Chemoprevention Against Chemoprevention Against Environmental CarcinogensEnvironmental Carcinogens

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 controlTreatment and control

•Early detection and diagnosisEarly detection and diagnosis

•PreventionPrevention

Incidence Incidence MortalityMortality(600,000 new cases)(600,000 new cases) (280,000)(280,000)

From: Breast Cancer Prognosis, Treatment and PreventionFrom: Breast Cancer Prognosis, Treatment and Prevention

Examples of incidence and mortality of various women’s cancers in the United StatesExamples of incidence and mortality of various women’s cancers in the United States(in percentages). Values for 1990.(in percentages). Values for 1990.

What Causes Cancer?

• Genes: < 10% of all cancers are the result Genes: < 10% of all cancers are the result of inherited gene mutations.of inherited gene mutations.

• Tobacco use: 250,000 deaths per year in Tobacco use: 250,000 deaths per year in the U.S.the U.S.

• Infections/inflammatory disorders.Infections/inflammatory disorders.

• Diet: high intake of fats, sugars, and total Diet: high intake of fats, sugars, and total calories. calories.

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.

Hypothetical mechanism that can be involved in the effect of maternal and fetal factors on breast cancer risk in female offspring. E2: estradiol. (Modified from Hilakivi-Clarke et al., 1994)

CancerCancer

Antioxidants

•AscorbateAscorbate

•Vitamin EVitamin E

•CarotenoidsCarotenoids

•Glutathione: GSHGlutathione: GSH

Is Cancer Preventable?

The incidence of breast and prostate cancer is The incidence of breast and prostate cancer is markedly higher in the Western world markedly higher in the Western world compared to Asian countries. Asian immigrants compared to Asian countries. Asian immigrants to the US who maintain an “Eastern” diet retain to the US who maintain an “Eastern” diet retain the lower rates of cancer development, while the lower rates of cancer development, while those who adopt a “Western” diet increase their those who adopt a “Western” diet increase their cancer risk (WHO data as adapted by the cancer risk (WHO data as adapted by the American Cancer Society, 1992).American Cancer Society, 1992).

Fruit and Vegetable Consumption and Cancer Risk

(Ames and Gold, (Ames and Gold, Drug Metabolism ReviewsDrug Metabolism Reviews 3030 :201-223, 1998):201-223, 1998)

Fraction of studiesFraction of studiesshowing cancer protectionshowing cancer protection Relative risk Relative risk

Cancer siteCancer site (p < .05) (p < .05) (low vs. high quartile)(low vs. high quartile)

EpithelialEpithelialPancreasPancreas 9/11 9/11 2.82.8StomachStomach 17/1917/19 2.52.5LungLung 24/2524/25 2.22.2EsophagusEsophagus 15/1615/16 2.02.0CervixCervix 7/87/8 2.02.0ColorectalColorectal 20/3520/35 1.91.9

Hormone DependentHormone DependentOvary/endometriumOvary/endometrium 3/43/4 1.81.8Breast Breast 8/14 8/14 1.31.3ProstateProstate 4/14 4/14 1.31.3

Diets rich in fruits and vegetables are Diets rich in fruits and vegetables are associated with a reduced risk of most types associated with a reduced risk of most types

of cancers.of cancers.

Why?Why?

Fruits, vegetables, and grains contain Fruits, vegetables, and grains contain thousands of chemicals, called thousands of chemicals, called

phytochemicals.phytochemicals.

Do phytochemicals prevent cancer?Do phytochemicals prevent cancer?

The inhibition, reversal, or retardation of The inhibition, reversal, or retardation of carcinogenesis by the administration of carcinogenesis by the administration of

natural or synthetic agents is termed natural or synthetic agents is termed chemoprevention.chemoprevention.

