STRAGIC PLANNING IN CANCER PREVENTIONMitchell Gaynor, MDFounder and President,Gaynor Integrative Oncology(www.gaynoroncology.com)Assistant Clinical Professor of Medicine,Weill-Cornell Medical College
To waste, to destroy our natural resources, toskin and exhaust the land instead of using itso as to increase its usefulness, will result inundermining in the days of our children thevery prosperity which we ought by right tohand down to them amplified and developed.— Theodore Roosevelt
EPIC : DIET AND CANCERPreliminary results:May,2004• The European Prospective Investigation intoCancer and Nutrition (EPIC) :The studyregistered 519, 978 participants between 1992and 2000 in 10 European countries. Cancerincidence and cause-specific mortality to bef/u for several decades.• “Diet is the second leading cause (25%) ofall cancers”
Cancer Incidence Americans had a 132% increase inmelanoma, the deadliest skin cancerbetween 1979 - 1998 In New York State – Rates of non-Hodgkinslymphoma increased 76% for males and 49%for females between 1975 - 1994 In the US, incidence of lymphomahas tripled since 1950 Cancer is the leading cause of disease-related deaths inchildren under the age of 15 and about one-third ofchildhood cancers are leukemia
PBDEs(polychlorinated biphenyl ethers) Ethers that are used as flame retardants Levels in harbor seals increased 100 foldbetween 1989 and 1998 Levels in human tissue in US were 10-40 times ashigh as levels reported in earlier Swedish study Levels of PBDEs are now doubling every 5yearsSan Francisco Bay Area – Breast tissue samples of womenshowed highest levels in the world, up to 25 x greater thanEuropean samplesPetreas, Myrto et.al. Env. Health Perspective, Vol 3, No. 9, July 2003
Solvents Chlorox (chlorine bleach), Freon (CFC) are examples of the30,000 branded solvents available to households andindustry Uses: thinning paint, glues, washing electronics, drycleaning fabrics Most used trichloroethylene and methylene chloride 1.5 billion pounds produced yearly in US Only 1% are reused or recycled 94% released into environment – mostly air Many tied to cancer, birth defects, liver andkidney damage
Bisphenol A• ubiquitous polymer found in many everyday products that we use.• also found in breast milk, placental tissue, fetuses• Potential neurotoxicity due to pre-and perinatal exposure to BPA.• lactating rats exposed to low levels bisphenol A (BPA) had offspring with a higher risk of developingmammary cancers (Jenkins S, Raghuraman N, Eltoum I, Carpenter M, Russo J, Lamartiniere CA. Oral exposure to bisphenol A increasesdimethylbenzanthracene-induced mammary cancer in rats. Environmental Health Perspectives. 2009;117(6):910.• A single exposure of BPA in mice during brain development disrupts spontaneous behavior andcognitive function (Viberg H, Fredriksson A, Buratovic S, Eriksson P. Dose-dependent behavioral disturbances after a single neonatal Bisphenol A dose.Toxicology. 2011.BPA is found in paper and paper products such as newspapers, napkins, printer paper, toiletpaper, and receiptsStudy evaluated over 200 paper samples from 15 different sources of paper products and reportedthat BPA levels in paper and paper products were 100 to 1 million times greater than the amountsdetected in canned and packaged food products Liao C, Kannan K. Widespread Occurrence of Bisphenol A in Paper and PaperProducts: Implications for Human Exposure. Environmental Science & Technology. 2011/11/01 2011;45(21):9372-9379.• Most absorb only a fraction of BPA through skin than from foods and beverages• Amounts of BPA may be significantly higher for cashiers or printers (contact with more with BPA-contaminated products)
What Are the Major Concerns When aToxic Disaster Happens• What You Can Do to Protect Your Community• Water, air, and soil are contaminated• PCBs become dioxins and furans when incinerated, which means there’san increased risk of developing cancer• Fetuses and children exposed to dioxins and furans are at risk for learningdisabilities and developmental disorders (e.g., ADHD and autism)• Find and join your local environmental organization to stay informedcompanies that handle toxic chemicals and wastes in your area• Elect government officials in your community who have acted in supportof environmental protection• Start a petition, hold community board meetings, call on local officials toraise awareness in your community
