Tobacco Carcinogen and Toxicant Biomarkers Stephen S. Hecht, Ph.D. Masonic Cancer Center University...

Tobacco Carcinogen and Toxicant Biomarkers

Stephen S. Hecht, Ph.D.

Masonic Cancer Center

University of Minnesota

Outline of Presentation

• Tobacco and cancer• Background on tobacco carcinogen biomarkers• Examples of tobacco carcinogen biomarkers

– Total NNAL– Formaldehyde-DNA adducts

Cancers Caused by Smoking:IARC Monograph Series

Volume 38, 1986

• Lung

• Oral cavity

• Pharynx

• Larynx

• Esophagus

• Pancreas

• Bladder

Volume 83, 2004, added:

• Nasal Cavity

• Stomach

• Liver

• Kidney

• Ureter

• Cervix

• Myeloid leukemia

Volume 100E, 2009, added:

• Colorectum

• Ovary (mucinous)

Cancer Deaths Due to Smoking

• Worldwide: 21% (1,420,000 per year)

• United States: 33% (185,000 per year)

IARC World Cancer Report, 2008

Tobacco Use Prevalence, 2008

• Adult smokers, U.S.: 46,000,000 (20.6%)

• Ex-smokers, U.S.: 48,100,000 (21.5%)

• Smokers, worldwide: 1,300,000,000

• Smokeless, worldwide: xxx,000,000

CDC, MMWR, November 13, 2009

O. Shafey, M. Ericksen, H. Ross, J. Mackay (2009) The Tobacco Atlas, 3 rd Ed.

World Smoking Prevalence: Males

O. Shafey, M. Ericksen, H. Ross, J. Mackay (2009) The Tobacco Atlas, 3 rd Ed.

World Smoking Prevalence: Females

Overall Goal

Elucidate mechanisms of tobacco-induced cancer and apply this

knowledge to cancer prevention.

Conceptual Framework for Understanding Tobacco Carcinogenesis

S.S. Hecht, JNCI, 91:1194-1210 (1999), Nature Rev. Cancer 3:733-744 (2003); Cancer: Principles and Practice of Oncology, 8th Edition, 147-155 (2008)

Significantly Mutated Genes in Lung Adenocarcinoma:Based on Sequencing of 623 Genes in 188 Tumors

Ding et al, Nature, 455:1069-1075, 2008

Other Factors Contributing to Tobacco-Induced Cancer

• Receptor mediated effects:nicotine, nitrosamines• Direct activation of EGFR and COX-2• Down-regulation of FHIT• Hyper-methylation of tumor suppressors• Tumor promotion and co-carcinogenesis• Oxidative damage and inflammation• Cilia-toxicity

H. Takahashi et al, Cancer Cell 17: 89 (2010); H. Schuller, Nature Rev. Cancer 9: 195-205 (2009); K.A. West et al, J. Clin. Invest. 111: 81-90 (2003); S.A. Belinsky, Carcinogenesis 26: 1481 (2005); D’Agostini et al, Cancer Res 66: 3936-3941 (2006); Jin et al, Carcinogenesis 29: 1614-1622 (2008); Bhutani et al, Cancer Prev. Res. 1: 39-44 (2008)

Conceptual Framework for Understanding Tobacco Carcinogenesis

S.S. Hecht, JNCI, 91:1194-1210 (1999), Nature Rev. Cancer 3:733-744 (2003); Cancer: Principles and Practice of Oncology, 8th Edition, 147-155 (2008)

IARC Carcinogens in Tobacco Smoke

S.S. Hecht, In: DeVita et al, Cancer (2010); IARC Monographs No. 83 (2004); D. Hoffmann and S.S. Hecht, Handbook Exp. Pharmacol. 94:63-102 (1990)

Goal

• Develop and validate tobacco carcinogen and toxicant biomarkers– Urinary metabolites– DNA and protein adducts– Metabolites in blood, saliva, breath, nails, hair

• Use these biomarkers to identify those smokers susceptible to cancer.

