Biochemistry of Carcinogens

1. BCH475 Biochemistry of Carcinogens Md. Ashrafuzzaman, D.Sc. Known as: Dr. Ashraf Email: mashrafuzzaman@ksu.edu.sa Emergency contact cell: 0564174931 Office: 2B10, Bldg # 5, KSU Biochemistry of Carcinogens Carcinogens are agents that can cause cancer Cancer -The disease caused by an uncontrolled division of abnormal cells in a part of the body. -A malignant growth of tumor resulting from such a division of cells.

2. Normal cell, cancer cell and tumour

3. Comparison between the characteristics of normal and cancer cells Normal cells Normal body cells have a number of important characteristics. They can • Reproduce themselves exactly • Stop reproducing at the right time • Stick together in the right place • Self destruct if they are damaged • Become specialized or 'mature‘ • Show specific and normal functioning  Cancer cells • Cancer cells are different to normal cells in several ways. • They don't die if they move to another part of the body • Cancer cells don’t stop reproducing • Cancer cells violate signals from other cells • Cancer cells stay immature and don’t specialize • Cancer cells do not stick together

4. State of Cancer in USA According to the National Cancer Institute, USA in 2010, the most common cancers (excluding non-melanoma skin cancers) are listed below. Cancer type,Estimated new cases,Estimated deaths Bladder 70,530 14,680 Breast (female-male) 207,090-1,970 39 840-390 Colon and rectal (combined) 142, 570 51 370 Endometrial 43,470 7 950 Kidney (renal cell)  53,581 11,997 Leukemia 43,050 21,840 Lung (including bronchus) 222,520 157,300 Melanoma 68,130 8,700 Non-Hodgkin lymphoma 65,540 20,210 Pancreatic 43,140 36,800 Prostate 217,730 32,050 Thyroid 44,670 1,690 The three most common cancers in men, women and children in the U.S. are as follows: Men: Prostate, lung, and colorectalWomen: Breast, colorectal, and lung

5. State of Cancer in Saudi Arabia and the world According to the Saudi Cancer Registry The average yearly number of cancer incidences reported in the Kingdom of Saudi Arabia over a decade between 1997 and 2007 was 10,000. Importantly, the yearly number has been found to show a tendency of fast growth in recent years. The reporting sources for Saudi Cancer registry include all health care practitioners who diagnose or treat cancer, as well as hospitals, clinical laboratories, and other cancer diagnosis and treatment facilities within Saudi Arabia. Due to heavy presence of foreign workers and professionals in Saudi Arabia who often avoid reporting their cancer or other cases of diseases to the Saudi Cancer Registry the real number of the cancer cases in the Kingdom is predicted to be much higher than the reported statistics. World stages In the world stages especially in the developed world countries where the disease screening and the related medical statistics are most up-to-date the scenarios are found to be with dangerous trends. US: According to a recent USA study overall 8% of adults aged 18 years and over had ever been told by a doctor or other health professional they had some form of cancer. It also suggests that as age increased, the percentage of adults who had ever been told by a doctor or other health professional that they had cancer increased. Canada: According to Canadian Cancer Society’s report, an estimated 177,800 new cases of cancer (excluding about 74,100 non-melanoma skin cancers) and 75,000 deaths would occur in Canada in 2011. 29.6% of all deaths happened due to cancer in Canada in 2007. At the beginning of 2007, there were approximately 748,897 Canadians who had been diagnosed with cancer in the previous 10 years. This represents about 2.3% of the Canadian population or 1 out of every 44 Canadians. World: According to 2002 report, worldwide, it is estimated that there were 10.9 million new cancer cases, 6.7 million deaths, 24.6 million persons living with cancer . The rates had been increasing since then.

6. Tumor • An abnormal mass of tissue. Tumors are a classic sign of inflammation, and can be benign or malignant (cancerous). There are dozens of different types of tumors. Their names usually reflect the kind of tissue they arise in, and may also tell you something about their shape or how they grow. For example, a medulloblastoma is a tumor that arises from embryonic cells (a blastoma) in the inner part of the brain (the medulla). Diagnosis depends on the type and location of the tumor. Tumor marker tests and imaging may be used; some tumors can be seen (for example, tumors on the exterior of the skin) or felt (palpated with the hands). • Treatment is also specific to the location and type of the tumor. Benign tumors can sometimes simply be ignored, or they may be reduced in size (debulked) or removed entirely via surgery. For cancerous tumors, options include chemotherapy, radiation, and surgery. See also blastoma, carcinoembryonic antigen test, desmoid tumor, ear tumor, epidermoid carcinoma, epithelial carcinoma, esophageal cancer, syringoma, fibroid, tumor marker.

