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22 Cards in this Set

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Where do many of the important concepts regarding carcinogenesis develop from?
Most concepts regarding carcinogenesis is developed from work with chemicals that cause cancer in experimental animals, but pertain to all causes to some degree.
What an important and common theme for the mechanisms of carcinogenesis?
The common theme is that there are various agents that can cause DNA damage that results in

- mutations
- gene rearrangements
- gene amplification
- gene deletion
- altered expression of genes that control normal cellular growth, survival, and differentiation
Regarding the hypothesis related to neoplasia...
The hypothesis that neoplasia is genetically determine is old- - basically taht these neoplasms have abnormal mitoses, nuclei, and abnormal karyotypes
Regarding CHEMICALS, VIRUSES, and RADIATION...
CHEMICALS, VIRUSES, AND RADIATION have been documented to cause neoplasms for >50 years, but mechanisms of carcinogenesis is still in debate.

Debate is between REGULATION and MUTATION
What are 6 important points regarding CHEMICAL CARCINOGENS?

How do chemicals cause cancer?
1) Exposure to some chemicals can cause cancer.
- ex1) epidemiologic observation of cancer in chimney sweepers
- ex2) lab studies on animals

2) Most chemical carcinogens are MUTAGENS
- ex) AMES TEST and other invitro mutagenicity tests

3) Specific chemical carcinogens may cause DNA damage (see next card for details)

4) Direct acting mutagenic chmicals do not require metabolic activation to be reactive with DNA.

5) HOWEVER, Indirect mutagens do require metabolic activation
- ex) because agents are metabolized to electrophilic spp that are able to react with cellular DNA

6) Targeting (which is the cell type affected) is determined by the route of contact, distribution of carcinogen in the body, and the ability fo the cell or organ to activate or detoxify the carcinogen.
What are the CRITICAL types of DNA damage?
1) ALKYLATION: causes mismatches in base- pairing

2) DAMAGE LEADING TO DEPURINATION/ DEPYRIMIDINATION

3) Bulky DNA adducts that may interfere with base pairing

4) DOUBLE STRAND BREAKS
What is the AMES TEST specifically, and what does it test for?
*
* VIRUSES, RADIATION, STOCHASTIC EVENTS *

How do each cause cancer?
*
1) VIRUSES

How does it work?
DNA can be integrated into the host genome leading to the expression of viral proteins.

It works via REVERSE TRANSCRIPTASE which allows viral RNA code to be transcribed to DNA that can be integrated into the host genome.
2) RADIATION

What types of DNA/ cellular damage does it cause?
Basically, RADIATION exposure increases the risk of getting cancer.

Radiation causes
- DNA damage
- chromosomal breakage
- and cytogenic abnormalities
3) STOCHASTIC EVENTS
Genetic accidents leading to mutation happen during DNA replication, though at a very low rate.

Oxidative damage to DNA is implicated as a mechanism of stochastic mutation.

ex) mutation results from aberant intracellular events that do not require an external agent such as chemical, virus, or radiation
* DNA REPAIR *
*
Why is DNA repair important?

What are 2 types of DNA repair?
It is important because DNA repair mechanisms are important defenses against mutation and may be defective.

Two types of repair:
1) Prereplicative DNA repair- high fidelity
2) Postreplicative DNA repair- high and low fidelity
What are 3 pieces of evidence that support the role of DNA damage
1) XERODERMA PIGMENTOSUM: it is a rare human recessive hereditary disease characterized by a predisposition to develop skin cancer following exposure to sunlight.
a) cells are prereplicative
b) cells exhibit decreased survival and increased mutation following DNA damage.

2) Hereditary nonpolyposis colon cancer (HNPCC) is associated with a defect in DNA mismatch repair linked to hMSH2 and related genes

3) BLOOM'S SYNDROME: a rare human recessive hereditary disease characterized by chromosomal instability with a predisposition to develop

- leukemia
- lymphoma
- carcinoma
* MODIFIERS OF CARCINOGENESIS *
*
What are the modifiers of carcinogenesis? (5)
1) ENZYME INDUCTION
- CYP induction. Indirect acting carcinogens are usually activated by CYP enzyme

2) DETOXIFICATION
- these are protective enzymes, molecules, and antioxidants

3) GENETIC POLYMORPHISMS
- this deals with the fact that we're all not the same, and some of get cancer and some of us don't
- variations in activity of the following pathways make us different
- activation enzymes
- protective enzymes and pathways including DNA repair

4) DIET
- antioxidants
- vitamin A
- caloric intake

5) CELL CYCLE
- dividing cell populations are at greater risk for mutation than stable populations
- labile cell populations are vulnerable when in the cell cycle
What are 3 steps in CARCINOGENESIS? (in the context of chemical carcinogenesis)
1) INITIATION is the initial exposure to carcinogen

2) PROMOTION deals with the subsequent events that accelerate the development of neoplasms
for ex) there was a skin carcinogen experiment done in mice (LOOK AT SLIDES!!)
- PROMOTION is now used to refer to epigenetic events that favor tumor development

3) PROGRESSION deals with the subsequent events that are required to confer malignant phenotype
What is the summary of the STEPS IN CARCINOGENESIS?

What is important to note about the process?
1) INITIATION, first genetic event

2) PROMOTION, epigenetic factors that "promote" carcinogenesis

3) PROGRESSION, subsequent genetic events

* CARCINOGENESIS is a multistep provess that may require years to complete
What is the concept of TWO STAGE CARCINOGENESIS?
The first step is thought to result from MUTATION, and several steps later in this process is now regarded to reflect additional mutations,
What are PROMOTING AGENTS with regards to the TWO STAGE CARCINOGENESIS?
The PROMOTING AGENTS are redarded as STIMULANTS to growth of initiated cells that substitute for second and subsequent mutations until the latter occur.

When fully autonomous growth is established as a result of multiple genetic changes, the promoters are no longer needed.
What is the LATENT PERIOD?
The LATENT PERIOD = is the time between initiation and clinical detection of a tumor
What does the evidence that tumors are clonal in origin suggest?
This evidence suggests that most neoplasms originate from progeny of a single initiated cell.