DETOXIFYING ENZYMES and BREASTCANCER• JOHNS HOPKINS UNIVERSITY STUDY– Compared genetic detoxifying enzyme ability of110 patients with breast cancer vs. 113 controls– Abnormal glutathione-S-transferase genes causingdecreased enzyme activity resulted in a fourfoldincreased risk of breast cancer(Helzlsouer, K. et al., J. Nat. Can. Inst. 1998)
CT Scan Hazards• Researchers in Great Britain• Evaluated the records of patients with any cancerdiagnosis.• Those younger than 22 y.o. -correlation betweenleukemia and brain tumors with radiation dosefrom CT scans.• dose of 50mGy or 60 mGy (mGy is a measure ofabsorbed radiation dose) associated with 3X riskdeveloping leukemia or brain cancer.• Pearce MS, Salotti JA, Little MP, et al. Radiation exposure from CT scans in childhoodand subsequent risk of leukaemia and brain tumours: a retrospective cohort study. TheLancet. 2012;380(9840):499-505.
OBESITY VS. DETOXIFICATION•Fat production or fatty acid synthesis depletesstores of NADPH, which is the body’s ultimatereducing (antioxidant) agent.•NADPH stores are required for theregeneration of antioxidants (ARE) andglutathione.
Hyperglycemia andCancer MortalityElevated fasting serum glucose levelswere associated with a 27% increase incancer mortality among men and a 31%increase among women.JAMA January 12, 2005 - Vol 293, No 2
NEJM Twin Study Identical twins developed same diseaseonly 10% of the time Both develop either breast, colonor prostate cancer 14 – 30% ofthe timeNew England Journal of Medicine, 2000
Cancer-causing cellular changesHow it Leads to Cancer Development• DNA damage• DNA damage leads to ineffective cellular replication and uninhibited cellular proliferation is ahallmark of cancer cells.• Inflammation• Chronic inflammation --associated with pro-inflammatory molecules (e.g. cytokines) thatdamages tissues --lead to interrupted communication between cells that prevent normal cell-to-cell interactions.• Loss of Apoptosis - cells grow uncontrollably• Invasiveness of cancerous tissue into healthy tissues through the use of tendrils• Abnormal Angiogenesis• Blood vessels supply normal tissues with nutrients, and cancer tissue also needvascularization in order to survive and grow. Angiogenesis is the process in which new bloodvessels are formed, and in cancer cells these vessels form spontaneously to aid in the growthof tumors.• Metastasis• Spread to other tissues in a process called metastasis, which is a defining characteristic ofmalignancy.
Omega 3 and Barret’s• Can an omega-3 fatty acid fish oil supplement increase tissue levelsin humans? Can the supplements actually suppress theinflammatory COX-2 enzyme in humans?• Patients with Barrett’s esophagus.• Half of the patients were given 1500 mg of the omega-3 (EPA)supplement, and the other half were not• EPA-treated group had higher omega-3 fatty acid in their cells, andthe COX-2 protein was significantly decreased in the tissues of theomega-3 supplemented group.•• Mehta SP, Boddy AP, Cook J, et al. Effect of n–3 polyunsaturatedfatty acids on Barretts epithelium in the human lower esophagus.The American Journal of Clinical Nutrition. 2008;87(4):949-956.
Metformin• Shown to reduce the risk of breast and colorectalcancers in type II diabetics.• Why are researchers interested in metformin?• To target (activate) AMPK, which is an enzyme thatpromotes the uptake of glucose by muscle tissue.• Also plays vital role in cancer prevention because anenzyme called LKB1 (a tumor suppressor) is increasedby activation of AMPK.• Diego E-P. Metformin May Lower Cancer Risk in People with Type 2 Diabetes. 2012;http://www.sciencenewsline.com/articles/2012062523160029.html. Accessed July 18, 2012.Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk ofcancer in diabetic patients. Bmj. 2005;330(7503):1304-1305.