7. Tumor versus Cancer A collection of pus is by definition a tumor. A cancer is a particularly threatening type of tumor. • neoplasm- An abnormal new growth of tissue that grows more rapidly than normal cells and will continue to grow if not treated. These growths will compete with normal cells for nutrients. This is a non-specific term that can refer to benign or malignant growths. A synonym for tumor. • tumor- The more commonly used term for a neoplasm. The word tumor simply refers to a mass. This is a general term that can refer to benign or malignant growths. • benign tumor- A non-malignant/non-cancerous tumor. A benign tumor is usually localized, rarely spreads to other parts of the body and responds well to treatment. However, if left untreated, benign tumors can lead to serious disease. • malignant tumor- Cancer. A malignant tumor is resistant to treatment, may spread to other parts of the body and often recurs after removal. cancer- A malignant tumor (a malignant neoplasm).

8. Anaplasia • Anaplasia is the abnormal lack of differentiation in cells. It is characteristic of malignant tumors and usually refers to a reversal in cell differentiation. However, it can also refer to the failure of cells to differentiate in the first place. • Many tissues in the human body contain stem cells, which are undifferentiated and can self-renew through cell division. Being undifferentiated means that stem cells are multipotent or multidifferential; they can become one of several cell types depending upon the needs of the body. For example, stem cells in the bone marrow are able to differentiate into all the different types of blood cells. • Anaplasia occurs when differentiated body cells return to an undifferentiated state, often forming a tumor. Cells undergoing anaplasia also often show an increased ability to multiply. Stem cells that fail to differentiate properly can also be the source of cancerous tumors. • Most body cells contain a nucleus, which can be considered the control center of the cell and contains most of the cell's genetic material. Cytoplasm fills the area between the cell membrane, the outer boundary of the cell, and the nucleus. Cells that undergo anaplasia are characterized by large, darkly-colored nuclei and large cytoplasm-to-nucleus ratios, 1:1 instead of the normal 1:4 or 1:6. Anaplasia may result in cells with multiple nuclei, and the cells themselves are often abnormally large.

9. Anaplasia and plemorphism Anaplastic cells display marked plemorphism where cells appear with marked nuclear shape and size variation.

10. Tumorigenesis Carcinogenesis or oncogenesis or tumorigenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells • What causes cancer? • It is complex. Effects of many things like exposure of carcinogens (various types) tobacco use, certain infectious, radiation (persons working with radiation hazards), lack of physical activity, poor diet and obesity, abnormal physical activity, etc. All these factors can directly or indirectly damage genes or combine with existing genetic faults within cells to cause the disease. • Hereditary: 5-10% of cancers.

11. Tumorigenesis By reducing ambient oxygen exposure in de novo cancer models, this study shows the potential importance of oxygen in influencing the initiation of tumorigenesis. Although large human epidemiologic datasets have correlated exposure to higher altitudes with lower cancer incidence, this study demonstrates that lower ambient oxygen levels delay tumorigenesis, independent of other variables such as barometric pressure and ultraviolet exposure associated with high altitude Ambient oxygen increases DNA damage and promotes tumorigenesis in cancer cell p53−/− mice

12. Cell differentiation Some tumors may experience poor cell differentiation Some cancer cells begin to multiply before they are fully mature. This causes disturbances, both in the shape and structure of the cell, and also possibly of the architecture of the tumor as a whole. The sooner the cells begin to divide, the "wilder" they become, both in the way they look, and in their behavior. Tumors that have a greater proportion of these rapidly-dividing cells will grow faster, and tend to spread earlier. Such cancer is said to be more aggressive. Stem cell specific and conventional cancer therapies

13. Apoptosis • Apoptosis, or programmed cell death, is a normal component of the development and health of multicellular organisms. • Controlled versus uncontrolled cell death. Cells die in response to a variety of stimuli and during apoptosis they do so in a controlled, regulated fashion. This makes apoptosis distinct from another form of cell death called necrosis in which uncontrolled cell death leads to lysis of cells, inflammatory responses and, potentially, to serious health problems. • Cell Suicide. Apoptosis, by contrast, is a process in which cells play an active role in their own death (which is why apoptosis is often referred to as cell suicide). • Cell signalling and apoptosis. Upon receiving specific signals instructing the cells to undergo apoptosis a number of distinctive changes occur in the cell. A family of proteins known as caspases are typically activated in the early stages of apoptosis. These proteins breakdown or cleave key cellular components that are required for normal cellular function including structural proteins in the cytoskeleton and nuclear proteins such as DNA repair enzymes. The caspases can also activate other degradative enzymes such as DNAses, which begin to cleave the DNA in the nucleus.

14. Apoptotic pathway The receptor aggregation stimulates recruitment of FADD and caspase (casp) 8 activation, which is regulated by cFLIP and growth factor signalling through the MAPK pathway. Casp 8 activation leads to casp 3 cleavage, which initiates multiple proapoptotic processes, including CAD stimulation of DNA cleavage. Through the mitochondrial pathway, prosurvival signaling through AKT activation stimulates phosphorylation of BAD, which allows BCL2 to exert its antiapoptotic effects by blocking proapoptotic proteins NOXA and BAX.

15. Biomarker in Apoptosis PS externalization. Early in the apoptotic process there is a rapid redistribution and exposure of phosphatidylserine (PS) on the cell surface mediated by the enzyme scramblase. PS is normally restricted to the inner leaflet of the lipid bilayer by an ATPdependent enzyme called flippase (translocase). Flippase, in concert with a second ATP-dependent enzyme, floppase, that pumps cationic phospholipids such as phosphatidylcholine (PC) and sphingomyelin to the cell surface, maintains an asymmetric distribution of different phospholipids between the inner and outer leaflets of the plasma membrane.

