Carcinogenesis

Question 1

Proto-oncogene

Answer 1

A gene which, if mutated, becomes an oncogene. Generally associated with restricting some key area of growth or replication.

Question 2

Tumor Suppressor Genes

Answer 2

Block tumor development by regulating the cell’s progress through the cell cycle - “gates”

Promote Apoptosis, causing damaged cells to die in a controlled fashion.

Question 3

Loss of heterozygosity

Answer 3

If the patient has only one copy of the active tumor suppressor due to an inherited mutation, a mutation on the second gene will result in deactivation.

Question 4

What are some functions of p53 that make it important?

Answer 4

Cell cycle arrest
Apoptosis
Inhibition of angiogenesis and metastasis
DNA repair

Question 5

Oncogenes vs Tumor Suppressor Genes

Answer 5

Oncogenes - mutated to become active, resist endogenous control. DOMINANT ACTING

TS Genes - mutated to become inactive. RECESSIVE ACTING.

Question 6

Genotoxic carcinogens mechanism (general)

Answer 6

DNA damage, leading to genetic lesions. Can be effective after a single exposure, cumulative, and additive with similar carcinogens

Question 7

What are some organic genotoxic carcinogens?

Answer 7

Polycyclic organic hydrocarbons, products of incomplete combustion

Mycotoxins

Question 8

What are some physical genotoxic carcinogens?

Answer 8

Radiation
Asbestos
Heavy metals (nickel, cadmium)

Question 9

Metabolism has 2 phases. What is phase 1?

Answer 9

Alteration of the molecule to add or modify a functional group - carried out by P450.

Question 10

Metabolism has 2 phases. What is phase 2?

Answer 10

Changes in the molecule to further increase water solubility for excretion - TRANSFERASES- glucoronidation, sulfation, acetylation, amino acid/glutathione

Question 11

Where do the 2 phases of metabolism mostly take place?

Answer 11

The Liver

Question 12

Benzene Chronic Toxicity

Answer 12

Hematotoxicity, Leukemias. P450 dependent bioactivation, myeloperoxidase in bone marrow.

Question 13

What are some mechanisms of non-genotoxic carcinogens?

Answer 13

They impact cellular growth, DNA synthesis, inhibit enzyme function, chromatin modification, signalling pathways, or just plain old inflammation.

Question 14

When are non-genotoxic carcinogens effective?

Answer 14

At high dose and chronic exposure.

Question 15

Initiation vs promotion in carcinogenesis

Answer 15

Initiation - Mutagenic, irreversible, effects 1 cell.

Promotion - non mutagenic, reversible, promotes cell proliferation

Question 16

What if you get exposed to a promoter several times, THEN get exposed to an initiator once?

Answer 16

No cancer, probably. It has to happen the other way around.

Question 17

What if you get exposed to an initiator once, then several doses of a promoter later?

Answer 17

cancer.

Question 18

Can repeated doses of an initiator cause cancer without the action of a promoter?

Answer 18

Yes.

Question 19

How do we assess environmental genotoxic vs nongenotoxic carcinogens for a safe level?

Answer 19

There is NO safe level for genotoxic carcinogens - one exposure may be enough. Nongenotoxic carcinogens represent a qualitative risk and “safe” levels can be determined.