Definitions

• Biomarker: A distinctive biological or biologically derived indicator (as a metabolite) of a process, event, or condition (Merriam-Webster’s Collegiate Dictionary)

• Tobacco carcinogen biomarker: Any quantifiable substance, such as a metabolite, that can be specifically related to human exposure to a given tobacco carcinogen.

Tobacco Carcinogen Biomarkers

• DNA Adducts• Protein Adducts

– Hemoglobin– Albumin

• Metabolites– Breath– Saliva– Nails and Hair– Urine– Blood

Reviewed in Carcinogenesis 23: 907 and 1979 (2002); Nature Rev. Cancer 3: 733 (2003)

Applications of Tobacco Carcinogen Biomarkers

• Assessing exposure in smokers, smokeless tobacco users, and non-smokers exposed to secondhand smoke

• Regulation of tobacco products

• Understanding mechanisms of human carcinogenesis and identifying susceptible individuals

• Not specifically designed for early detection of cancer, but could have applications in screening

Range of recent mean values (nmol/24h unless noted otherwise)

Urinary biomarkers Source Smokers Non-smokers

Nicotine equivalents Nicotine 70.4-154 µmol/24 h Not Detected

Total NNAL NNK 1.1 - 2.9 Not Detected

Total NNN NNN 0.049 - 0.24 Not Detected

1-HOP or PheT PAH 0.50 - 1.45 0.18 - 0.50

MHBMA 1,3-Butadiene 15.5 - 322 0.65 - 7.5

SPMA Benzene 3.2 - 32.1 0.17 - 3.14

HPMA Acrolein 5,869 - 11,190 1,131 - 1,847

HBMA Crotonaldehyde 1,965 - 26,000 242 - 3,200

HEMA Ethylene oxide 19.1 - 102 6.51 - 38.8

Cd Cadmium 2.3 - 12.8 1.34 - 8.04

8-epi-PGF2 Oxidative damage 1.48 - 2.80 0.62 - 1.13

PGE-M Inflammation 54 - 60 31.6 - 45.3

Based on 1.3g creatinine per 24h in smokers and 1.5g creatinine per 24h in non-smokers, or 1.5 l urine per 24h.

A Panel of Tobacco Carcinogen and Toxicant Biomarkers

S.S. Hecht, J-M Yuan, and D. Hatsukami, Chem. Res. Toxicol., 2010

OH

1-HOP

HO

SR

RS

OH

+

MHBMA SPMA

SR RS OH

HPMA

OH

HBMA

SR HOSR

HEMANHCOCH3

COOHCH2R=

COOH

OH

HO

HO

8-epi-PGF2

COOH

HO

PGE-M

OCOOH

O

OH

PheT

OH

OHHO

N

N

CH3N

NCH3

OH N O

NNAL

N

N

N O

NNNNicotine

N

N

CH3

O

Cotinine

N

N

CH3

O

3'-Hydroxycotinine

OH

Structures of the Urinary Biomarkers

Recent data (pmol/g globin; mean ± S.D.)

Hemoglobin adducts Source Smokers Non-smokers

Cyanoethylvaline Acrylonitrile 112 ± 81 6.5 ± 6.4

Carbamoylethylvaline Acrylamide 84.1 ± 41.8 27.8 ± 7.1

Hydroxyethylvaline Ethylene oxide 132 ± 92 21.1 ± 12.7

4-Aminobiphenyl-globin 4-Aminobiphenyl 0.26 ± 0.006a 0.067 ± 0.009a

(fmol/µmol dN; mean ± S.D.)