Many phytochemicals are believed to affect every stage of the cancer process

ChemopreventiveChemopreventive Cancer Prevented Cancer Prevented Mechanisms Mechanisms PhytochemicalsPhytochemicals SourceSource (animal models) (animal models) of Action of Action

Alkyl sulfides and disulfidesAlkyl sulfides and disulfides AlliumAllium Esophagus, Colon,Esophagus, Colon, Phase II, GSTPhase II, GSTSulfide volatiles Sulfide volatiles LungLungAllyl cystenesAllyl cystenes

MonoterpenesMonoterpenes CitrusCitrus Mammary, Pancreas,Mammary, Pancreas, Phase II, GST,Phase II, GST,LemoneneLemonene Skin, Lung, LiverSkin, Lung, Liver UDP-GT,UDP-GT,

Phase IPhase I

IsothiocyanatesIsothiocyanates CrucifersCrucifers Liver, Lung,Liver, Lung, Phase II, GSTPhase II, GST MammaryMammary

PolyphenolsPolyphenols TeasTeas Colon, Lung,Colon, Lung, Phase II (GST,Phase II (GST,Epigallocatechin gallateEpigallocatechin gallate Skin, LiverSkin, Liver QR), Phase I,QR), Phase I,

AP-1AP-1

CurcuminCurcumin TurmericTurmeric Colon, SkinColon, Skin Phase II, GST,Phase II, GST,Cox IICox II

Mechanisms of Action ofPhytochemicals in Cancer Prevention

Anti-oxidant Anti-oxidant

Anti-hormonal Anti-hormonal

Anti-angiogenic Anti-angiogenic

Pro-apoptotic Pro-apoptotic

Anti-proliferative Anti-proliferative

Anti-inflammatory Anti-inflammatory

ImmunomodulatoryImmunomodulatory

Chemoprevention Studies

• Large-scale demonstration trials aim to establish Large-scale demonstration trials aim to establish definitively the efficacy and toxicity of potential definitively the efficacy and toxicity of potential chemopreventive agents in a healthy population of chemopreventive agents in a healthy population of subjects with a high risk of cancer.subjects with a high risk of cancer.

• Small Phase I and II chemoprevention trials are Small Phase I and II chemoprevention trials are conducted in individuals with premalignant lesions conducted in individuals with premalignant lesions or cancer to investigate mechanisms of action, or cancer to investigate mechanisms of action, pharmacokinetics, pharmacodynamics, and pharmacokinetics, pharmacodynamics, and modulation of biomarkers.modulation of biomarkers.

Lung Cancer Chemoprevention Trials

PatientsPatients End EndTrialTrial (n) (n) PopulationPopulation CompoundsCompounds Result Result

Physician’s Health Study Physician’s Health Study MaleMale ββ-carotene-carotene(Hennekens, 1996)(Hennekens, 1996) 22,07122,071 physiciansphysicians AspirinAspirin N.B.N.B.

ATBC Study, 1994ATBC Study, 1994 29,13329,133 M. smokersM. smokers αα-tocopherol-tocopherol NegativeNegative ββ-carotene-carotene

CARET, 1996CARET, 1996 18,31418,314 SmokersSmokers ββ-carotene-carotene NegativeNegativeAsbestos Asbestos Retinyl PalmitateRetinyl Palmitate

Kurie, 2000Kurie, 2000 82 82 SmokersSmokers 4-HPR4-HPR N.B.N.B.

Intergroup Study, 2001Intergroup Study, 2001 1,166 1,166 Prior Stage 1Prior Stage 1 Isotretinoin Isotretinoin N.B.N.B.NSCLCNSCLC

Pastorino, 1993Pastorino, 1993 307307 PS 1, NSCLCPS 1, NSCLC Retinyl Palm.Retinyl Palm. N.B.N.B.

CA Cancer J. Clin. 54:2004.CA Cancer J. Clin. 54:2004.

N.B.: No benefit or harmN.B.: No benefit or harm

Colorectal Chemoprevention Trials PatientsPatients End End

TrialTrial (n) (n) PopulationPopulation CompoundsCompounds Result Result

ATBC Study, 2000ATBC Study, 2000 29,13329,133 M. smokersM. smokers αα-tocopherol-tocopherol N.B.N.B. ββ-carotene-carotene

Physician’s Health, 1996 Physician’s Health, 1996 22,07122,071 M. physiciansM. physicians ββ-carotene-carotene N.B.N.B.

