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PHAR 303 > 10. Carcinogens and Targets > Flashcards

10. Carcinogens and Targets Flashcards

1
Q

What is cancer? What are the 2 different types?

A

A disease where:
– Normal cells are damaged
– There is abnormal growth of cells
– There is dysregulation between cell proliferation and cell death
– There are multiple changes in gene expression
• Neoplasia
– New or autonomous growth of tissue (neoplasm is the lesion)
2 Types:
• Benign
– Stay localized in one place (does not invade surrounding tissue)
– Example: fibroma (fibrous or connective tissue)
• Malignant
– Invasive growth, capable of metastases (secondary growths)
– Example: carcinoma (malignant neoplasia of epithelial origin)

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2
Q

What is a carcinogen? What are the different types?

A

A carcinogen is:
– An agent that causes or induces a neoplasm
– Carcinogens damage the genome or disrupt cellular metabolic processes.
– To be a carcinogen, the substance may require
metabolic activation (toxication)
Different types:
• Physical
• Chemical
• Biological
• A natural substance

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3
Q

What is an example of a natural carcinogen?

A

Aflatoxin B1 (from certain molds)

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4
Q

Give 3 examples that start from a carcinogen and end in a cancer.
Provide the human exposure, the carcinogen, and the resulting disease.

A

Human exposure:carcinogen:disease

  • Chimney sweeps : Benzo(a)pyrene : scrotal cancer
  • Aspergillus flavus : Aflatoxin B1 : Liver cancer
  • Cigarettes : Benzene, BaP, Formaldehyde, Acetaldehyde, etc : Lung and many other cancers
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5
Q

What is Edwin Smith Papyrus?

A

Edwin Smith Papyrus
– An ancient Egyptian medical text named after the antiquities dealer who bought the papyrus in 1862
– Oldest known surgical document:
• 3000 BC
• 48 cases of wounds, injuries and fractures
– Oldest description of cancer (word “cancer” not used)
– Describes 8 cases of tumors of the breast:
• About the disease: “There is no treatment”

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6
Q

Who is Hippocrates?

A

– Father of modern medicine (Greek Physician)
– Believed diseases were caused naturally (not because of punishment inflicted by gods):
• Product of environmental factors, diet and living habits
– Described several kinds of cancer
– Karkinos (carcinos)/karkinoma (carcinoma):
• Greek word for crab/crayfish due to the appearance of a solid malignant tumor as its “veins stretched out like a crab has its feet”
• Celsus (Roman physician) translated Greek term into cancer (Latin word for crab)

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7
Q

Who is Paracelsus?

A
  • What is it that is not poison?
  • All things are poison and none without poison. Only the dose determines that a thing is not poison.
  • First to describe occupational carcinogens. Cuz he noticed that men that worked in mines got serious respiratory conditions that prematurely ended their lives.
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8
Q

What is Miner’s sickness?

A 
– Mining-related lung disease
• Pneumonia
• Tuberculosis
• Bronchitis
• Fibrosis
• Lung cancer
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9
Q

What is Schneeberger Lung Disease?

A

– Schneeberger Lung Disease

• Lung cancer named for the Saxonian mining district (Germany/Czech)

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10
Q

Who is Percivall Pott?

A
  • English Surgeon
  • Associated that a cancer could be caused by an environmental carcinogen
  • 1775- Soot causes scrotal cancer in chimney sweeps:
    • Originally termed “Pott’s cancer”
    • “Chimney sweepers’ cancer”
    • Onset was at puberty
  • Act of Parliament: 1875
    • No chimney sweep under the age of 21
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11
Q

Who were the first to show that a chemical could produce cancer? How?

A
  • Who: Yamagiwa and Ichikawa
  • How: Application of coal tar (what the chimney sweepers were exposed to) on rabbit ears produced skin cancer
    • 250 days of painting crude coal tar on inner surface of rabbits ears
    • Malignant epithelial tumors
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12
Q

Who identified the carcinogenic components in soot? How?

A

the British identified the carcinogenic components from the mixtures:
• Cook, Hewett & Hieger- 1933:
• Identification of the polycyclic aromatic hydrocarbons (PAH) benzo[a]pyrene (B[a]P) as the active component of coal tar
• How? Used 2 tons of coal tar pitch (thick, black liquid after distillation of coal tar)
• Pitch is used as base coating of paint, roofing/paving, etc.

