Relationship of Nutrition to Cancer Prevention and Treatment Northwestern

Relationship of Nutrition to Cancer Prevention and Treatment Arline McDonald, Ph.D Department of Preventive Medicine September 25, 2001 9/25/01 Nutrition 1 Proportion of Cancer Deaths Attributable to Various Factors (Doll and Peto, 1981) Factor Tobacco Alcohol Diet Best Estimate 30 3 35 Range of Acceptable Estimates 25-40 2-4 10-70 Food Additives Reproductive/Sexual Behavior Occupation Pollution 1 7 4 2 (-5**)-2 1-13 2-8 1-5 Industrial Products Medicines/Medical Products Geophysical Factors Infection 9/25/01 1 1 3 10 Nutrition 1-2 0.5-3 2-4 1-? 2 Worldwide Cancer Data in 2000 25 20 Millions 15 10 5 0 Mortality Incidence Prevalence U.S. 9/25/01 Nutrition 3 Impact of Nutrition on Cancer Mortality  Prevention   Treatment     balanced intake of nutrients sufficient intake of non-nutrient factors appropriate preparation methods adequate storage conditions mitigate dose-limiting complications        mucositis diarrhea myalgia, arthralgia premature CHD peripheral neuropathy neurovascular damage radiation enteritis  9/25/01 Nutrition synergistic effects 4 Cancer Continuum Nerve damage, pulmonary diffusion capacity, hypertension, CHD, hi freq hearing loss Death from Cancer Therapy Diagnosis Survivorship Begins 9/25/01 Post Therapy Long-term Survival Death from Other Causes Nutrition 5 Goals of Cancer Survivors  Reduce risk of recurrence  apply preventive approaches insure sufficient intakes of immunosupportive micronutrients prevent weight loss (energy) preserve lean body mass (energy and protein) preserve lean body mass (energy and protein) adequate intake of iron, copper, magnesium, B-vitamins Nutrition 6  Rebuild and improve immune system     Eliminate debilitating fatigue   9/25/01 Evidence-based relationship established between diet and cancer Epidemiology • inverse relationship with fruit & vegetable intake • incidence of site specific tumors varied with diet Animal Studies • compelling but not generalizeable Clinical Studies • mainly retrospective • used supplements • equivocal findings Cell Lines • elucidation of mechanisms • evaluate genetic interactions Molecular Biology • confirmation of mechanisms • demonstration of gene binding Nutrition 7 Randomized Clinical Trials • large prospective underway • biomarkers as endpoints 9/25/01 Epidemiologic Data on Fruit and Vegetable Intake and Cancer By Site Site All Lung Oral Cavity Esophagus Stomach Colorectal Bladder Pancreas Cervix Ovary Breast Prostate 9/25/01 No. of Studies 170 25 13 16 19 27 5 11 8 4 14 14 Nutrition Protective (p < 0.05) 132 24 13 15 17 20 3 9 7 3 8 4 Harmful (p < 0.05) 6 0 0 0 1 3 0 0 0 0 0 2 8 Dietary Factors Associated with Reduced Cancer Risk  Dietary fiber   colorectal, pancreas, breast cervix, colorectal colorectal, breast  Vitamin C from foods   Folic acid  oral cavity, esophagus, lung, stomach, pancreas, cervix lung, colorectal lung  Vitamin D and calcium  Tea (flavonoids)   Antioxidants (nutrient and non-nutrient) from foods   Alpha-tocopherol  colorectal, lung, breast, cervix, prostate, esophagus, stomach Nutrition  Soy isoflavones?  