Leukocyte DNA adducts Source Smokers Non-smokers

N6-hydroxymethyl-dAdo Formaldehyde 179 ± 205 15.5 ± 33.8

N2-ethylidene-dGuo Acetaldehyde 1,310 ± 1,720 705 ± 438

Mean concentrations

Other Source Smokers Non-smokers

Exhaled CO Carbon monoxide 17.4 - 34.4 ppm 2.6 - 6.5 ppm

Carboxyhemoglobin Carbon monoxide 3.4 - 7.1 % 0.35 - 1.45 %

A Panel of Biomarkers

Biomarker Validation

• Analytical– Specificity, sensitivity, accuracy, precision

• With respect to tobacco– Decreases upon cessation– Dose-response

• With respect to cancer risk

Persistence of Biomarkers Study

• Smokers provide baseline 24h urine samples.

• Eight days later, they quit smoking and receive nicotine replacement therapy.

• They provide 24h urine samples on days 3, 7, 14, 21, 28, 42, and 56 after quitting.

• Urine samples are analyzed for mercapturic acids (by LC-MS/MS) and other biomarkers.

S.G. Carmella, M. Chen, S. Han, A. Briggs, J. Jensen, D. K. Hatsukami, and S. S. Hecht Chem. Res. Toxicol., 22: 734-741 (2009)

Metabolism of 1,3-Butadiene to Mercapturic Acids

C.L. Sprague and A.A. Elfarra, Chem. Res. Toxicol., 17: 819-826 (2004)

1,3-butadiene

P450s O a-dHO

SCOOH

NHAcS

HOOC

AcNHOH

MHBMA

+

EH

OH

HO

ADHO

HO

a-dS

COOH

NHAc

O

HO

CRS

COOH

NHAc

OH

HO

DHBMA

a. GSH, GSTs; b. -glutamyltranspeptidase; c. cysteinylglycine dipeptidase; d. cysteine S-conjugate N-acetyltransferase

Mean Urinary MHBMA Reduction Upon Smoking Cessation, N=17

DAYS POST CESSATION

0 10 20 30 40 50 60

% R

ED

UC

TIO

N F

RO

M B

AS

ELI

NE

SM

OK

ING

0

20

40

60

80

100

Metabolism of Acrolein, Crotonaldehyde, Benzene, and Ethylene Oxide to Mercapturic Acids

a. GSH, GSTs; b. -glutamyltranspeptidase; c. cysteinylglycine dipeptidase; d. cysteine S-conjugate N-acetyltransferase

O

acrolein

S

HOOC

AcNHa-d O CR S

HOOC

AcNHOH

HPMA

O

crotonaldehyde

S

HOOC

AcNHa-d O CR S

HOOC

AcNHOH

HBMA

H3C

CH3 CH3

benzene

P450s O a-dOH

SNHAc

COOH

SNHAc

COOHSPMA

O

ethylene oxide

a-d S

HOOC

AcNH OH

HEMA

Mean Urinary HPMA Reduction Upon Smoking Cessation, N=17

DAYS POST CESSATION

0 10 20 30 40 50 60

% R

ED

UC

TIO

N F

RO

M B

AS

ELI

NE

SM

OK

ING

0

20

40

60

80

100

Mean Urinary HBMA Reduction Upon Smoking Cessation, N=17

DAYS POST CESSATION

0 10 20 30 40 50 60

% R

ED

UC

TIO

N F

RO

M B

AS

ELI

NE

SM

OK

ING

0

20

40

60

80

100

Mean Urinary SPMA Reduction Upon Smoking Cessation, N=17

DAYS POST CESSATION

0 10 20 30 40 50 60

% R

ED

UC

TIO

N F

RO

M B

AS

ELI

NE

SM

OK

ING

0

20

40

60

80

100

Mean Urinary HEMA Reduction Upon Smoking Cessation, N=17

DAYS POST CESSATION

0 10 20 30 40 50 60

% R

ED

UC

TIO

N F

RO

M B

AS

ELI

NE

SM

OK

ING

0

20

40

60

80

100

Structures of Urinary Biomarkers

S.G. Carmella, et al, Chem. Res. Toxicol., 22: 734-741 (2009)