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13
Q

Explain the experimental production of carcinoma with cigarette tar.

A

Smoking apparatus: smoked a bunch of cigarettes at a time, collected smoke, and condensed it. This allowed for the collection of tobacco tars which was then dissolved in acetone. The tar was then applied to the dorsal area of mice. A cancer developed.

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14
Q

What does IARC stand for? What is it?

A

International Agency for Research on Cancer
• The IARC is the specialized cancer agency of the World Health Organization (WHO)
• The objective is to promote international collaboration in cancer research:
– To identify causes of cancer so preventative measures can be adopted.
– Elucidating the role of environmental and lifestyle risk factors using population based studies (human) and experimental models (animal)

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15
Q

What are IARC monographs?

A

– Series of scientific reviews that identify environmental factors that increase cancer risk
– Classify carcinogens

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16
Q

How does the IARC classify carcinogens? What evidence is needed for each classification?

A

Group 1: Carcinogenic to humans
Evidence: Human data strong OR when evidence in humans is less than sufficient but there is sufficient evidence in experimental animals and strong evidence that the agent acts through a relevant mechanism of carcinogenicity (Animal data strong)

Group 2A: Probably carcinogenic to humans
Evidence: Human data suggestive but limited, Animal data positive

Group 2B: Possibly carcinogenic to humans
Evidence: Human data weak/limited, Animal data positive or limited

Group 3: Not classifiable as to its carcinogenicity to humans
Evidence: Human data inadequate, Animal data inadequate or limited

(no longer a classification group) Group 4: Probably not carcinogenic to humans
Evidence: Human and animal data negative

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17
Q

What are examples of a Group 1 carcinogen?

A 
Asbestos
Soot
Tobacco
TCDD (dioxin)
Diesel exhaust
Alcohol
Charboiled red meat (B[a]P)
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18
Q

What is an example of a Group 2A carcinogen?

A

DDT, high temperature frying (acrylamide), red meat

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19
Q

What is an example of a Group 2B carcinogen?

A

Chloroform

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20
Q

What is an example of a Group 3 carcinogen?

A

Coffee, chlorinated drinking water

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21
Q

What is an example of a Group 4 carcinogen?

A

Caprolactam

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22
Q

What are the different physical carcinogens?

A

– Radiation

– Fibres: Asbestos

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23
Q

What are the different biological carcinogens?

A

– Viruses
• Human papillomavirus [HPV]- cervical cancer
• Eptein-Barr virus [EBV]- stomach cancer
• Hepatitis B virus [HBV]-liver cancer
– Toxins
• Aflatoxin B1 (AFB1)

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24
Q

What are the different chemical carcinogens?

A

– Genotoxic

– Non-genotoxic

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25
Q

What are genotoxic carcinogens?

A

– interact physically with DNA (damage or change its structure) to initiate tumors:
• Cause DNA adducts (DNA damage cause by covalent attachment of DNA to a chemical)
– DNA-reactive

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26
Q

What are the different types of genotoxic carcinogens?

A

Direct or indirect.

27
Q

What is a direct genotoxic carcinogen?

A

– Active in their parent form
– Activation-independent
– Do not require metabolic activation or chemical modification
– Usually cause tumor formation at site of exposure
– Ultimate carcinogens (the chemical alone can kill you)

28
Q

What are examples of direct genotoxic carcinogens? What is their IARC classification?

A
  1. Nitrogen mustard (mechlorethamine)
    • Group 2A
    • Alkylating agent (Prevent proper DNA replication)
  2. Methyl methanesulfonate (MMS)
    • Group 2A
    • Alkylating agent
    • Used for research
  3. Ethylene oxide (Oxirane)
    • Group 1
    • Alkylating agent
    • Manufacturing (Ethylene glycol)
4. Bis (chloromethyl) ether
• Group 1
• Alkylating agent
• No longer used
• Manufacturing (textile)
29
Q

What are indirect genotoxic carinogens?

