β-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