Broccoli and Prostate Cancer• Volunteers were randomly assigned to either a broccoli-rich or a pea-rich diet.• After six months• no differences in gene expression between glutathione S-transferase mu 1 (GSTM1) positiveand null individuals on the pea-rich diet but significant differences between GSTM1genotypes on the broccoli-rich diet, associated with transforming growth factor beta 1(TGFβ1) and epidermal growth factor (EGF) signalling pathways.• Comparison of biopsies obtained pre and post intervention revealed more changes in geneexpression occurred in individuals on a broccoli-rich diet than in those on a pea-rich diet.• men on the broccoli diet had additional changes to mRNA processing, and TGFβ1, EGF andinsulin signalling.• sulforaphane chemically interacts with TGFβ1, EGF and insulin peptides to form thioureas• This study provides, for the first time, experimental evidence obtained in humans to supportobservational studies that diets rich in cruciferous vegetables may reduce the risk of prostatecancer and other chronic disease.• Traka M, Gasper AV, Melchini A, et al. Broccoli consumption interacts with GSTM1 to perturb oncogenic signallingpathways in the prostate. PLoS ONE. 2008;3(7):e2568.
Green Tea and Prostate Cancer• Bertuzzi,S AACR 2005(abstract)• 30 men with high grade PIN• Randomized Control vs 600 mg/d green tea catechins• Bx done at 0 and 12 mo• 9 cases prostate CA control and 1 in Rx group at 1year• The 30% incidence at 1 year is c/w literature• No adverse effects in Rx group
LIFESTYLE CHANGE-A NEW PROSTATECANCER RX ?• 93 men with biopsy proven prostate CA• Gleason’s score< 7• All elected to forego conventional RX• Randomized:• Vegan diet, exercise, yoga/meditation vs.control group• After 1 year PSA decreased in LS group butincrease in control (J.Urol)2005.174(3)
Broccoli-prostate cancer prevention.Ecogenetic Implications• Volunteers were randomly assigned to either abroccoli-rich or a pea-rich diet.• given broccoli or peas in addition to their normaldiet for over a year.• tissue samples obtained before during and afterthe trial were examined.• gene expression associated with a lower risk forprostate cancer development was highlyassociated with men who ate a broccoli rich diet.• Traka M, Gasper AV, Melchini A, et al. Broccoli consumption interacts with GSTM1 to perturb oncogenic signallingpathways in the prostate. PLoS ONE. 2008;3(7):e2568.
Mature analysis from Women’sIntervention Study (WINS)• Chlebowski,RT,et al SABCS 2006 Gen.Session5:Abst 32 and JNCI Dec.2006• 2400 women with early breast cancer atUCLA: randomized prospective trial--low fat(less than 20% cal. from fat) vs. control• At 5.8 yrs; 22% fewer deaths- low fat diet• Those with ER-/PR- there was a 66% reductionin mortality
Fasting Insulin and Outcome in Early-Stage BreastCancer: Results of a Prospective Cohort StudyPurpose: Insulin, a member of a family of growthfactors that includes insulin-like growth factor (IGF)-I andIGF-II, exerts mitogenic effects on normal and malignantbreast epithelial cells, acting via insulin and IGF-I receptors.Because of this and because of its recognized associationwith obesity, an adverse prognostic factor in breastcancer, we examined the prognostic associations of insulinin early-stage breast cancer.J Clin Oncol 20(1):42-51, January 1, 2002
Fasting Insulin and Outcome in Early-Stage BreastCancer: Results of a Prospective Cohort StudyHigh levels of fasting insulin identify womenwith poor outcomes in whom more effectivetreatment strategies should be explored.J Clin Oncol 20(1);42-51, January 1, 2002
VITAMIN D AND BREAST CANCERGarland,Cedric et al.(UCSD) AACR 2006Meta-analysis 1,760 women- 25-OH Vit. D levelsMultiple regression analysis: D3 level>52ng/ml assocwith 50% lower risk breast CA compared withlevels<12 ng/ml.Previous study (Prev Med 1990:19:614-22):Demonstrated women living closer to theequator, had significantly lower risk of breast cancerdeath
Deficiency of Vitamin D, a Membrane BoundAntioxidant, Linked to Poorer outcome in BreastCancer• Vitamin D receptors found in breast cancercell nuclei• Effects: slow cell growth, induces apoptosoisand differentiation• 37.5% had levels < 50 (deficient), 38% 50-71(insufficient), 24%>72(sufficient)• Median f/u 11.6 years-Deficient patents 94%>chance mets and 73%.chance of death thanpatients with levels over 50.