A

– Require metabolic activation (toxication)
– Parent compound is called a pro-carcinogen
– Form that interacts with DNA is called the ultimate (final/complete) carcinogen
– Usually forms tumor where metabolic activation occurs (and not necessarily at the site of exposure)
– Mutagenic
– Tumorigenicity is dose-responsive
– No theoretical threshold

30
Q

What are examples of indirect genotoxic carcinogens?

A 
– Aromatic hydrocarbons
• PAHs (B[a]P)
• Benzene
– Aromatic amines
• Industrial chemicals used to make pigments, dyes, drugs (2-Naphthylamine (no longer used))
– N-nitrosamines
• Food and tobacco products
– Aflatoxin
• AFB1
31
Q

What are non-genotoxic (epigenetic) carcinogens? What are its mechanisms of action?

A

– Non- mutagenic: does not involve direct binding, damage or interaction with DNA (but usually perturbs some other biological function)
– Usually requires prolonged exposure at high levels
– Changes how information is expressed from DNA
– Altered signal transduction
– Tumorigenicity is dose-responsive
– Species-, tissue-specificity
– Threshold
– Increase cell proliferation and decrease apoptosis
– Diverse biochemical modes of action:
• Cytotoxicity
• Oxidative stress (Reactive oxygen species)
• Receptor-mediated (receptor activation)
• Methylation (epigenetics)
• Inflammation

32
Q

Explain the difference between genotoxic and non-genotoxic carcinogens in terms of thresholds.

A

Genotoxic: The dose response relationship is linear. There is no threshold and therefore no safe dose.
Non-Genotoxic: there is a threshold below which there is no adverse effect because the lower concentration doesn’t perturb the cellular function in any way.

33
Q

What IARC groups are non-genotoxic? What percentage of chemicals does this make up?

A

Chemicals in IARC Groups 1, 2A and 2B:

12% are non-genotoxic

34
Q

What is the multi-stage model of carcinogenesis?

A

3 steps that describe the development of cancer:

  1. Initiation
  2. Promotion
  3. Progression
35
Q

What is initiation in the multi-stage model of carcinogenesis?

A
  • Irreversible genetic change
  • Most initiators (chemical carcinogens) are genotoxic and lead to mutations; bind DNA and form adducts
  • Initiating event is “fixed” when the DNA damage is not/incompletely repaired prior to DNA synthesis or cell division
  • Fate of initiated cells: (1) non-dividing state, (2) apoptosis, (3) proliferation of initiated cell
36
Q

What is promotion in the multi-stage model of carcinogenesis?

A
  • Clonal expansion of initiated cells to form a pre-neoplastic lesion
  • Promoters (tumor promoters) do not bind DNA but may affect signaling pathways causing cell proliferation and/or inhibition of apoptosis
  • Reversible
  • Threshold of effect; non-genotoxic; repeated application
  • High tissue specificity (TPA is skin-specific)
37
Q

What is progression in the multi-stage model of carcinogenesis?

A
  • Conversion of benign pre-neoplastic lesion into neoplastic cancer (malignancy)
  • May involve additional genotoxic events = more DNA damage; genotoxic chemicals
  • Irreversible; neoplasm formation occurs
  • Autonomous growth is achieved, increased invasiveness, ability to metastasize
38
Q

What is the primary site of metabolism? What are other possible sites?

A

Primary: Liver
Other: kidney, lung, GI track, and other organs

39
Q

What is biotransformation?

A

Metabolic conversion of endogenous/xenobiotic chemicals.

40
Q

What is detoxification?

A

When chemicals are transformed to eliminate the toxicant or prevents its formation.

41
Q

What is Toxication?

A

Chemicals are converted to products that are more toxic (carcinogenic) compared to the parent substance. The more toxic metabolic product can be:

(1) The chemically-reactive form
(2) Metabolite electrophilic to bind DNA
(3) DNA adducts formed can initiate carcinogenic process

42
Q

What are polycyclic aromatic hydrocarbons (PAHs)? What type of carcinogen are they? What is their major route of exposure? Give an example.

A 
• Indirect genotoxic carcinogens
• Ubiquitous contaminants
• Products of incomplete combustion of organic compounds:
– Burning of wood or fuel
– Motor vehicle exhaust
– Charbroiled foods
– Cigarette smoke
• Major route of exposure is inhalation
• Present as mixtures
– Identified in cigarette smoke = > 500 (μg/cigarette)
• Ex: Benzo[a]pyrene
43
Q

What is the metabolic activation of PAHs? What is the end result?