16. Occupational CancerOccupational cancer is cancer that is caused wholly or partly by exposure to a carcinogen at work. • How common is occupational cancer? The US data here gives an idea. Type of Cancer Related to Occupational Exposure % Lung 6.3-13% Bladder 3-19% Mesothelioma 85-90% (men); 23-90% (women*) Leukemia 0.8-2.8% Laryngeal 1-20% (men) Skin Cancer (non-melanoma) 1.5-6% (men) Sinonasal and nasopharyngeal 31-43% (men) Kidney 0-2.3% Liver 0.4-1.1 (vinyl chloride only; men) • In general, the overall attributable risk for mesothelioma in women is 23%. However, if the woman has had "take-home" exposure to asbestos, the risk may be around 90%. "Take-home" exposure results from asbestos being carried home on contaminated work clothing or other items. Mesothelioma is a rare form of cancer that develops from transformed cells originating in the mesothelium, the protective lining that covers many of the internal organs of the body. It is usually caused by exposure to asbestos-silicate minerals. Reference: Data From: Steenland, K., et al. Dying for work: the magnitude of US mortality from selected causes of death associated with occupation. American Journal of Occupational Medicine. Vol. 43 (2003). p. 461-482

17. Extrinsic factors in Cancer Intrinsic and extrinsic factors in estrogen action in human breast cancer: role of polyamines and pituitary factors. Although polyamines are important in regulating proliferation of mammalian cells, their role in hormone induction of cell growth has not been delineated. It has have identified both intrinsic (polyamines) and extrinsic (pituitary/serum) factors that are importance for estrogen to exert its mitogenic action.

18. Cell intrinsic & extrinsic factors in cervical carcinogenesis • Human papillomavirus (HPV) infection is a common sexually transmitted infection which a majority of infected women are able to clear by mounting an effective immune response. Individuals with a suboptimal immune response may be at increased risk of persistent HPV infection leading to sequelae of various grades of dysplasias and / or associated malignancy. HPV in cervical cancer progression. Human cervix is covered by squamous or columnar epithelium. The squamocolumnar junction has certain reserve cells that can differentiate into either of the cell fate. HPV infects the basal cells of squamous epithelium. Viral particles are released by the mature differentiated cells which can reinfect. With the expression of viral oncoproteins the lesions progress from Low grade squamous intraepithelial Lesion (LSIL) to high grade (HSIL). The presence of estrogen and high expression of viral proteins after the integration of the viral genome initiates squamous cell carcinoma (SCC) progression in the reserve cells of transition zone.

19. Chimney-sweeps and cancer A chimney sweep is a worker who clears ash and soot from chimneys. Chimney sweep's cancer called Soot wart (formerly known as Percival Pott), is a squamous cell carcinoma of the skin of the scrotum. It has the distinction of being the first reported form of occupational cancer, 1775. Pott was the first person to demonstrate that a malignancy could be caused by an environmental carcinogen. How to avoid (first aid): Wash your body with clean water immediately after work.

20. Dye workers and cancer of the lungLuminous paint and bone cancerMining and lung cancerUV-light and skin cancer • 5% of cancer in men 1% of cancer in women result from exposure to carcinogenic substances in their work environment: • lung and pleura • bladder • skin • laryngeal • nasal cavity • leukemia • Throat • lymphoma • soft-tissue sarcomas • Liver Read more:http://www.answers.com/topic/occupational-exposures-and-cancer#ixzz1mFMqdk3R Such a Budhdha costume is good to divert a lot of work related cancers. Think of its suitability, confortability and affordability.

21. Classification of carcinogens • People are continuously exposed to varying amounts of chemicals that have been shown to have carcinogenic or mutagenic properties in experimental systems. • Chemical carcinogens can occur exogenously or endogenously in living organisms (aerobic metabolic processes, hormonal changes, oxygen uptake and distribution, pathophysiologic states such as inflammation, genetic factors, etc.). • Exogenous exposure to carcinogens can occur through food consumption, air, occupational exposure and drinking water. • Exposure to extrinsic or environmental carcinogens may 75-80% human cancers. • Epidemiology study suggests that lifestyle causes of cancer such as diet, tobacco smoking, obesity, alcohol, random sex, etc., are the major contributors to human malignant neoplasms. Old people are most vulnerable to carcinogens and other causes of cancers. Carcinogenesis is a multistep process that affects to a great extent old age. Youths are vulnerable to oral sex related cancer. The incidence of oral cancer due to a virus transmitted during oral sex has increased steeply over the last 30 years. And scientists relate this trend to changes in people's sexual behaviour. The number of tongue, mouth and throat cancers due to the sexually transmitted human papilloma virus (HPV), which can also cause cervical cancer in women, rose by about a third from 1973 to 2004. The carcinogenic risk to chemical carcinogens is a composite of its effects on multiple genetic and epigenetic processes. Policy making. Various international and national agencies collect experimental data and risk assessment studies on chemical carcinogens through in vivo studies on experimental animals and in vitro studies in cell lines. They set the limits of exposure (especially in the working environment) and legislate to restrict the use of chemical carcinogens in other applications.