OH

1-HOP (from pyrene)

N

NNAL (from NNK)NCH3

OH N O

MHBMA(from 1,3-butadiene)

DHBMA (from 1,3-butadiene)

HPMA (from acrolein)

HBMA (from crotonaldehyde)

SPMA (from benzene)

HEMA (from ethylene oxide)

HO

SCOOH

NHAc+ S

OH

HOOC

AcNH

HOS

OHCOOH

NHAc

HO S

COOH

NHAc

HO S

COOH

NHAc

CH3

HOS

COOH

NHAc

S

COOH

NHAc

N

N

N O

NNN (from NNN)

Mean Urinary 1-HOP Reduction Upon Smoking Cessation, N=15

Mean Urinary Total NNAL Reduction Upon Smoking Cessation, N=17

DAYS POST CESSATION

0 10 20 30 40 50 60

% R

ED

UC

TIO

N F

RO

M B

AS

ELI

NE

SM

OK

ING

0

20

40

60

80

100

Range of recent mean values (nmol/24h unless noted otherwise)

Urinary biomarkers Source Smokers Non-smokers

Nicotine equivalents Nicotine 70.4-154 µmol/24 h Not Detected

Total NNAL NNK 1.1 - 2.9 Not Detected

Total NNN NNN 0.049 - 0.24 Not Detected

1-HOP or PheT PAH 0.50 - 1.45 0.18 - 0.50

MHBMA 1,3-Butadiene 15.5 - 322 0.65 - 7.5

SPMA Benzene 3.2 - 32.1 0.17 - 3.14

HPMA Acrolein 5,869 - 11,190 1,131 - 1,847

HBMA Crotonaldehyde 1,965 - 26,000 242 - 3,200

HEMA Ethylene oxide 19.1 - 102 6.51 - 38.8

Cd Cadmium 2.3 - 12.8 1.34 - 8.04

8-epi-PGF2 Oxidative damage 1.48 - 2.80 0.62 - 1.13

PGE-M Inflammation 54 - 60 31.6 - 45.3

Based on 1.3g creatinine per 24h in smokers and 1.5g creatinine per 24h in non-smokers, or 1.5 l urine per 24h.

A Panel of Tobacco Carcinogen and Toxicant Biomarkers

S.S. Hecht, J-M Yuan, and D. Hatsukami, Chem. Res. Toxicol., 2010

Essential Facts About NNK,A Tobacco-Specific Lung Carcinogen

• Present in tobacco and tobacco smoke; specific to tobacco products

• Systemic lung carcinogen in rats, mice, hamsters, and ferrets.

• Also induces tumors of the pancreas, nasal cavity, and liver in rats

• Considered to be a cause of lung, oral cavity and pancreatic cancer in people exposed to tobacco products

• NNK and NNN- Carcinogenic to humans; Group 1 (IARC Volume 89, 2007); reaffirmed (Vol 100E, 2009)

S.S. Hecht, Chem. Res. Toxicol. 11:559 (1998); Nature Rev. Cancer 3:733 (2003)

N

NCH3

O N O

Metabolism of NNK by Carbonyl Reduction

N

NCH3

O N O11-HSD-1CRAKR1C1,2,4

NNKN

NCH3

OH N O

NNAL

carcinogenicity similar to NNK

NNAL-Glucs

(R)-NNAL-O-Glucinactive

Nicotine-derivedNitrosamino Ketone

UGTs

NNAL Plus NNAL-Glucs (Total NNAL): A Biomarker of NNK Exposure

• Quantified by GC-TEA or LC-MS/MS

• High analytical specificity and sensitivity

• Specific to tobacco product exposure

• Responsive to dose

• Measures uptake of a lung carcinogen

S.S. Hecht, Carcinogenesis 23 907 (2002); S.G.Carmella et al, CEBP 4: 635 (1995); 12: 1257 (2003); D. Hatsukami et al, Nic. Tob. Res. 8: 169 (2006)