Obesity /Survival /Ovarian Cancer-Pavelka et al., Cancer (Published Online): 28 August 2006●Evaluated association of of excess body weight onovarian cancer survival●For patients with advanced stage disease, obesity wasindependently associated with both shorter time torecurrence and shorter overall survival. Findings suggestadverse effect of excess body weight on tumor biology.
SOY ISOFLAVONES AND BREASTPROLIFERATION• Palomares,M San Antonio Breast Cancer Symposium(2005)(Poster)• 23 postmenopausal breast cancer (Stage I, II, DCIS) patients atCity of Hope National Medical Center• Randomized:Isoflavone tab 100mg/d vs.placebo for 1 year• Bx contralat. breast at 0, 6, and 12 mo:Ki67 index decreasedfrom baseline in Rx group by 3.1% vs.0.9% control (6 mo.) and4.9% vs.4.1% (12 mo.) “Our findings suggest no negativeeffects of soy and perhaps even a beneficial effect”
NF kappa-B Inhibitors• Turmeric has been found to suppress the growth of many tumor cell linesand causes regression of some precancerous lesions in humans.• Nuclear factor-kappaB (NF-kB) proteins control inflammatory andimmune responses and are involved in cancer-related inflammation.Studies show that curcumin blocks NF-kB.• A major promoter of lung cancer is NF kappa B• Transcription turned off by:• turmeric (curcumin)• kaempferol [found in teas and broccoli]• procyanadins [grapes]• sulforaphane [Brussels sprouts])Bachmeier BE, Killian P, Pfeffer U, Nerlich AG. Novel aspects for the application of Curcumin in chemoprevention of variouscancers. Frontiers in bioscience (Scholar edition). 2010;2:697.• Sikora E, Bielak-Zmijewska A, Mosieniak G, Piwocka K. The promise of slow down ageing may come from curcumin. Currentpharmaceutical design. 2010;16(7):884-892.
NF Kappa B and AP 1•Transcription factors produced in excess by cancer cells•Stimulate cancer cell proliferation•Inhibit apoptosis•Enhance inflammation•Increased NF Kappa B activity in cancer cells is associated with poorerprognosis, invasiveness and metastasis(Nakshatri H, et al. Mol Cell Biol 1997 Jul; 17(7): 3629-39Bours V, et al. Biochem Pharmacol 1994 Jan 13; 47(1): 145-9)
Honey• Medicinal properties— antioxidant, anti-inflammatory, antimicrobial, and antithrombotic• Darker –colored honeys - more antioxidants thanlighter colored honeys• Contains:• Chrysin blocks the formation of estrogens fromandrogens in the body.• Galangin inhibits growth of breast cancer andleukemic cells• Mutation Research/Reviews in Mutation Research• Volume 488, Issue 2, May 2001, Pages 135–150
Selenium• Selenium supplementation (200 mcg/d) didnot affect primary endpoint of study, skincancer; but prostate cancer decreased by justover 50% and colorectal cancer by62%.(Clark, LC, et al, JAMA 1996; 276: 1957-63)• National and international correlations oflower blood selenium with higher rates ofcancers.