22. A few specific types • Genotoxicity. A deleterious action on a cell's genetic material affecting its integrity. Chemical compounds and radiation both are responsible. Genotoxic substances have strong affinity to interact with DNA, may cause potentially mutagenic or cancerogenic effects. Activation-dependent and independent effects. (A) Microvessel density reduction by intramuscular and intratumoral IL12 electrotransfer. (B) Morphological change in microvessels in the tumors receiving intramuscular IL12 electrotransfer. Treatment was done by injection of the IL12 gene.

23. Solid state hormones. Neuropeptides and peptide hormones are packaged in a concentrated condensed form maintaining peptides in an aggregate or solid state. Structure in biological systems. The acidic environment helps this solid state/condensed form. • Carcinogenesis promoter. Promoters represent cancer risk factors that are capable of triggering the preferential multiplication of initiated cells without having the potential to initiate alone the process of carcinogenesis. Promoters should be inactive at increasing the risk of cancer when given alone. • Immunosuppressant/immunotoxins. An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone.When the immune system function is suppressed, there is an increased susceptibility to infectious diseases and cancers.

24. Procarcinogens Procarcinogens are chemical substances that becomes carcinogenic only after they are altered by metabolic processes. Example: Nitrites-when taken in by the diet. They are not carcinogenic themselves, but turn into nitrosamines in the body, which are carcinogenic. Example: The drug diethylstilboestrol (a synthetic oestrogen no longer in clinical use) is metabolized to an epoxide intermediate, which can cause cervical cancer. Process. It is during some enzymatic process of detoxification of foreign chemicals that a procarcinogen may be converted into an ultimate carcinogen Ultimate carcinogens:these are direct acting because they possess the correct chemical. Procarcinogens/precarcinogens: these require some kind of structural conversion. The whole conversion process is known as bioactivation. Fate of carcinogens??

25. Oxygenases or Oxidases An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 (as in air) to it. Types: There are two types of oxygenases: • Monooxygenases, or mixed function oxidase, transfer one oxygen atom as a hydroxyl group to the substrate, and reduce the other oxygen atom to water. • Dioxygenases, or oxygen transferases, incorporate both atoms of molecular oxygen (O2) into the product(s) of the reaction.[6] Example: Among the most important monooxygenases are the cytochrome P450 oxidases, responsible for breaking down numerous chemicals in the body. The monooxygenase reaction also requires a reduced substrate (NADH or NADPH) as an electron donor, according to the following equation: A + O2 + BH2 → AO + H2O + B where A represents an organic compound and B represents the electron donor.

26. Oxygenase reactions in cells of higher plants

27. POLYCYCLIC AROMATIC HYDROCARBONS (PAHs) or Polynuclear Aromatic Hydrocarbons, PNA Numbers: ~ 10,000 compounds Examples: Benzo(a)pyrene, Benzanthracene, Benzo(b)fluoranthene, Fluoranthene, Naphthalene,.. Sources. Mostly environment. They are from incomplete burning of carbon-containing materials like oil, wood, garbage or coal. Many useful products such as mothballs, blacktop, and creosote wood preservatives contain PAHs. Special-purpose skin creams and anti-dandruff shampoos that contain coal tars. ETC. • Automobile exhaust, industrial emissions and smoke from burning wood, charcoal and tobacco contain high levels of PAHs. In general, more PAHs form when materials burn at low temperatures, such as in wood fires or cigarettes. High-temperature furnaces produce fewer PAHs. • Fires can form fine PAH particles. They bind to ash particles and can move long distances through the air. Some PAHs can dissolve in water. PAHs can enter groundwater from ash, tar, or creosote that is improperly disposed in landfills. • HOW ARE PEOPLE EXPOSED TO PAHs? Breathing, drinking, eating, touching, etc. • Harmful health effects: Cancer, various organ systems, reproductive effects, etc.