GC-TEA Chromatogram of NNAL in a Smoker's Urine

Applications of the Total NNAL Biomarker

• Cessation of smoking or smokeless tobacco • Reduction of smoking• Carcinogen uptake from new and old tobacco products:

– Omni, light and ultra-light cigarettes – Snus and other smokeless products– Ultra low nicotine cigarettes

• Evaluation of carcinogen dose in various groups– Reducers vs. light smokers– Smokers of differing numbers of cigarettes– Ethnic groups, gender, and teen-age smokers– Smokeless vs. smokers– Duration of smokeless use

• Carcinogen uptake from secondhand cigarette smoke• Relationship to lung cancer

D. Hatsukami, J. Jensen, A. Joseph, S. E. Murphy, S.G. Carmella, S.S. Hecht, and co-workers.

Cancer Res., JNCI, CEBP, Nic. Tob. Res., 1999-2008

Tobacco Harm Reduction: Continuum of Risk

Conventional cigarettesModified tobacco cigarettesCigarette reduction

Cigarette-like delivery devices;Extra-low nicotine cigarettes

Smokeless tobacco products

Nicotine delivery devicesSmoking Cessation

Most toxic

Least toxic

D. Hatsukami et al., Nicotine Tob. Res. 9:S537-S553 2007

Non-Smokers’ Exposure to NNK Throughout Life by Measurement of Urinary Total NNAL

Exposed Group Type of ExposureTotal NNAL

(fmol/ml urine)% of Amount in Smokers' Urinea

Fetus Transplacental25 ± 29

(amniotic fluid)1.3

Newborns Transplacental 130 ± 150 6.5

Infants (<1 year old) Air 83 ± 20 4.2

Elementary School Children

Minneapolis Air 56 ± 76 2.8

Moldova Air 90 ± 77 4.5

Women Living with Smokers

Air 50 ± 68 2.5

Hospital Workers Air 59 ± 28 3.0

Casino Patrons Air 18 ± 15 0.9

Restaurant and Bar Workers

Air 33 ± 34 1.7

a based on 2 pmol/ml total NNAL in smokers

S.S. Hecht, Carcinogenesis 23:907 (2002); S.S. Hecht et al, CEBP 15:988 (2006)

Total NNAL measurements in secondhand smoke-exposed non-

smokers have impact

• It can only come from secondhand smoke.• It represents uptake of a lung carcinogen.• It is found in the urine of non-smokers.• It is the only lung carcinogen biomarker consistently

elevated in exposed non-smokers.• These studies should spur clean air legislation in

the remaining countries, states and localities.

Median Serum Cotinine Levels in Non-Smokers, by Age Group: 1988-2002

CDC NHANES Study; MMWR 55: 1130 (2006)

Regulation of Indoor Smoking and Tobacco Control

• Regulation of indoor smoking– Reduces cues for smoking– Reduces amount smoked– Can change social norms

• Regulation of indoor smoking, along with counter-advertising and taxation, are the most effective methods in tobacco control.

Relationship of Urinary NNAL to Lung Cancer in Two Prospective Cohorts of Cigarette Smokers

• Collaboration with Professors Mimi Yu and Jian-Min Yuan

• Two prospective cohorts of Chinese cigarette smokers: Shanghai and Singapore

• Nested case control study of 246 cases of lung cancer and 245 matched controls

• Total NNAL and cotinine quantified in stored urine samples collected prior to lung cancer diagnosis

Joint Effect of Urinary Total NNAL and Cotinine on Lung Cancer Risk

NNAL in tertile

Cotinine in tertile

1st (low) 2nd 3rd (high)

Ca/Co1 OR (95% CI)2 Ca/Co1 OR (95% CI)2 Ca/Co1 OR (95% CI)2

1st (low) 9/47 1.00 23/253.93 (1.54, 10.05)

11/10 5.08 (1.63, 15.89)