A
  1. Benzo[a]pyrene: Pro-carcinogen that requires metabolic activation
  2. Metabolized to Benzo[a]pyrene diol epoxide (BPDE) by 2xCYPs and an epoxide hydrolase.
  3. BPDE binds DNA to form DNA adducts
  4. Mutations
  5. Lung tumours
44
Q

What is the metabolic activation of B[a]P?

A

The AhR Pathway.
AhR is the Aryl hydrocarbon receptor.
1. B[a]P gets into the cytoplasm and binds AhR
2. B[a]P + activated AhR translocate to the nucleus
3. Binds a nucleus protein (Arnt)
4. This dimer binds DNA at DRE
5. Causes transcriptional up-regulation of CYP450s including CYP1a1
Trick to remember: B[a]P [a]=CYP1[a]1

45
Q

What is the relationship between CYP1a1, AhR, and B[a]P?

A

CYP1a1 if only induced if mice have AhR and are exposed to B[a]P. Therefore, B[a]P carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor.

46
Q

What is Benzene? What is the major exposure route? What IARC class is it?

A
  • Widely-used industrial chemical- plastics, resins, synthetic fibers, rubber lubricants, dyes, detergents, drugs and pesticides.
  • Crude oil; found in gasoline.
  • Produced naturally by volcanoes and forest fires.
  • Inhalation is the major exposure route.
  • IARC class 1 carcinogen
47
Q

How is benzene metabolized? (L10 S59)

A
  • Can be metabolized in the lungs, but mainly done in the liver
    1. Benzene metabolized mostly by CYP2E1 to benzene oxide
    2. Spontaneous change to phenol
    3. Phenol to hydroquinone by CYP2E1. This reactive intermediate can enter the bone marrow and be further metabolized to form other reactive intermediates.
    4. Hydroquinone to benzoquinone (toxic)
    Trick: benzEEEne CYP2EEE1
48
Q

What are Aflatoxins? What are the main fungi that produce them?

A

• Aflatoxins are mycotoxins
– Mycotoxins are secondary metabolites of fungi (mold) • Total of 20 (major are AFB1, B2, G1 and G2)
– Main fungi that produce aflatoxins are Aspergillus flavus and Aspergillus parasiticus

49
Q

What is Aflatoxin B1? Where are they found? What is the primary target organ? What is the end result?

A

• Aflatoxin B1 (AFB1)
– Group 1 carcinogen- IARC
– Potent naturally-occurring carcinogen

• Found on agricultural crops
– Corn, peanuts, cottonseeds, tree nuts
– Exposure by consuming contaminated products or inhalation of dust during handling/processing

• Liver is primary target organ. Causes Hepatocellular carcinoma (HCC).

50
Q

What does Aflatoxin B1 have synergy with?

A

Synergy with HBV (hepatitus B) so that the risk of HCC is 30 times greater than AFB1 alone.

51
Q

How does AFB1 get metabolised?

A

AFB1 is a pro-carcinogen.
1. Ingested
2. In liver it is metabolized into AFBO by CYP3A4 (major) and CYP1A2 (minor). This is the reactive intermediate that can bind DNA.
Trick: AFB1 (ONE) -> CYP1A2 (ONE) -> CYP3A4. SO AFB ONE 2,3,4.

52
Q

What are examples of non-genotoxic carcinogens? What mechanism do they work through?

A

• Chloroform
– cytotoxicity and compensatory cell proliferation

• Trichloroethylene (TCE)
– Receptor-mediated (PPARα)

• Dioxin (TCDD)
– Receptor-mediated (AhR)

• Hormones
– Receptor/non-receptor

• Ethanol
– Oxidative stress

53
Q

What is the IARC classification of Trychloroethylene? What has it been used for?

A
  • IARC group 1
  • Used as: ♦ a general anesthetic,
    ♦ an alternative to ether or chloroform;
    ♦ a dry-cleaning solvent;
    ♦ to extract oils, caffeine and flavours from plants
    ♦ a metal degreasing agent (best-known use)
54
Q

What is the exposure routes of TCE? where is it distributed to? where is it metabolized?