28. PAHs cause breast cancer in humans!Liver cancer! • Most carcinogens bind (covalent bond) with proteins, RNAs, DNAs. Lead to cancers. • It is not known whether PAHs affect breast cancer risk in humans. Studies done to date are not conclusive. Some of the research on PAHs and breast cancer in humans is summarized below. • Cigarette Smoking: While cigarette smoking is a major source of exposure to PAHs, most studies have not seen a higher risk of breast cancer in women who smoke. • Workplace studies: A small number of studies have been conducted involving women with work exposure to PAHs. None have shown an increased breast cancer risk. • Markers of exposure: More recent studies have begun to evaluate whether measurable markers (indicators) of exposure to PAHs are associated with breast cancer risk. Once PAHs enter the body, they go to most internal organs, especially those containing fat. Most PAHs are converted in the body to non-toxic materials and leave the body in a few days in urine and bowel movements. Some become activated and bind to genetic material (DNA) forming PAH-DNA adducts.PAH-DNA adducts are markers of PAH exposure. The formation of DNA adducts is thought to be necessary for the development of cancer. • One study compared PAH-DNA adduct levels in 100 women with breast cancer to 105 women without breast cancer. Twice as many of the women with breast cancer had high PAH-DNA adduct levels in their breast tumors compared to the levels in breast tissue of women without breast cancer. However, the average levels of DNA-PAH adducts was similar in the normal breast tissue of women with or without breast cancer. So, while PAH-DNA adducts may be formed in greater numbers and accumulate in breast tumors, breast cancer risk cannot be predicted from levels of PAH-DNA adducts in normal breast tissue. • Genetic differences: Studies are also underway to evaluate the risk of breast cancer due to differences in genes (called genetic polymorphism). Certain genes affect the way the body activates or breaks down PAHs. One gene of interest is called CYP1A1. In a study of 216 women with breast cancer and 282 women without breast cancer, women with different types of the CYP1A1 gene (polymorphism of CYP1A1) who also smoked cigarettes had a higher risk of breast cancer. A long-term national study, the Nurses Health Study, found no overall increase in risk of breast cancer in women with different types of CYP1A1. The results suggested that women with one type of CYP1A1 who had begun cigarette smoking before the age of 18 years were at increased risk of breast cancer. However, this finding involved only eleven women with breast cancer, which is a very small proportion of the total 466 breast cancer cases in the study. While not conclusive, these findings should be investigated in further studies.

29. Mid Term I, 25 marks-Performance indices Excellent Poor MCQ: 25 marks Mean=22.9, S.D.=1.4, No.=19 Median= 23 Min=20(20) Max=24(25) Written type (bonus): 2 marks Mean=0.75, S.D.=0.6 Median=0.63 Min=0 Max=2 Recommendation!!! Need to study more to understand the general concepts!

30. Aromatic amines USED IN: Tobacco smoke, diesel exhaust, formed in production of polyurethane foams, dyes, pesticides and pharmaceuticals FOUND IN: plastic and chemical industries, as byproducts of the manufacturing of compounds such as polyurethane foams, dyes, pesticides, pharmaceuticals and semiconductors. Environmental pollution such as diesel exhaust, combustion of wood chips and rubber, tobacco smoke and grilled meats and fish are other sources. TYPES: 3 types of aromatic amines: monocylic, polycyclic and heterocyclic. Some monocyclic amines, including o-toluidine (C7H9N), have been identified in the breast milk of healthy lactating women. o-toluidine is known to cause mammary tumors in rodents. This indicate that the mother’s mammary tissue and the nursing child are exposed to environmental (mainly work related) carcinogens during breast-feeding. Risk: breast cancer Heterocyclic aromatic amines (HAAs) are formed, along with PAHs, when meats or fish are grilled or otherwise cooked at high temperatures. Risk: Increased amount of DNA adducts (in association with HAAs) that are indicators of problems in DNA repair in cells, one of the early hallmarks of tumor development. HAAs can mimic estrogen, and also can have direct effects on cell division processes in ways that might enhance the development of tumors.

31. AZO dyes. -Contain an azo group, -N=N-,  which links two hybridised carbon atoms. Often, these carbons are part of aromatic systems.-Azo dyes give bright, high intensity colours.-azo compound class accounts for 60-70% of all dyes. Aniline. -an organic base used to make dyes, drugs, explosives, plastics, and photographic and rubber chemicals. -Aniline was first obtained in 1826. -Chemical formula: C6H5NH2. -Pure aniline is highly poisonous, oily, colorless with a pleasant odor Benzidine. the trivial name for 4,4'-diamino biphenyl, is the solid organic compound with the formula (C6H4NH2)2. This aromatic amine is a component of a test for cyanide and also in the production of dyes. -Benzidine has been linked to bladder and pancreatic cancers. Naphthylamine. It is an aromatic amine. 1-naphthylamine sulfonic acids are used for the preparation of azo dyes.

32. Aromatic amines and their conversion to ultimate carcinogens Aromatic amines are indirectly acting carcinogens requiring multiple metabolic transformation to hydroxylamines and their ultimate active form. E.g. DNA Damage by Aromatic Amines – Are Arylamine Adducts responsible for the Induction of the Chemical Carcinogenesis? The initial step is an oxidation catalyzed by cytochrome of the arylamine to the corresponding N-hydroxylamine, followed by esterification into an N-acetoxyarylamine by N-acetyl transferase (NAT) or into a sulfate by a sulfotransferase (ST) to give the ultimate carcinogens. See here: http://www.chemie.uni-hamburg.de/oc/meier/research/oligos.html DNA addducts. a DNA adduct is a piece of DNA covalently bonded to a (cancer-causing) chemical. This process could be the start of a cancerous cell, or carcinogenesis. Covalent adducts between chemical mutagens and DNA. Such couplings activate DNA repair processes and, unless repaired prior to DNA replication, may lead to nucleotide substitutions, deletions, and chromosome rearrangements. This is the beginning of causing cancer. • Chemicals which form DNA adducts include: • acetaldehyde, is a significant constituent of tobacco smoke • cisplatin binds to DNA and causes crosslinking, leading to death of the cell • DMBA (7,12-dimethylbenz(a)anthracene) • malondialdehyde, a naturally occurring product of lipid peroxidation[3] See here: http://www.reference.md/files/D018/mD018736.html