2nd 14/24 3.01 (1.11, 8.10) 31/324.15 (1.70, 10.12)

22/26 4.48 (1.78, 11.31)

3rd (high) 8/103.41 (1.08, 11.25)

30/255.58 (2.25, 13.84)

93/46 8.47 (3.69, 19.46)

J. Yuan, M. Yu, S.E. Murphy, S. Carmella, S.S. Hecht et al., Cancer Res.,69: 2990 (2009)

1 No. of cases/no. of controls

2 Odds ratios (OR) were adjusted for age, year of interview, year of sample collection, gender and dialect group, study location (Shanghai versus Singapore), number of cigarettes smoked per day, and number of years of smoking; CI, confidence interval.

Conclusions of the Shanghai and Singapore Study

• Total NNAL significantly associated with risk of lung cancer in a dose-dependent manner, after adjustment for smoking history and urinary cotinine.

• Cotinine was independently associated with lung cancer, consistent with previous data.

• Smokers in the highest tertiles of urinary total NNAL and cotinine exhibited an 8.5 fold increased risk for lung cancer, relative to those with comparable smoking history, but in the lowest tertiles.

J. Yuan et al, Cancer Res. 69: 2990 (2009)

Similar Results in the PLCO Study

• The Prostate, Lung, Colon, and Ovarian Cancer Screening Trial: started 1993

• 77,468 subjects (25,000 smokers) screened; over 1,000 lung cancer cases diagnosed

• Questionnaire data and blood samples collected prospectively

• 100 lung cancer cases and 100 controls without lung cancer selected – all were smokers of > 10 CPD

• Pre-diagnostic serum analyzed for total NNAL and cotinine

T. Church, K. Anderson, M. Geisser, Y. Zhong, C. Le, N. Caporaso, S. Carmella, A. Benoit, S. S. Hecht, CEBP,18: 260 (2009)

Total NNAL and Lung Cancer

• Total NNAL is a risk biomarker.

• Results are consistent with all experimental and previous clinical and epidemiologic data.

• Results further implicate NNK as an independent etiologic risk factor in lung cancer.

Cigarette Smoke Constituents Targeted for Regulation by WHO, and Their Biomarkers

• Benzo[a]pyrene• NNK, NNN • Acrolein• Benzene• 1,3-Butadiene• Carbon monoxide• Acetaldehyde• Formaldehyde• Nicotine

• 1-HOP or PheT in urine• NNAL and NNN in urine• 3-HPMA in urine• SPMA in urine• MHBMA in urine• Exhaled CO • Leukocyte DNA adducts• Leukocyte DNA adducts• Nicotine metabolites

D.M. Burns et al. Tob. Control. 17: 132-141 (2008); S.S. Hecht, Carcinogenesis 23: 907-922 (2002); L. Chen et al. Chem. Res. Toxicol. 20: 108-133 (2007); S.G. Carmella et al. Chem. Res. Toxicol., 22: 734-741 (2009)

Formaldehyde – Genetic Toxicology

• Genotoxic – Mutagenic– DNA protein cross-links– DNA strand breaks– Sister chromatid exchanges– Chromosomal aberrations

• These changes initiated by reactions with DNA to form adducts

• No previous reports of formaldehyde DNA adducts in humans

International Agency for Research on Cancer Monographs, Volume 88 (2006)