Whole-grains and Cancer● Fermented in the colon---1)Yields short-chain fattyacids(SCFA) 2) SCFAs associated with reduced CRP 3)provides immune protection by supporting GALT.● Improve insulin and glucose responses.● Bioflavonoids, phytates, lignans, stanols and sterols, B-vitamins and minerals.– Ajani et al., J Nutr. 2004 May;134(5):1181-5
FISH OIL• Reduced risk of cancer• EPA and DHA reduced the risk of further breast cancer events by 25%among women with a history a breast cancer• Consumption of 4000 milligrams of EPA supplements daily: reduces DNAdamage from UV light and increases the threshold in which skin burns dueto exposure of UV light by 36%--reduced the risk of skin cancer• Risk of colon cancer –Subjects taking 2000 mg of EPA daily• The consumption of 1000 mg of EPA and 1835 mg of DHA fish oil takenbefore radical prostate surgery- reduction in cancer cell proliferation inprostate tissue• Patterson RE, Flatt SW, Newman VA, et al. Marine fatty acid intake is associated with Breast cancer prognosis. The Journal of nutrition.2011;141(2):201-206.• Rhodes LE, Shahbakhti H, Azurdia RM, et al. Effect of eicosapentaenoic acid, an omega-3 polyunsaturated fatty acid, on UVR-related cancer risk inhumans. An assessment of early genotoxic markers. Carcinogenesis. 2003;24(5):919-925.• Courtney E, Matthews S, Finlayson C, et al. Eicosapentaenoic acid (EPA) reduces crypt cell proliferation and increases apoptosis in normal colonicmucosa in subjects with a history of colorectal adenomas. International journal of colorectal disease. 2007;22(7):765-776.• Aronson WJ, Kobayashi N, Barnard RJ, et al. Phase II Prospective Randomized Trial of a Low-Fat Diet with Fish Oil Supplementation in MenUndergoing Radical Prostatectomy. Cancer Prevention Research. 2011;4(12):2062-2071.
Curcumin-Induced Antiproliferative andProapoptotic Effects in Melanoma Cells AreAssociated with Suppression of Nuclear Factor KBNF-kappaB plays a key role in cell survival and proliferation in humanmelanomaEvaluated NF-kappaB inhibition for melanoma treatment.Curcumin, an agent with known, potent, NF-kappaB- inhibitory activity andlittle toxicity in humans demonstrated antiproliferative and apoptosisenhancing effects in melanoma cells.Cancer 2005 Aug 15;104(4)879-90
Are we born with our geneticdestiny or can it be changed?Agouti mice-- epigenetic changescarried across generations(Waterland and Jirtle, Mol.Cell.Biol.23:5293-5300, 2003) (Env.Health Perspect 2006 April,114(4)567-572)Nutritional genomics vs.toxicogenomicsEpigenetics :DNA methylationand histone modification
Epigenetic Effect of Targeted NutrientsFolic Acid Leafy vegetables, sunflower seeds,bakers yeast, liverMethionine synthesisVitamin B12 Meat, liver, shellfish, milk Methionine synthesisVitamin B6 Meats, whole grain products,vegetables, nutsMethionine synthesisSAM-e (SAM) Popular dietary supplement pill;unstable in foodEnzymes transfer methyl groups from SAM directly tothe DNACholine Egg yolks, liver, soy, cooked beef,chicken, veal and turkeyMethyl donor to SAMBetaine Wheat, spinach, shellfish, and sugarbeetsBreak down the toxic byproducts of SAM synthesisResveratrol Red wine Removes acetyl groups from histones, improving healthGenistein Soy, soy products Increased methylation, cancer prevention, unknownmechanismSulforaphane Broccoli Increased histone acetylation turning on anti-cancergenesButyrate A compound produced in the intestinewhen dietary fiber is fermentedIncreased histone acetylation turning on protectivegenes, increased lifespan (shown in the lab in flies)