A

Exposure routes:

  • Inhalation (major)
  • Ingestion (mid)
  • Dermal (minor)

Distributed to: Lungs, liver, & kidney

Metabolized by liver.

55
Q

Explain a TCE contamination situation we learned about.

A
  • TCE contamination in Shannon, Quebec
  • High TCE levels were found in some homes (1,000 ppb); the Quebec Government maximum allowable level is five ppb.
  • Why? SNC Technologies, a munitions factory near the Canadian Army Base Valcartier, used TCE (trichloroethylene) as an industrial solvent and simply buried or dumped the waste on their property so it seeped into the ground
  • The cancer risks were therefore sky high in Shannon
56
Q

What is a peroxisome?

A

Organelles that have enzymes for cholesterol, lipid metabolism, bile acid synthesis, and metabolism of ROS.

57
Q

What is the mechanism of action of TCE?

A
  1. TCE gets into the cytoplasm along with PERC (a peroxisome proliferator) and CH
  2. TCE is then metabolized by CYP2E1 (using the other things mentioned as substrates too) into TCOH (trichloroethanol), TCA (trichloroacetate), and DCA (dichloroacetate). TCA and DCA are also peroxisome proliferators.
  3. TCA and DCA interact with PPAR-alpha (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) which bind to PPRE on DNA and alters transcription
  4. This causes an increase in number and size of peroxisomes which causes an increase in oxidative stress
  5. Leads to an increase in proliferation and a decrease in apoptosis in the liver = liver cancer.
    Trick: TCEEEEEE -> CYP2EEEE1
58
Q

What are Dioxins? What are the 3 main classes?

A

• Persistent organic pollutants (POPs; includes pesticides, industrial chemicals and by-products)
• Dioxins (dioxin-like chemicals [DLCs])
– General term to describe a family of compounds that have a similar structure and act through a similar mechanism
– Three main classes:
• Polychlorinated dibenzo-p-dioxin (PCDDs)
• (Polychlorinated) Dibenzofurans (PCDFs)
• (Polychlorinated) Biphenyls (PCBs)

59
Q

How does one get exposed to dioxin?

A

Most people exposed through the diet because they don’t stay in the air or water for very long. They also get into the soil. They bioaccumulate in fatty tissue.

60
Q

Where do Dioxins come from? What is the most toxic type?

A 
PCDD and PCDFs:
– Industrial processes: Primary source
• Incineration of waste- municipal solid waste, medical waste, sewage sludge
– Burning of fuel:
• wood, coal, petroleum
– Manufacturing:
• Chlorine bleaching of paper pulp
• Manufacturing of some pesticides and herbicides
Polychlorinated Biphenyls (PCBs):
– Manufactured intentionally (until1979):
• Plasticizers, fire retardant for fabrics, adhesives, fluids for capacitors and transformers

Most toxic: TCDD (also referred to as dioxin)

61
Q

What pathway dies TCDD (dioxin) act through? How can it be a non-genotoxic carcinogen?

A

The AhR pathway (same as B[a]P).

Can be a non-genotoxic carcinogen:
♦ Tumour promotion (prevented initiated cells from dying)
♦ Cell Growth/ Differentiation
♦ Inflammation

62
Q

What are the carcinogens in cigarette smoke?

A

There are at least 60. The ones we are focused on are:

  • PAHs (products of combustion: B[a]P
  • Nitrosamines (tobacco specific indirect genotoxic carcinogens): NNK (also requires metabolic activation that can occur in the lungs)
63
Q

How does cigarette smoke affect your body?

A

The cigarette smoke contains many carcinogens such as NNK and B[a]P, once they are metabolically activated, they form DNA adducts, mutations, and they grow and proliferate which results in lung cancer. The other chemicals in the smoke inhaled, even if they aren’t direct carcinogens, affect the survival, proliferation, and differentiation of cells to ultimately enhance carcinogenicity.

64
Q

What is an example between other chemicals and cigarettes smoke?

A

Cigarette smoke interacts synergistically with asbestos. Asbestos alone has a 5x increase in lung cancer. Smoking alone has a 10x increase. Together there is a 53x increase.

PHAR 303 (21 decks)

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