1. Mini Lecture 1 Module: Tobacco Effects and Neoplasia
TOBACCO AND CARCINOGENESIS
Mini Lecture 1 Module: Tobacco Effects and Neoplasia

2. Objectives of the Mini Lecture
GOAL OF MODULE: Increase students’ knowledge of the potential threat of developing cancer in different parts of the body as a result of tobacco use.
LEARNING OBJECTIVES
Students will understand:
How smoking causes lung cancer.
How tobacco is a risk factor for digestive cancers.
The types of urogenital cancer associated with smoking.
The adverse effects of smoking on cancer management.
The effects of tobacco cessation on risk and management of cancers.

3. Contents Core Slides Optional Slides
Carcinogenic Content of Cigarettes
Tobacco Carcinogenesis Mechanism (1)
Tobacco Carcinogenesis Mechanism (2)
Behavioural Model of Tobacco Addiction
Nicotine Addiction and Invasive Cancers

4. CORE SLIDES Tobacco and Carcinogenesis
Mini Lecture 1 Module: Tobacco Effects and Neoplasia

5. Carcinogenic Content of Cigarettes
Cigarette smoke:
Contains 72 carcinogens3
Most potent are polycyclic aromatic hydrocarbons (PAHs) and tobacco specific nitrosamines (TSNs)
Notes:
Phenol, isolated from cigarette tar, has long been known to possess tumor-promoting activity. Both whole tobacco extract and whole cigarette tar were active tumor-promoting agents. Seven aromatic hydrocarbons are listed as known carcinogens in tobacco or smoke. These compounds are: benzo(a)pyrene, dibenz(a,i)pyrene, dibenz- (a,h)anthracene, benzo(c)phenanthrene, dibenz(aj)acridine, dibenz(a,h)acridine, and 7H-ibenzo(c,g)carbazole. A recent review also lists chrysene, benz(a)anthracene, benzo(e)-pyrene, benzo(b)fluoranthene, benzo(j)fluoranthene, and indeno(l,2,3-cd)pyrene as known carcinogenic hydrocarbons from cigarette smoke. Nitrogen oxides and nitroso compounds have shown moderate to weak carcinogenic activity.2
Several factors determine the biologically effective dose of carcinogens, including the number of cigarettes smoked per day, type of cigarette, smoking topography, carcinogen metabolism, and DNA repair. Many studies have shown a relationship between tobacco smoke exposure, carcinogen-DNA adduct formation, tumor specific mutations (e.g., p53 mutational spectra), and cancer risk. The level of tar and nicotine in cigarettes has decreased along with the level of PAHs, but the level of TSNs has increased. Genetically determined host capacity can influence these outcomes and the risk for tobacco addiction.1
According to Hecht, “Cigarette smoke contains 72 carcinogens with ‘sufficient evidence for carcinogenicity’ in either laboratory animals or humans.”3
References:
Shields PG. Epidemiology of tobacco carcinogenesis. Curr Oncol Rep. 2000; 2(3):257–62.
Van Duuren BL. Tobacco carcinogenesis. Cancer Res. 1968; 28(11):2357–62.
Hecht, SS. More than 500 trillion molecules of strong carcinogens per cigarette: use in product labelling? Tob Control. 2011; doi: /tc June: 13th 2011.
1. Shields 2000; 3. Hecht 2011

6. Tobacco Carcinogenesis Mechanism (1)
First PAH (polynuclear aromatic hydrocarbon) identified as a carcinogen in tobacco smoke was benzopyrene.
Benzopyrene and acrolein irreversibly binds to DNA, causes mutations and cancer.1
Notes:
About 95% of mainstream smoke is made up of gases, chiefly nitrogen, oxygen, and carbon dioxide. There are 72 carcinogens in cigarette smoke that have been evaluated by the International Agency for Research on Cancer (IARC) and for which there is “sufficient evidence for carcinogenicity” in either laboratory animals or humans. Among the PAHs, benzo[a]pyrene (BaP) is the most extensively studied compound, and its ability to induce lung tumors upon local administration or inhalation is well documented.
Cigarette smoke is also a tumor promoter. The majority of the activity seems to be due to uncharacterized weakly acidic compounds. Substantial levels of co-carcinogens such as catechol are present in cigarette smoke. Other co-carcinogens include methylcatechols, pyrogallol, decane, undecane, pyrene, benzo[e]pyrene, and fluoranthene. In addition, cigarette smoke contains high levels of acrolein, which is toxic to the pulmonary cilia, and other agents, such as nitrogen oxides, acetaldehyde, and formaldehyde, that could contribute indirectly to pulmonary carcinogenicity. Benzopyrene toxicates into an epoxide that irreversibly attaches to a cell’s nuclear DNA, which may either kill the cell or cause a genetic mutation. If the mutation inhibits programmed cell death, the cell can survive to become a cancer cell. Similarly, acrolein, which is abundant in tobacco smoke, also irreversibly binds to DNA, causes mutations and thus also cancer. However, it needs no activation to become carcinogenic.1
Reference:
Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst. 1999; 91:1194–1210.
1. Hecht 1999

