Carcinogenesis and Chemotherapy Flashcards
Differentiate between ‘oncogenes’ and ‘tumor suppressor’ genes
Oncogenes generally function normally to promote cell growth and survival (gas pedal on car). Mutations to oncogenes (which tend to be dominant-acting) prevent modulation and regulation of these genes (gas can’t be lifted), leaving them constitutively active.
TS Genes (like p53) are like brakes or check-points for a car. They are recessive-acting, so inactivation requires mutations to both alleles (often one is inherited, the other is acquired–loss of heterogeneisity).
List 5 important genotoxic carcinogens:
- polycyclic aromatic hydrocarbons (PAHs)
- Mycotoxins
- Radiation
- Asbestos
- Heavy metals
Describe how Benzene can cause cancer:
Exposure is occupational or through tobacco smoking. Benzene is activated to toxic metabolites via a p450 dependent mechanism. Converted to 1,4 benzoquinone by myeloperoxidase in bone marrow.
Susceptibility depends on individual’s p450 genetic variant.
Toxic to bone marrow, blood. Causes leukemia.
How do non-genotoxic carcinogens cause cancer?
**They do not interact with DNA, but instead impact cellular growth, increase DNA synthesis (mitosis), inhibit repair functions, alter chromatin modifications, alter cell signalling pathways, and induce inflammation.
They are effective at high concentrations and over chronic exposures.
Differentiate between ‘initiation’ and ‘promotion’ as they pertain to carcinogenesis:
Initiation is a mutagenic event, irreversible, and occurs in one cell (clone) - could be result of a genotoxic exposure.
Promotion is non-mutagenic and reversible. Continued exposure will promote cell proliferation. This could be a non-genotoxic exposure. Promoter may also be a true DNA-bound promoter of an oncogene initiator region.
How does the EPA assess environmental carcinogens?
Non-threshold assumption, allow for 0 exposure (no safe level, where the EU allows some safe level of exposure for non-genotoxic carcinogens).
Does the FDA require any carcinogenicity testing on new drugs?
Yes, require drug sponsors to submit data on carcinogenicity testing.
Define: S-phase
the DNA Synthesis stage of cell replication
Define: G1 phase
A growth phase that follows mitosis in preparation for the next division (as opposed to G0- differentiation)
Define: G2 phase
follows S phase. Includes synthesis of mitotic componants
Define: M-phase
Mitosis
Define: cell cycle specific
Drugs that inhibit or kill cells only if they are cycling at a specific stage (DNA synthesis inhibitors, mitotic inhibitors)
Define: cell cycle non-specific
Drugs that work throughout the cell cycle (alkylating agents)
Log kill hypothesis
Cytotoxic drugs kill a constant FRACTION of cells, rather than a specific dose
How did resistance to chemotherapy come about? What is the mechanisms (5)?
Happens due to repetitive therapy. Mechanisms:
- Decreased target sensitivity
- Detoxifying enzymes (increased inactivation)
- Decreased uptake (reduced permeability or inc. efflux)
- Increased expression of target enzyme (requires more drug for inhibition)
- Increased levels of competitive substrate for enzyme
