Chapter 3 Flashcards
Describe each stage of multistep carcinogenesis
Initiation: a mutation is formed in DNA. This requires a chemical carcinogen to cause the mutation, failure of DNA repair, and cell proliferation so the mutation becomes permanent in the cell. *Irreversible, but cell does not have autonomy of growth.
Promotion: Clonal expansion of an initiated cell via altered gene expression giving cell selective growth advantage. Proliferation of preneoplastic cells. Causes benign lesions (papillomas). IF addt’l mutations occur, can become malignant.
Progression: Process by which tumors acquire ability to grow, invade local tissue, and establish distant mets
Describe the role of 2 classes of drug metabolizing enzymes…
Phase 1 enzymes: introduce or unmask functional groups on the parent substrate. *cytochrome p450 superfamily
Phase II enzymes usually detoxify reactive metabolites. *glucuronyltransferases, sulfotransferases, acetyltransferases. Often conjugate molecules allowing excretion.
Alkylating agents work by adding a ___ to an electron/proton (pick one) rich site on DNA
Alkyl (-CH2+)
Electron rich
What is genetic polymorphism and how does it play a role in cancer susceptibility
Genetic polymorphisms relate to the variation present in alleles between individuals. In the case of dealing w/ carcinogens…ppl w/ different p450 alleles have varying susceptibilities to developing different types of cancer (such as lung).
What are DNA adducts? Why do we care?
Addition of groups (ex. Alkyl groups, arylaminating groups) to DNA to alter the accuracy of DNA replication.
Can result in base substitutions
Name the 4 DNA bases? Pair them as would in DNA. How is RNA different?
Adenine w/ Thymine (uracil in RNA)
Guanine w/ Cytosine
DNA repair of chemical carcinogen damage can be (1) direct (2) Mismatch Repair (3) Base Excision Repair
Describe these methods.
Give 1 important example of direct repair
DIRECT: involves breaking the bond bt the adduct and nucleotide resulting in recreation of the initial normal DNA configuration
*Most NB: O6 methylated derivative of guanine. If not fixed, G can pair w/ Thymine and result in GC to AT mutation when DNA is replicated. This can be repaired by O6 alkylguanine DNA alkyltransferase (AGT) which is encoded by the gene O6 methylguanine DNA methyltransferase (MGMT)
MMR: removes incorrectly placed base in the newly synthesized daughter strand. Problem is that it doesn’t fix the adduct in the parent which can lead to repeat of problem.
BER: removes the non-bulky base adducts that don’t distort the DNA helix.
2 targets of chemical carcinogens are TSG and oncogenes. Define each. Include their normal cellular functions and what type of mutation is needed to result in a cell’s increase susceptibility to cancer.
TSG: normally regulate the cell cycle, monitor for DNA dmg and control DNA repair. To lead to cancer, the gene must acquire a loss of function mutation usually in BOTH alleles (RECESSIVE).
ONCOGENE: genes that upon ACTIVATION (gain of function mutation) can lead to unregulated cell growth). Often constituively activated. Requires only 1 mutation and is DOMINANT trait.
State whether the following genes are TSG or oncogenes:
ras, p53, Met, BCR-ABL, PTEN, Myc, Rb, Bcl-2
ras (GTPase) - oncogene
p53 - TSG
Met (hepatocyte GFR) - oncogene
BCR-ABL (protein tyrosine kinase) - oncogene
PTEN (nb in apop and prolif regulation - TSG
Myc - transcription factor - oncogene
RB - cell cycle regulation - TSG
Bcl-2 - anti-apoptosis protein - oncogene
What is a non-genotoxic carcinogen?
More restricted than genotoxic carcinogens. Effects often limited to a single organ.
Ex: a hormone that has a proliferative effect (like a tumor promoter)
Briefly describe the Ames Assay to test mutagenic chemicals
Most widely used short term assay. Test uses a mutant version of Salmonella typhimurium unable to synthesize their own histidine (an essential AA).
This leaves them unable to grow in media lacking this AA. The bacteria are exposed to a mutagen and if they regain the ability to grow a mutation has occurred.
The # of growing colonies gives an indication of how mutagenic the substance is.
Mutagenic is NOT carcinogenic.
Why might p450 enzyme inhibitor make a good chemopreventative agent?
Most pro-carcinogens require bioactivation by various p450 enzymes. T/F, p450 inhibition might minimize activation.
Alternatively, drugs that increase conjugation and t/f clearance may also act as chemopreventatives. Unfortunately, you would want VERY selective p450 inhibition so as not to prevent a patients’ ability to clear toxins, etc.
Glutathione S transferase has what nb function?
Nb phase II enzyme that conjugates reactive metabolites w/ glutathione
Name a selective estrogen receptor modulator.
What type of cancer is it used to prevent in people?
Tamoxifen/Raloxifene
Breast cancer
In what part of the radiation cell survival curve does the # of transformed cells increase w/ dose?
In the shoulder, ie at lower doses usually less than 4 Gy.
At higher doses the cell killing increases and the # of transformed cells decreases. There is an intermediate dose that gives maximal transformation. (3.14 p40)
RT acts to cause genetic instability which then increases the likelihood of developing a less common mutation.
Mechanisms by which genetic instability is introduced by RT includes:
- mutations in genes that control DNA synthesis or repair (ex faulty MMR enzymes
- induction of chromosomal instability
- persistent production of oxygen radicals which damage DNA