7. Tobacco Carcinogenesis Mechanism (2)
Nicotine, per se, is not carcinogenic or mutagenic.
However, it inhibits apoptosis, therefore accelerating existing cancers.1
NNK, a nicotine derivative converted from nicotine, can be carcinogenic.2
Notes:
Tobacco smoke contains several carcinogenic pyrolysis products that bind to DNA and cause genetic mutations. The formation of NNN, NNK, and NNA from nicotine and of NNN, NAB, and NAT from nomicotine, anabasine, and anatabine are alkaloid-derived nitrosamines called "tobacco-specific nitrosamines.” In cigarette smoke, 25 to 45% of the tobacco-specific nitrosamines originate by transfer from the tobacco and the remainder is pyrosynthesized, probably by reaction of the alkaloids with nitrogen oxides. Since the ribs and stems of the tobacco leaf contain the greatest proportion of nitrate, they have a profound influence on the levels of nitrosamines in tobacco products and in smoke. NNN and NNK induce benign and malignant tumors in mice, rats, and hamsters. NNK is the most potent carcinogen among the tobacco-specific nitrosamines. 1
References:
Tsurutani J, Castillo SS, Brognard J, Granville CA, Zhang C, Gills JJ, et al. Tobacco components stimulate Akt-dependent proliferation and NFkB-dependent survival in lung cancer cells. Carcinogenesis. 2005; 26(7):1182–95.
Hoffmann D, Hecht SS. Nicotine-derived JV-nitrosamines and tobacco-related cancer: current status and future directions. Cancer Res. 1985; 45:935–44.
1. Hoffmann and Hecht 1985; 2. Tsurutani et al. 2005

8. Biobehavioural Model of Nicotine Addiction and Tobacco Related Cancers
Social Factors
Culture
SES
Peer/family/media influences
politics
Behavioural, Neurochemical and Psychological Factors
Tobacco use
Dependence
Cessation
Relapse
Psychological Factors
Co morbidity
Personality
Stress
Cancer
Notes:
Cancer control strategies must be based on a recognition of the critical role of human behavior in the control of cancer and must effectively apply the wide-ranging discoveries in the basic cancer sciences, including basic behavioral research, to improve public health. This framework was adapted from a more general biobehavioral model of health outcomes developed by Norman Anderson. This adaptation illustrates the complex interplay of social, psychological, and biological factors that interact with genetic vulnerabilities to result in tobacco use, nicotine addiction, and cancer. The three overarching categories of factors—social, psychological, and biological—are mediated by behavioral, neurochemical, and physiological factors to influence behavioral end points in the individual, including tobacco use, dependence, cessation, and relapse. By recognizing the complexity of the determinants of tobacco use and addressing these behavioral mediators, we have the potential to reduce tobacco related cancers dramatically.
Reference:
Hiatt RA, Rimer BK. A new strategy for cancer control research. Cancer Epidemiol Biomarkers Prevent. 1999; 8:957–64.
Biological Factors
Genetics
Nutrition
1. Hiatt and Rimer 1999

9. OPTIONAL SLIDES Tobacco and Carcinogenesis
Mini Lecture 1 Module: Tobacco Effects and Neoplasia

10. Nicotine Addiction and Invasive Cancer
Long -term exposure of DNA to metabolically activated carcinogens leads to formation of DNA adducts (pieces of DNA that are covalently bonded to a cancer causing chemical) and resultant genetic changes.
This barrage of DNA damage, taking place daily over many years, is fully consistent with multiple genetic changes in lung cancer.
The time frame and sequence of genetic changes are uncertain.
Notes:
Carcinogens form the link between nicotine addiction and lung cancer. Nicotine is the reason people continue to smoke despite the well-known adverse effects on health. Nicotine is not generally considered to be a carcinogen, although it can induce tumours under certain special conditions such as hyperoxia. Nicotine can also be converted into carcinogens such as NNK in the body. The cigarette has been engineered to be a nicotine delivery device, which is quite dangerous because more than 60 carcinogens, including PAHs and NNK, accompany nicotine in each puff. Although the dose of each carcinogen per cigarette is quite small, the cumulative dose in a lifetime of smoking is substantial. Intermediates formed by the interaction of cytochrome P450 enzymes with carcinogens are reactive, generally having an electrophilic (electron-deficient) centre. Such intermediates or metabolites can react with DNA, resulting in the formation of covalently bound products known as DNA adducts. This process, which converts an unreactive carcinogen to a form that binds to DNA, is known as metabolic activation. The balance between metabolic activation and detoxification varies among individuals and is likely to affect cancer risk, because DNA adducts are central to the carcinogenic process.
Reference:
Hecht SS. Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention. Lancet Oncol. 2002; 3:461–9.
1. Hecht 2002

11. The most important health message a doctor can give to patients is to quit smoking.