Giardiello, 1993Giardiello, 1993 2222 FAPFAP SulindacSulindac PositivePositive(150 mg 2/day)(150 mg 2/day)

Steinback, 2000Steinback, 2000 7777 FAPFAP CelecoxibCelecoxib PositivePositive(100 or 400 mg)(100 or 400 mg)

Aspirin/Folate Polyp, 2003Aspirin/Folate Polyp, 2003 1,1211,121 PriorPrior Aspirin (81–325 mg)Aspirin (81–325 mg) PositivePositivecarcinomacarcinoma Folate (1 mg)Folate (1 mg)

The Polyp Prevention, 2000The Polyp Prevention, 2000 2,0792,079 PriorPrior FiberFiber N.B. N.B. adenomaadenoma (18 g/1000 kcal)(18 g/1000 kcal)

The Calcium Polyp, 1999 The Calcium Polyp, 1999 930930 Prior adenoPrior adeno CalciumCalcium PositivePositiverecurrencerecurrence carbonate (3 mg)carbonate (3 mg)

Cascinu, 2000Cascinu, 2000 9090 Prior Duke’sPrior Duke’s Vit. A (30,000)Vit. A (30,000)B-C cancerB-C cancer Vit. C (1 gm)Vit. C (1 gm) N.B. N.B.

Vit. E (70 mg)Vit. E (70 mg)

CA Cancer J. Clin. 54:2004.CA Cancer J. Clin. 54:2004.N.B.: No benefit or harmN.B.: No benefit or harm

Selected Breast Cancer Chemoprevention Trials PatientsPatients End End

TrialTrial (n) (n) Population Population Compounds Compounds Result Result

Dunn, 2000Dunn, 2000 13,38813,388 Healthy + risk Healthy + risk Tamoxifen (20 mg)Tamoxifen (20 mg) Positive for Positive for Dunn, 2001Dunn, 2001 factorsfactors ER+ tumorsER+ tumors

Royal MarstenRoyal Marsten 2,494 2,494 Healthy volunteersHealthy volunteers Tamoxifen (20 mg)Tamoxifen (20 mg) N.B.N.B.Hospital, 1998Hospital, 1998

Italian Trial, 1998Italian Trial, 1998 5,408 5,408 Healthy with priorHealthy with prior Tamoxifen (20 mg)Tamoxifen (20 mg) PositivePositivehysterectomieshysterectomies

InternationalInternational 7,152 7,152 Healthy with Healthy with Tamoxifen (20 mg)Tamoxifen (20 mg) PositivePositiveIntervention, 2002Intervention, 2002 increased riskincreased risk

RaloxifeneRaloxifene 7,705 7,705 Postmenopausal w/Postmenopausal w/ Raloxifene (60 mg)Raloxifene (60 mg) PositivePositiveTrial, 2001Trial, 2001 osteoporosisosteoporosis

Veronesi, 1999Veronesi, 1999 2,9722,972 Stage 1 or DCISStage 1 or DCIS 4-HPR (200 mg)4-HPR (200 mg) N.B.N.B.

Arimidex/Arimidex/ 9,366 9,366 Postmenopausal, Postmenopausal, Anastrozole (1 mg)Anastrozole (1 mg) PositivePositiveTam. 2003Tam. 2003 prior breast cancerprior breast cancer

Goss, 2003Goss, 2003 5,187 5,187 PostmenopausalPostmenopausal Letrozole (2.5 mg)Letrozole (2.5 mg) PositivePositivePrior tam. 5 yr.Prior tam. 5 yr.

CA Cancer J. Clin. 54:2004.CA Cancer J. Clin. 54:2004.N.B.: No benefit or harmN.B.: No benefit or harm

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Cellular Defense and Carcinogenesis Section

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Curcumin, DBMCurcumin, DBM

ResveratrolResveratrol

Diosmetin, DiosminDiosmetin, Diosmin

GalanginGalangin

Kaempferol, QuercetinKaempferol, Quercetin