Carcinogenesis (Toxicology Exam 3)

Front 1

Define Cancer

Back 1

uncontrolled division of abnormal cells that invade other tissues or spread to distant sites (metastasis)

Front 2

Name 3 types of DNA mutations

Back 2

1. Single base change
2. Additions
3. Deletions

Front 3

What are the integral genes in CA development?

Back 3

1. Proto-oncogenes (gas pedal)
2. Tumor Suppressor Genes (brake pedal)
3. DNA Repair Genes

Front 4

Other than the integral genes, mutations can also occur in these genes:

Back 4

Cell death genes
Cell signaling genes
Cell cycle checkpoint genes
Cellular senescence genes
Cellular differentiation genes
Metastasis/invasion genes
Carcinogen activating/deactivating genes

Front 5

Name the parts of the cell cycle

Back 5

Mitosis (division)
Interphase - consists of Gap - G0, G1, Synthesis (S) phase, and G2

Front 6

Where are the checkpoints in the cell cycle?

Back 6

G1/S
G2/M

Front 7

If a cell is not dividing appropriately, what could happen to it (provided there are no cancerous changes?)

Back 7

Senescence - just sits in G0
Necrosis - traumatic cell death, releases enzymes, oxidants that could damage surrounding cells
Apoptosis - programmed cell death. Organized, packaged so contents can be re-used.

Front 8

What is Hayflick's Limit?

Back 8

the max # of times a particular cell can divide. Regulated by telomere length.

Front 9

What are the 6 hallmarks a cell must acquire before becoming cancerous?

Back 9

1. Sustaining Proliferative Signaling
2. Evading Growth suppressors (i.e. p53)
3. Enabling Replicative Immortality
4. Inducing angiogenesis
5. Activating Invasion and Metastasis
6. Resisting Cell Death

Front 10

Name the 4 emerging hallmarks for cells becoming cancerous

Back 10

1. Deregulating cellular energetics
2. Avoiding immune destruction
3. Tumor-promoting inflammation
4. Genome instability and mutation

Front 11

What do carcinogens to do DNA that allows cells to acquire the hallmarks of cancer?

Back 11

1. Intercalating Agents - chem sticks to DNA ladder rungs
2. Adduct Formation - some electrophilic compounds form covalent bonds with DNA
3. Alkylating Agents - can lead to cross-linking of bases, where bases can't separate for transcription

Front 12

What are examples of intercalating agents?

Back 12

Ethidium bromide, Acradine (dye), Aflatoxin B1 (epoxide metabolite)

Front 13

What are two kinds of adduct formation?

Back 13

Direct - binds to DNA
Indirect - metabolized to carcinogen that binds DNA

Front 14

What are examples of alkylating agents?

Back 14

Nitrosamines, nitrosureas, Aromatic amines, Vinyl Chloride )monomer) Epoxides i.e. Polycyclic aromatic hydrocarbons (PAH) metabolites

Front 15

What are epigenetics as r/t carcinogenesis?

Back 15

Changes occur in molecules other than DNA, that influence the sequence of DNA --> RNA --> protein.

Front 16

Name some epigenetic mechanisms that could lead to development of CA hallmarks.

Back 16

- Substance binds receptors on cell surface or in cytosol - ie. aryl hydrocarbon receptors bind PCBs and TCDD (dioxin); HORMONES i.e. estrogen
- Substance interferes with gene activity - binds to histone that DNA is wrapped around, interfering with DNA translation/transcription
- If these changes impact proteins involved in DNA repair, proto-oncogene, or tumor suppressor gene formation, could lead to hallmarks

Front 17

Describe the Ames Assay

Back 17

- used for screening substances for MUTAGENICITY not carcinogenicity.
- salmonella in histidine negative medium, add the chemical in question. If the salmonella mutate to make their own histidine, the substance is mutagenic and needs further testing

Front 18

Desribe the Comet Assay

Back 18

Tests substances for DNA damage
Expose cell to test substance & lyse cells in electrical field
DNA fragments migrate toward field, the more migration, the more broken DNA there is

Front 19

Describe cytogenic assays

Back 19

Grow eukaryotic cells in culture, expose to test material.
Examine under microscope for structural abnormalities in chromosomes. (Intact, broken?)

Front 20

Name some characteristics of epidemiologic cancer studies that make them difficult to utilize

Back 20

1. Long latencies of CA - studies long and expensive
2. Mixed exposures - can't single out exposre->cancer
3. Many factors other than specific occ/env exposures cause CA (confounding)
4. Many CA types are rare (small sample size)
5. Massive commitment/cost
6. Hard to ascertain dx by tissue type (could have started in liver, mets to brain)

Front 21

IARC Group 1

Back 21

CARCINOGENIC TO HUMANS
- Sufficient evidence in humans OR
-Evidence less than sufficient in humans AnD evidence sufficient in animals ADN mech of toxicity observed in animals is relevant in humans

Front 22

IARC Group 1 Examples

Back 22

Asbestos --> mesothelioma
Benzene --> Leukemia
Aflatoxin, Arsenic, chromium VI, coke production, diesel engine exhaust, Diethylstilbesterol, Post-menopausal estrogen, ethylene oxide, Hep B infection, Plutonium, Rubber production

Front 23

IARC Group 2A

Back 23

PROBABLY CARCINOGENIC TO HUMANS
-Limited evidence in human studies AND sufficient evidence from animal studies OR
- Inadequate human evidence AND sufficient animal evidence AND evidence that the mechs observed in animal studies occur in humans

Front 24

IARC Group 2A Examples

Back 24

Application of non-arsenical insecticides, inorganic lead, occupation as hairdresser/barber, PCBs, shiftwork involving circadian rhythm disruption, trichloroethylene

Front 25

IARC Group 2B

Back 25

POSSIBLY CARCINOGENIC TO HUMANS
- Limited evidence in human studies AND less than sufficient evidence from animal studies OR
- Inadequate human evidence AND sufficient animal evidence OR
-Inadequate human evidence AND less than sufficient animal evidence AND evidence that the mech. in animals occurs in humans

Front 26

IARC Group 2B examples

Back 26

Acetaldehyde, acrylonitrile, carbon black, cobalt & cobalt compounds, diclorvos (organophosphate), gas engine exhaust, hydrazine, firefighter work, occ exposure in printing processes, styrene

Front 27

IARC Group 3

Back 27

NOT CLASSIFIABLE - most chems are in this category
- Inadequate human evidence AND inadequate/limited evidence in animals
- Agents that don't fit in to any other category

Front 28

IARC Group 3 examples

Back 28

Atrazine, caffeine, crude oil, hydrogen peroxide, jet fuel, static magnetic fields, saccharine

Front 29

IARC Group 4

Back 29

LACK OF CARCINOGENICITY
- Human studies AND animal studies show evidence of NO carcinogenicity OR
- Inadequate human studies AND animal evidence lack carcinogenicity AND mechanistic and other data support lack of carcinogenicity

Front 30

EPA Classification System

Back 30

A- Carcinogenic to humans
B- Likely to be carcinogenic to humans
C- Suggestive evidence of carcinogenic potential
D- Inadequate information to assess carcinogenic potential
E- Not likely to be carcinogenic to humans