Carcinogenic Agents - Reed

Question 1

Describe both the genetics and environmental factors that contribute to the epidemiology of human cancers (4)

Answer 1

1. cancer incidence and distribution varies with geography.
2. Social/dietary/environmental correlations with cancer incidence.
3. Cancer incidence in populations changes with time.
4. Cancer incidence in populations changes following migration.

Question 2

What is a carcinogen in rats but not humans?

Answer 2

saccharin…only in male rats (not even mice)

Question 3

How many known carcinogens are there in humans? some examples?

Answer 3

55; tars, soots, metals, radiation, alcohol, tobacco, estrogens, tamixifen, hepatitis B and C, human papillomavirus

Question 4

why are there more known animal carcinogens than known human carcinogens?

Answer 4

1. single experimental variable
2. accurate documentation of exposure
3. ethics of performing experiments
4. high dose exposure (maximum dose tolerated - MDT)…major problems in interpretation of animal study results and extrapolation to humans

Question 5

What do you need to think about when looking at animal carcinogenesis studies?

Answer 5

1. exposure to carcinogen (MDT)
2. relation between dose/duration and result…how many animals get tumors? how big are tumors? how fast do the tumors grow?
3. lag time between exposure and disease

Question 6

What was the main result of 1915 Yamagiwa and Ichikawa? 1932 Kennaway et al.? 1935 Sasaki and Yoshida? 1947 Jim and Betty Miller? 1950s Jim and Betty Miller?

Answer 6

1915: apply a carcinogen topically and cause a cancer at site of application.
1932: isolated carcinogens in the tar - carcinogens require a specific structure.
1935: ingestion of carcinogen - tissue specificity (in liver in this case).
1947: covalent binding of proteins in affected cells.
1950s: range of carcinogenity of the metabolites

Question 7

What characteristic of carcinogens give them the ability to cause mutations?

Answer 7

carcinogens or their metabolites are reactive electrophiles, which react with sites in DNA to alter the DNA.

Question 8

what is the difference between genotoxic and mutagenic?

Answer 8

genotoxic: chemical agent that damages the genetic information within a cell causing mutations, which may lead to cancer.
mutagenic: physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level.

Question 9

all AAA is BBB, but not all CCC is DDD.

genotoxic and mutagenic

Answer 9

All mutagens are genotoxic, but not all genotoxins are mutagens.

Question 10

what are DNA adducts?

Answer 10

NOT A MUTATION - just damaged DNA; before S/mitosis, the cell will attempt to repair the DNA adduct. if it cannot repair it, the DNA will become mutated (best guess or deletion)

Question 11

what types of mutations cause cancer?

Answer 11

the ones that allow the cell to better survive…silent mutations or non-critical mutations

Question 12

are all carcinogens mutations? are all mutagens carcinogens?

Answer 12

all carcinogens are not mutagens

all mutagens are not carcinogens

Question 13

describe hormonal carcinogens.

Answer 13

excessive or inappropriate exposure to hormones or hormone-modulating agents that can be carcinogenic (but not genotoxic); may result from spontaneous DNA lesions, pre-existing lesions or epigenetic changes

ex: estrogens, androgens, goitrogenic agents

Question 14

describe some infectious agents and the types of cancers they are linked to.

Answer 14

1. bacteria: H. pylori - gastric cancer
2. parasites: plasmodium (malaria) - lymphoma
3. viruses: Hep B and C - liver cancer; HPV - cervical cancer

Question 15

what is the deal with chronic inflammation/ erosion? causes, action, result

Answer 15

causes: bacteria - stimulates infiltration of inflammatory cells (cytokines, GF, reactive O/N species)
action: infiltration of inflammatory cells and proliferatin to replace damaged cells
result: bacteria may die but also reactive species are released that are good mutagenic agents

correlation between chronic inflammation and cancer

Question 16

how do viruses contribute to cancer?

Answer 16

viral promoters can activate c-onc: enhanced/inappropriate expression of GF

viruses can contain v-onc: introduce altered growth control

want to insert their genome into our chromosomes

Question 17

describe the process of carcinogenesis

Answer 17

1. initiation: genetic change; reversible; phenotypically normal cells (only detect via sequencing)
2. promotion: clonal expansion, phenotypic change, reversible (to initiated cells), clear threshold, yields pre-neoplastic lesions
3. progression: genotypic and phenotypic changes; complex genetic changes (genomic instability); irreversible; selection for malignant phenotype

Question 18

what cancers are easy to see the various stages of carcinogenesis? what is this model called?

Answer 18

colon cancer, skin cancer and glioblastoma

Vogelstein model

Question 19

what causes Burkitt’s lymphoma?

Answer 19

parasites - insert genome into B lymphocyte cells

Question 20

describe the mouse experiment that showed the multifactorial nature of cancer.

Answer 20

the mom had to be exposed to the carcinogenic factor; only female babies from the mom developed the cancer (other females from a different mom did not get cancer even though drank affected mother’s milk)

genetics and environment important for getting cancer

Question 21

what are some methods for detecting possible carcinogens?

Answer 21

clinical observation, epidemiologic studies, experimental animal studies (bioassays), mutagenesis assays, cell culture transformation assays, DNA damage

Question 22

What is the IARC classification scheme of human carcinogenic risk?

Answer 22

1. carcinogenic - sufficient (human)
   2A. probably carcinogenic - limited (human) and sufficient (animal)
   2B. possible carcinogenic - limited/inadequate (human) and sufficient (animal)
2. Not classifiable
3. Probably not carcinogenic - inadequate (human and animal)