Structures of Formaldehyde-DNA Adducts

N

N

N

N

N

dR

H CH2 NH

N

N N

N

dR

N

NN

N N

O

CH2 N

N

N N

N

dR

H

dR

dR = 2'-deoxyribose

N

N

O

N

H

CH2 N N

N

N

N

dR

O

H

H

HN

N

dR

N6-HOMe-dAdo N4-HOMe-dCyd

dAdo-CH2-dAdo dGuo-CH2-dAdo dGuo-CH2-dGuo

H

H

N

NN

N

NH CH2OH

dR

N

N

NH CH2OH

dR

O

N2-HOMe-dGuo

N

NN

N

dR

O

H

N CH2OH

H

R. Shapiro et al. (1980); F. Beland et al. (1984)

Conversion of N6-HOMe-dAdo to N6-Me-dAdo

N6-HOMe-dAdo

N

NN

N

NH CH2OH

dR

N6-Me-dAdo

N

NN

N

NH CH3

dR

NaBH3CN

pH 7.0

M. Wang et al. Chem. Res. Toxicol. 20: 1141-1148 (2007)

Outline of Analytical Method for N6-HOMe-dAdo in DNA

LC-ESI-MS/MS-SRM Chromatograms of N6-Me-dAdo in Smokers' Leukocyte DNA

Typical LC-ESI-MS/MS-SRM Chromatograms of N6-Me-dAdo in Leukocyte DNA

Levels of N6-HOMe-dAdo (as N6-Me-dAdo) in Leukocyte DNA of Smokers and Non-smokers

Previous Studies of Leukocyte DNA Adducts in Smokers vs. Non-smokers

• Most used 32P-postlabelling and immunoassay – inconsistent results comparing smokers and non-smokers

• Mixed results in 8-OH-dG analyses• Marginally higher levels of acetaldehyde-DNA

adducts in smokers before stopping• Significant difference in BPDE-DNA adducts

(2 per 108 vs 1 per 108 nucleotides)• Our results: 5 per 108 vs. 0.5 per 108 nucleotides

IARC Monographs, Vol 83 (2004); Pavanello et al. Mutat. Res 611: 54 (2006); Chen et al Chem. Res. Toxicol. 20: 108 (2007)

Sources of Formaldehyde-DNA Adducts

• Formaldehyde itself in cigarette smoke, but blood levels were not elevated in volunteers exposed to similar amounts

• Smoking effect on endogenous metabolism• Released as a metabolite from nicotine, NNK, or

related compounds• Transfer from formaldehyde-histone adducts• Secondary metabolite from lipid peroxidation or

inflammation caused by smoking

Conclusions – Formaldehyde DNA Adducts

• First study to detect formaldehyde-DNA adducts in humans

• Highly significant differences between smokers and non-smokers

• Results indicate a previously unrecognized and potentially important role for formaldehyde in smoking-induced cancer

M. Wang, G. Cheng, S.S. Hecht et al. Cancer Res., 69: 7170 (2009)

Overall Goal

Elucidate mechanisms of tobacco-induced cancer and apply this

knowledge to cancer prevention.

We are Making Progress in Tobacco Control

• Smoke-free legislation

• Increased taxation

• Aggressive anti-tobacco advertising

Age-Adjusted Total U.S. Mortality Rates for Lung and Bronchus Cancer

Source: SEER data http://seer.cancer.gov/faststats/

0

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19

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Year of Death

Rat

e p

er 1

00,0

00

Both sexes

Males

Females

Dorothy Hatsukami

Acknowledgements

• Hecht Lab– Steven Carmella– Mingyao Wang– Irina Stepanov– Pramod Upadhyaya– Brad Hochalter– Silvia Balbo– Shaomei Han– Menglan Chen– Guang Cheng– Lei Meng– Yan Zhong– Aleks Knezevich– John Muzic

• Core Facilities– Pete Villalta– Chap Le– Xianghua Luo– Yan Zhang– Bruce Lindgren

• Dorothy Hatsukami – Joni Jensen– Amanda Anderson– Rachel Feuer

• Tim Church• Kristin Anderson• Mindy Geisser• Jian-Min Yuan• Mimi Yu

Research Support

• National Cancer Institute• National Institute of Environmental Health

Sciences• National Institute on Drug Abuse/NCI/NIAAA

(TTURC)• American Cancer Society• Wallin Chair in Cancer Prevention

Tobacco Carcinogen and Toxicant Biomarkers Stephen S. Hecht, Ph.D. Masonic Cancer Center University...

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