33. Nitronium Ion The nitronium ion, , NO+2, is a generally reactive cation created by the removal of an electron from the paramagnetic nitrogen dioxide molecule, or the protonation of nitric acid. • It is reactive enough to exist in normal conditions, but it is used extensively as an electrophile in the nitration of other substances. The ion is generated in situ for this purpose by mixing concentrated sulfuric acid and concentrated nitric acid according to the equilibrium: 2 H2SO4 + HNO3 → 2 HSO−4 + NO+2 + H3O+ -The aryl nitrenium ions are believed to be the ultimate reactive metabolites, which attack DNA to form DNA adducts

34. Urinary Pathway 1. Human urinary system: 2. Kidney, 3. Renal pelvis, 4. Ureter, 5. Urinary bladder, 6. Urethra. (Left side with frontal section)7. Adrenal gland Vessels: 8. Renal artery and vein, 9. Inferior vena cava, 10. Abdominal aorta, 11. Common iliac artery and vein With transparency: 12. Liver, 13. Large intestine, 14. Pelvis

35. Urinary bladder cancer Definition of bladder cancer Cancer that forms in tissues of the bladder (the organ that stores urine). Most bladder cancers are transitional cell carcinomas (cancer that begins in cells that normally make up the inner lining of the bladder). Other types include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). The cells that form squamous cell carcinoma and adenocarcinoma develop in the inner lining of the bladder as a result of chronic irritation and inflammation.  Estimated new cases and deaths from bladder cancer in the United States in 2012:New cases: 73,510Deaths: 14,880 Drugs Approved for Bladder Cancer Adriamycin PFS (Doxorubicin Hydrochloride)Adriamycin RDF (Doxorubicin Hydrochloride)CisplatinDoxorubicin HydrochloridePlatinol (Cisplatin)Platinol-AQ (Cisplatin)

36. Biliary pathway The biliary system is comprised of the organs and duct system that create, transport, store and release bile into the duodenum for digestion. Includes the liver, gallbladder and bile ducts (named the cystic, hepatic, common, and pancreatic duct). Bile (yellow material) in a liverbiopsy in the setting of bile stasis, i.e. cholestasis. H&E stain • Action of bile salts in digestion • Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum. Bile is a composition of the following materials: water (85%), bile salts (10%), mucus and pigments (3%), fats (1%), inorganic salts (0.7%) and cholesterol (0.3%).

37. Intestinal cancer(Also called: Duodenal cancer, Ileal cancer, Jejunal cancer, Small intestine cancer)  Your small intestine is part of your digestive system. It is a long tube that connects your stomach to your large intestine. Intestinal cancer is rare, but eating a high-fat diet or having Crohn's disease, celiac disease, or a history of colonic polyps can increase your risk. Potential intestinal cancer symptoms: • Abdominal pain, cramps (i.e., after eating) • Unexplained weight loss • Weak or tired feeling • Nausea or vomiting • Bloody stool • A lump in the abdomen • Jaundice • Loss of appetite Diagnosis: Imaging tests that create pictures of the small intestine and the area around it can help diagnose intestinal cancer and show whether it has spread. Treatment: Surgery is the most common treatment. Additional options include chemotherapy, radiation or a combination.

38. Intestinal Flora Intestinal Flora Intestinal flora are harmless microorganisms such as bacteria, yeasts, and fungi that inhabit and grow in the intestines. These microorganisms are essential to the normal functioning of the digestive tract, and certain species of intestinal flora are beneficial to the human body. These “good” bacteria often have a symbiotic relationship with the human body as both derive benefit from one another. For example, “The normal [intestinal] flora derive from their host a steady supply of nutrients, a stable environment, and protection and transport. The host obtains from the normal [intestinal] flora certain nutritional and digestive benefits, stimulation of the development and activity of immune system, and protection against colonization and infection by pathogenic microbes. Beneficial bacteria such as intestinal flora are often referred to a probiotics. “Probiotics...is an umbrella term given to any live microorganism that is beneficial to its host. Eat probiotic bacteria containing yogort regularly

39. Alkylating agents and related carcinogenesis A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes. • Alkylating agents are a class of chemotherapy drugs that bind an alkyl group (CnH2n+1) to DNA and prevent proper DNA replication and transcription of RNA. • They have chemical groups that can form permanent covalent bonds with nucleophilic substances in the DNA. • Alkylating agents are used as part of chemotherapy in different types of cancers. • Synthetic compounds containing alkyl groups that combine readily with other molecules. • The major site of action is on the base guanine. • They are primarily used in chemotherapy of cancer (see antineoplastic therapy). However, they do not damage malignant cells selectively, but also have a toxic action on normal cells; all killing occurs primarily in rapidly proliferating tissue. Different C4-alkanes and -cycloalkanes (left to right): n-butane and isobutane are the two C4H10 isomers; cyclobutane and methylcyclopropane are the two C4H8 isomers.Bicyclo[1.1.0]butane is the only C4H6 compound and has no isomer; tetrahedrane (not shown) is the only C4H4 compound and has also no isomer.

