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Chemoprevention 1

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Transcript

  • 1. Chemoprevention Against Environmental Carcinogens
  • 2. More than 1.2 million Americans develop cancer every year, and almost half of the die of the disease. How do we decrease the cancer death ?
    • Treatment and control
    • Early detection and diagnosis
    • Prevention
  • 3. Incidence Mortality (600,000 new cases) (280,000) From: Breast Cancer Prognosis, Treatment and Prevention Examples of incidence and mortality of various women’s cancers in the United States (in percentages). Values for 1990.
  • 4. What Causes Cancer?
    • Genes: < 10% of all cancers are the result of inherited gene mutations.
    • Tobacco use: 250,000 deaths per year in the U.S.
    • Infections/inflammatory disorders.
    • Diet: high intake of fats, sugars, and total calories.
  • 5. Proportional distribution of hereditary breast cancer. HNPCC includes MSH2, MLH1, PMS1, and PMS2 . Other single genes include TP53, PTEN, CHK2 , and STK11 , among others yet to be discovered.
  • 6. Hypothetical mechanism that can be involved in the effect of maternal and fetal factors on breast cancer risk in female offspring. E 2 : estradiol. (Modified from Hilakivi-Clarke et al., 1994)
  • 7. Cancer
  • 8. Antioxidants
    • Ascorbate
    • Vitamin E
    • Carotenoids
    • Glutathione: GSH
  • 9. Is Cancer Preventable?
  • 10.
    • The incidence of breast and prostate cancer is markedly higher in the Western world compared to Asian countries. Asian immigrants to the US who maintain an “Eastern” diet retain the lower rates of cancer development, while those who adopt a “Western” diet increase their cancer risk (WHO data as adapted by the American Cancer Society, 1992).
  • 11. Fruit and Vegetable Consumption and Cancer Risk (Ames and Gold, Drug Metabolism Reviews 30 :201-223, 1998) Fraction of studies showing cancer protection Relative risk Cancer 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
  • 12.
    • Diets rich in fruits and vegetables are associated with a reduced risk of most types of cancers.
    • Why?
  • 13.
    • Fruits, vegetables, and grains contain thousands of chemicals, called phytochemicals.
    • Do phytochemicals prevent cancer?
  • 14.
    • The inhibition, reversal, or retardation of carcinogenesis by the administration of natural or synthetic agents is termed
    • chemoprevention.
  • 15. Many phytochemicals are believed to affect every stage of the cancer process Chemopreventive Cancer Prevented Mechanisms Phytochemicals Source (animal models) of Action Alkyl sulfides and disulfides Allium Esophagus, Colon, Phase II, GST Sulfide volatiles Lung Allyl cystenes Monoterpenes Citrus Mammary, Pancreas, Phase II, GST, Lemonene Skin, Lung, Liver UDP-GT, Phase I Isothiocyanates Crucifers Liver, Lung, Phase II, GST Mammary Polyphenols Teas Colon, Lung, Phase II (GST, Epigallocatechin gallate Skin, Liver QR), Phase I, AP-1 Curcumin Turmeric Colon, Skin Phase II, GST, Cox II
  • 16. Mechanisms of Action of Phytochemicals in Cancer Prevention
        • Anti-oxidant
        • Anti-hormonal
        • Anti-angiogenic
        • Pro-apoptotic
        • Anti-proliferative
        • Anti-inflammatory
        • Immunomodulatory
  • 17. Chemoprevention Studies
    • Large-scale demonstration trials aim to establish definitively the efficacy and toxicity of potential chemopreventive agents in a healthy population of subjects with a high risk of cancer.
    • Small Phase I and II chemoprevention trials are conducted in individuals with premalignant lesions or cancer to investigate mechanisms of action, pharmacokinetics, pharmacodynamics, and modulation of biomarkers.
  • 18. Lung Cancer Chemoprevention Trials
    • Patients End Trial (n) Population Compounds Result
    • Physician’s Health Study Male  -carotene (Hennekens, 1996) 22,071 physicians Aspirin N.B. ATBC Study, 1994 29,133 M. smokers  -tocopherol Negative  -carotene
    • CARET, 1996 18,314 Smokers  -carotene Negative Asbestos Retinyl Palmitate
    • Kurie, 2000 82 Smokers 4-HPR N.B.
    • Intergroup Study, 2001 1,166 Prior Stage 1 Isotretinoin N.B. NSCLC
    • Pastorino, 1993 307 PS 1, NSCLC Retinyl Palm. N.B.
    CA Cancer J. Clin. 54:2004. N.B.: No benefit or harm
  • 19. Colorectal Chemoprevention Trials
    • Patients End Trial (n) Population Compounds Result
    • ATBC Study, 2000 29,133 M. smokers  -tocopherol N.B.  -carotene
    • Physician’s Health, 1996 22,071 M. physicians  -carotene N.B.
    • Giardiello, 1993 22 FAP Sulindac Positive (150 mg 2/day)
    • Steinback, 2000 77 FAP Celecoxib Positive (100 or 400 mg)
    • Aspirin/Folate Polyp, 2003 1,121 Prior Aspirin (81–325 mg) Positive carcinoma Folate (1 mg)
    • The Polyp Prevention, 2000 2,079 Prior Fiber N.B. adenoma (18 g/1000 kcal)
    • The Calcium Polyp, 1999 930 Prior adeno Calcium Positive recurrence carbonate (3 mg)
    • Cascinu, 2000 90 Prior Duke’s Vit. A (30,000) B-C cancer Vit. C (1 gm) N.B. Vit. E (70 mg)
    CA Cancer J. Clin. 54:2004. N.B.: No benefit or harm
  • 20. Selected Breast Cancer Chemoprevention Trials
    • Patients End Trial (n) Population Compounds Result
    • Dunn, 2000 13,388 Healthy + risk Tamoxifen (20 mg) Positive for Dunn, 2001 factors ER+ tumors
    • Royal Marsten 2,494 Healthy volunteers Tamoxifen (20 mg) N.B. Hospital, 1998
    • Italian Trial, 1998 5,408 Healthy with prior Tamoxifen (20 mg) Positive hysterectomies
    • International 7,152 Healthy with Tamoxifen (20 mg) Positive Intervention, 2002 increased risk
    • Raloxifene 7,705 Postmenopausal w/ Raloxifene (60 mg) Positive Trial, 2001 osteoporosis
    • Veronesi, 1999 2,972 Stage 1 or DCIS 4-HPR (200 mg) N.B.
    • Arimidex/ 9,366 Postmenopausal, Anastrozole (1 mg) Positive Tam. 2003 prior breast cancer
    • Goss, 2003 5,187 Postmenopausal Letrozole (2.5 mg) Positive Prior tam. 5 yr.
    CA Cancer J. Clin. 54:2004. N.B.: No benefit or harm
  • 21. Carcinogenesis TCDD Gene Mutation Proto-oncogene Tumor Suppressor Angiogenesis Program Cell Death DNA Damage Normal Cells Promotion Mutant Cells Progression Benign Tumors Malignant Tumors Initiation BP DMBA Chemopreventive Agents X Phase I + Phase II –
  • 22. Cellular Defense and Carcinogenesis Section Curcumin, DBM Resveratrol Diosmetin, Diosmin Galangin Kaempferol, Quercetin