breast 9/25/01 9 Dietary Factors Inversely Related to Cancer Risk  Alcohol    mouth, pharnyx, larnyx, esophagus, liverconvincing breast, colon, rectumprobable stomach- probable Meat (especially charbroiled)  colon and rectumprobable  Total and Saturated Fat   Salt  lung, colon, rectum, breast, prostate- possible  Sucrose  colon, rectum 9/25/01 Nutrition 10 Chemopreventive Non-nutritive Dietary Factors Compound Cinnamic acid Flavonoids (catechins, quercitin, isoflavones, anthocyanins) Indoles Isothiocyanates Lignans Organosulfur Terpenes 9/25/01 Food Source Fruit, vegetables, coffee beans vegetables, fruit, citrus fruit, celery, parsley,onions, grains, tea, soybean Cruciferous vegetables Cruciferous vegetables Whole grains, flax Garlic, Onion Citrus, spices Nutrition 11 Role of Dietary Factors in Carcinogenesis Exposure to Carcinogen Inhibitors of Activation DNA Binding Blocking Agents Reaction with Cellular Targets DNA Damage, Mutagenesis Suppressing Agents Neoplastic Manifestation 9/25/01 Nutrition 12 Inhibitors of Activation  Inducers of Phase I Biotransformation Enzymes   cytochrome P450 mono-oxygenase system converts hydrophobic to hydrophilic compounds for elimination by forming reactive intermediate 9/25/01 Nutrition 13 Phase I Activation and Phase II Detoxification Reactions Bioactivation Detoxification Primary Secondary Carcinogen Phase I Metabolite Phase II Metabolite Reactive Intermediate Covalent Binding Excretion Acute Cellular Injury 9/25/01 Delayed Toxicity Nutrition Mutations & Cancer 14 Blocking Agents  Inducers of Phase II Detoxification Enzymes    glutathione S-transferases, sulfotransferases, UDP-gluronosyltransferases phenols, isothiocyanates, flavones, and coumarins affect gene expression at transcriptional level antioxidants  Binders of free radical intermediates  9/25/01 Nutrition 15 Suppressing Agents  Inhibit development of cancer subsequent to administration of carcinogen     retinoids and carotenoids protease inhibitors phenols and polyphenols selenium  Antioxidant protection 9/25/01 Nutrition 16 Role of Antioxidants in Carcinogenesis Normal cell Cell repair Exposure of DNA Cell Death Lipid Peroxides Lipid peroxidation in cell membranes Reactive O2 + O2-Derived Free Radicals Compensatory Cellular Hypoproliferation Antioxidant Oxidized bases Scavengers & in DNA Enzyme Systems Mutations DNA Repair Normal Cell Cell Death No Repair Less regulation of cell growth & differentiation Cell Hyperproliferation Exposure of DNA 9/25/01 Nutrition Further Mutations 17 Antioxidant Protection Cellular Antioxidants Enzyme Systems Minerals Catalase Peroxidase Glutathione Peroxidase Superoxide Dismutase Membrane Lipid Protection Scavengers Vitamins Aqueous Comptmts Lipid Comptmts Fe Se, AA Cu/Mn E CoQ10 C Carotenoids Polyphenols Isothiocyanates 9/25/01 Non-nutrient Plant Chemicals Nutrition 18 Other Protective Effects: Folic Acid  Thymidine synthesis inhibited  lack of methyl donor from methylene-THF4 or S-adenosyl-methionine     DNA hypomethylation Uracil misincorporation DNA repair by excision Increase in fragile sites & chromosomal breaks Nutrition 19 9/25/01 Folate Deficiency and DNA Stability DNA TMP CH3 X dUMP U A Chromosomal damage double strand break 9/25/01 single strand break Nutrition DNA repair removes misincorporated uracil 20 Other Protective Effects: Moderators of Insulin Sensitivity and Resistance  Moderators of insulin and insulin-like growth factor (IGF-1)   IGF-1 protects against apoptosis insulin and IGF-1 increase aberrant crypt foci growth  precursor of colorectal tumors  Insulin resistance associated with increased tumor promotion in animal models (r=0.67) 9/25/01 Nutrition 21 Insulin Resistance and Relative Risk of Colon Cancer Dietary Glycemic Index Low 1.0 1.6 1.5 Medium 1.3 1.8 1.9 High 1.4 2.1 3.5 Physical Activity High Medium Low 9/25/01 Nutrition 22 Other Protective Effects  Inhibitors of invasive processes  Stimulate plasminogen activator inhibitors   reduces plasmin-stimulated degradation of extracellular membrane dietary fiber, low glycemic index sugars 9/25/01 Nutrition 23