40. Alkylating agents and related carcinogenesis A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes. • Alkylating agents are a class of chemotherapy drugs that bind an alkyl group (CnH2n+1) to DNA and prevent proper DNA replication and transcription of RNA. • They have chemical groups that can form permanent covalent bonds with nucleophilic substances in the DNA. • Alkylating agents are used as part of chemotherapy in different types of cancers. • Synthetic compounds containing alkyl groups that combine readily with other molecules. • The major site of action is on the base guanine. • They are primarily used in chemotherapy of cancer (see antineoplastic therapy). However, they do not damage malignant cells selectively, but also have a toxic action on normal cells; all killing occurs primarily in rapidly proliferating tissue. Symptoms -Locally they cause blistering of the skin and damage to the eyes and respiratory tract. -Systemic toxic effects are nausea and vomiting, reduction in both leukocytes and erythrocytes, hemorrhagic tendencies, amenorrhea or impaired spermatogenesis, damage to the intestinal mucosa, and alopecia. Among the agents of this group used in therapy are busulfan, cyclophosphamide, ifosfamide, and thiotepa; the nitrogen mustardschlorambucil, melphalan, and mechlorethamine; and the nitrosoureascarmustine, lomustine, and streptozocin. Carcinogenesis in humans. Linked to bladder cancer and acute leukemia. However, the major benefits obtained in treating diseases such as lymphoma, Hodgkin's disease, breast cancer, and multiple myeloma far outweigh the risks of developing a second malignancy.

41. Mustard Gas A poison gas attack using gas cylinders in World War I. The types of weapons employed ranged from disabling chemicals, such as tear gas and the severe mustard gas, to lethal agents like phosgene and chlorine. This chemical warfare was a major component of the first global war and first total war of the 20th century. British soldiers blinded by mustard gas Adolf Hitler According to his own account in Mein Kampf, Adolf Hitler was temporarily blinded by gas while healing in an hospital in Wervik. As a result, in part Hitler adamantly refused to authorize the use of poison gas on the battlefield during World War II.

42. Mustard gas and cancer The sulfur mustards, or sulphur mustards, commonly known as mustard gas, are a class of related cytotoxic and vesicant chemical warfare agents with the ability to form large blisters on the exposed skin and in the lungs. Pure sulfur mustards are colorless, viscous liquids at room temperature. When used in impure form, such as warfare agents, they are usually yellow-brown in color and have an odor resembling mustard plants, garlic or horseradish, hence the name. The compound readily eliminates a chloride ion by intramolecular nucleophilic substitution to form a cyclic sulfonium ion. This very reactive intermediate tends to permanently alkylate the guanine nucleotide in DNA strands, which prevents cellular division and generally leads directly to programmed cell death or, if cell death is not immediate, the damaged DNA may lead to the development of cancer. • Synthesis • Sulfur mustard (Cl-CH2CH2)2S. In the Depretz method, it is synthesized by treating sulfur dichloride with ethylene: • SCl2 + 2 C2H4 → (Cl-CH2CH2)2S • In the Levinstein process, sulfur monochloride is used instead: • 8 S2Cl2 + 16 C2H4 → 8 (Cl-CH2CH2)2S + S8 • In the Meyer method, thiodiglycol is produced from chloroethanol and potassium sulfide and chlorinated with phosphorus trichloride: • 3 (HO-CH2CH2)2S + 2 PCl3 → 3 (Cl-CH2CH2)2S + 2 P(OH)3 • In the Meyer-Clarke method, concentrated hydrochloric acid (HCl) instead of PCl3 is used as the chlorinating agent: • (HO-CH2CH2)2S + 2 HCl → (Cl-CH2CH2)2S + 2 H2O

43. Mustard gas , agents and treatment of Cancer -Mustard gas, more properly called nitrogen mustard, is an extremely toxic substance. Created by the Germans in World War I, -If respirators were not worn, the death rate was about 50 percent. Its exposure causes burning on the skin, severe irritation of the lung tissues if the gas is inhaled. Discovery of mustard gas based Chemotherapy During World War II, some soldiers who were accidentally exposed to mustard gas were found to have low white blood cell counts, leading doctors to suspect the substance might have possibilities as a chemotherapy agent. White blood cells and cancer cells both grow rapidly, and the theory was advanced that mustard gas might have the same effect on cancer cells as it did white blood cells. Some patients with advanced lymphomas -- lymphoma is a cancer of the white blood cells -- were given a form of mustard gas by vein. The patients improved, although the effects were not long-lasting.

44. Nitrogen Mustard and Chemotherapy • Nitrogen Mustard and Chemotherapy • Some drugs derived from nitrogen mustard are still used in chemotherapy today. They are usually used in combination with other chemotherapy drugs. Mustargen, mustine Drug ‘mechlorethamine hydrochloride CH3N(CH2CH2Cl)2•HCl are all forms of nitrogen mustard. These medications are injected into the veins for lymphomas and cancers, and also used as a lotion for skin lesions of one type of lymphoma. Nitrogen mustard preparations are used in the treatment of Hodgkin's disease (white blood cells originated cancer), non-Hodgkin's lymphoma, and as palliative chemotherapy in lung and breast cancers. Palliative chemotherapy is not a cure, but is used to shrink tumors or otherwise improve the quality of life. Toxicity. Nitrogen mustard drugs are extremely toxic. In fact, they can actually cause cancer as well as help cure it. Medical personnel who prepare these medications must wear protective garb such as gloves and avoid inhaling the powder. According to Drugs.com, treatment with Mustargen can result in the patient developing a second malignant tumor, and the International Agency for Research on Cancer calls it a "probable carcinogen," or cancer-causing agent. Consideration. Although mustard gas in its original form is not used as a treatment for lung cancer, nitrogen mustard derivatives are still in use.

45. Laboratory hazards-Chemicals • What types of hazardous chemicals are present in laboratories? Hazardous chemicals present physical or health threats to workers in clinical, industrial, and academic laboratories. They include carcinogens, toxins, irritants, corrosives, sensitizers, hepatotoxins, nephrotoxins, neurotoxins as well as agents that act on the hematopoietic systems (involved in blood production) or damage the lungs, skin, eyes, or mucous membranes. Current rules limit exposures to approximately 400 substances.

46. Chromosomal aberration The exposure of cells to ionising radiations such as X-rays, γ-rays or charged particles can result in an injury of different cellular constituents including DNA. DNA, which carries the genetic information of the cell, is the most critical target. In higher organisms the DNA is organised in chromosomes. During interphase (growth phase of the cell) the chromosomes are long, thin threads that are individually indistinguishable.  During cell division (mitosis) chromosomes reach their highest degree of condensation. A chromosome anomaly, abnormality or aberration reflects an atypical number of chromosomes or a structural abnormality in one or more chromosomes. Cancer causing agents are often responsible. Chromosomes are composed of long thin molecules of DNA. When cells are exposed to radiation or carcinogens, DNA sometimes breaks, and the broken ends may rejoin in different patterns from their original arrangement. The abnormalities that result are termed "chromosome aberrations" and may be visualized at mitosis when cells divide. Metaphases labeled with fluorescence in situ hybridization (FISH). The left metaphase shows a normal cell and the right, a translocation indicated by arrows The frequency of chromosome aberrations increases with radiation dose to the cells and serves as an indicator of radiation dose received, i.e., a biological dosimeter.

47. Chromosomal aberration-quantificationThe frequency of chromosome aberrations increases with radiation dose to the cells and serves as an indicator of radiation dose received, i.e., a biological dosimeter. World war II: USA bombed Japan Relationship between fraction of cells with chromosome aberrations and radiation dose to AHS survivors exposed in typical Japanese houses Cancer Cancer Cancer

48. NitrosaminesNitrosamines are chemical compounds of the chemical structure R1N(-R2)-N=O R stands for amine group (chemical compounds derived from ammonia) 90% of nitrosamines are carcinogenic. Discovery over 100 years ago, but not until 1956 did they receive much attention. In 1956 John Barnes and Peter Magee reported that dimethylnitrosamine produced liver tumors in rats. In the early 1970s, there were outbreaks of liver disorders, including cancer, in various farm animals in Norway. Intensive investigations revealed that all of the affected animals had consumed rations containing herring meal (protein feed supplement), which had been preserved by the addition of relatively large amounts of sodium nitrite. Further investigation showed that the herring meal contained dimethylnitrosamine, the same compound that Magee and Barnes had reported as a strong liver carcinogen nearly a decade earlier. Dimethylnitrosamine was formed in the fish meal as a result of a chemical reaction between dimethylamine, a commonly occurring amine in fish meal, and

49. Nitrosamines in Food, Body Fluids, and Occupational Exposure Fried bacon Cured (preserved) meats Beer Nonfat dry milk Tobacco products Gastric juices Rubber products Rubber manufacturing Metal industries,  Pesticide production and use Certain cosmetics Certain chemical manufacturing ETC.

50. Nitrosamines and cancer Physical appearance in stomach: yellow liquid Tobacco-specific nitrosamines These nitrosamine carcinogens are formed from nicotine and related compounds by a nitrosation reaction that occurs during the curing and processing of tobacco. Example: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are the most carcinogenic. Cancer NNK and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are potent systemic lung carcinogens in rats. Tumors of the nasal cavity, liver, and pancreas are also observed in NNK- or NNAL-treated rats. NNN is an effective esophageal carcinogen in the rat, and induces respiratory tract tumors in mice, hamsters, and mink. A mixture of NNK and NNN caused oral tumors when swabbed in the rat oral cavity. Cancer types Lung, pancreas, esophagus, and oral cavity in people who use tobacco products. Nitrates and Nitrites may also cause Alzheimer's, Diabetes and Parkinson's diseases