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326 Cards in this Set
- Front
- Back
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What are the two primary characters of cancer?
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1. An uncontrolled increase of cells ( increased proliferation rate & decreased death rate )
2. Ability to invade or implant (via metastasis) to other tissues. |
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Which two routes are used by cancer cells to metastasize?
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1. Bloodstream 2. Lymph System
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Describe the trend in number of new cancer cases. Why?
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The number of new cases are growing. As people live longer, cancer cells are more likely to develop into problems.
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4 most common cancers men and women?
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Men 1. Prostate 2. Lung and bronchus 3. Colon and Rectum 4. Urinary Bladder Women 1. Breast 2. Lung and bronchus 3. Colon & Rectum 4. Uterine corpus
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4 most deadly cancers men and women?
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1. Lung and bronchus 2. Men - prostate women - breast 3. colon and rectum 4. pancreas
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Men or women, higher cancer incidence and or mortality?
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Men for both
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Which are the general rates of cancer (incidence) in US per 100,000 in 2007.
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~160 prostate and ~ 120 breast ~70 male lung/bronchus cancer, <60 for the rest
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Total number of cancer deaths avoided from 1991 to 2006?
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550,000 males and 200,000 female
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Which two diseases account for 50% of deaths in the USA?
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Heart Disease and Cancer
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Explain the changes in cancer death rate since 1950.
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There is very minimal decrease. 190.1 from 193.9
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How is education associated with death rates from cancer?
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As education increases death rate from cancer decreases.
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Japanese in Japan have high rates of stomach cancer, but when they emmigrate to Hawaii their rates of cancer rates mimmick those of the local culture. What might explain this?
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It shows how the environment has an important causal role in cancer.
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According to the twin study does genetics play a role in cancer?
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For some cancers yes (up to 40%), for others, not at all.
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What six things can cause cancer?
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1. Viruses 2. Chemicals 3. Physical factors 4. Genetics 5. Therapy 5. Other factors
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Which virus is primary in causing cervical cancer? Which two strains cause nearly 70% of all cervical cancer?
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HPV-16 (53%), HPV-18 (17%)
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How does the HPV virus cause cervical cancer?
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Two oncoproteins that are made by the virus. 1. E6 2. E7
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How does oncoprotein E6 promote cancer?
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Promotes proliferation and inhibits apoptosis activation by p53 and BAK ( apoptosis is often induced by high expression of E7)
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How does oncoprotein E7 promote cancer?
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It promotes proliferation, but if it gets too active, it leads to cell death. It also helps E6 escape death by inhibiting the action of enzyme INK4A.
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AIDs patients have how much higher cancer risk? (Men and Women)
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100% Males 200% Females. Where did this come from?
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About how long does it take for lung cancer to develop?
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20 years
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Through what mechanism and chemical does smoking cause cancer?
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Benzo[a]pyrene undergoes CYP450 oxidation creating an epoxide structure which reacts with an amino group on guanine. (DNA Adduct formation)
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What three kinds of agents cause carcinogenesis through adduct formation?
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1. Alkylating agents 2. arylaminating agents 3. polycyclic aralkylating agents
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BBQ causes what kind of mutation via what reaction?
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Acrylamide is formed via the maillard Reaction between glucose and asparagine at temperatures over 180. Acrylamide is highly reactive towards DNA, causes DNA damage.
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In Vitro tests. Example, advantage, limitation.
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Ames Test :-D. Adv= Rapid/Inexpensive :-D. Lim: False extrapolations (doesn't acct for metabolism)
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Animal tests. Example, advantage, limitation.
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Rodent bioassays. Adv= More predictive than in vitro; Lim= expensive and human extrapolation is imperfect, takes much longer than Ames test.
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Human epidemiology. Example, advantage, limitation.
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Prospective cohort, case-control. Adv= direct measurement; Lim= Causation may be hard to determine; Confounding variables.
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What are the three carcinogenic physical factors?
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1. Ionization radiation (x-rays, gamma rays) 2. UV radiation A, B, C (240 to 400nm) 3. asbestos
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What are the sources of ionizing radiation?
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1. Earth - inherent to environment 2. Nuclear plants 3. X-Rays
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Which tissues are most sensitive to ionization radiation?
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Highly proliferating cells - blood and bone marrow. Most likely to cause leukemia.
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What is the mechanism of ionization damage?
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Base pair deletions leading to dsDNA breaks.
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UV light originates from where and causes what?
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The sun causing skin cancer
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UV light mechanism (two)?
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1. UVC/UVB (shorter wavelengths) -> pyrimidine dimers -> squamos and basal cell carcinomas || 2. UVA (longer wavelength) -> reactive oxygen species -> melanoma
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Asbestos mechanism is what?
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dsDNA breaks, reactive oxygen species generation, and cytokine induction
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Asbestos causes which two types of cancer?
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1. Malignant mesothelioma 2. bronchogenic cancer
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What three types of genes are involved in cancer?
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1. Tumor supressor genes 2. Tumor Oncogenes 3. DNA repair genes
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Name two tumor suppressor genes
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RB1 & p53
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CDK4 oncogene promotes what cancer?
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Melanoma
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RET oncogene promotes what cancer?
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multiple endocrine neoplasia type 2
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MET oncogene promotes what cancer?
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papillary renal cell carcinoma
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KIT oncogene promotes what cancer?
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gastrointestinal stromal tumors
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BRCA1 is what?
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tumor suppressor protein. 1. Repairs DNA breaks/adducts 2. modulates gene expression during cell stress 3. Arrests cell replication at checkpoints (G1/S, S, and G2/M) 4. Protein ubiquitination
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Why are carcinogenesis and cancer therapy two sides of the same coin?
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Because many agents that induce cancer are also used to treat cancer.
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Upon curing a primary tumor, what may happen to the RR of developing another type of malignancy?
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RR of other malignancies may increase depending on type of therapy.
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How does BMI affect cancer risk?
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Cancer risk is generally increased, except for lung CA in which an increased BMI --> decreased RR of CA
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Does stress cause cancer?
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Yes, there is an association, definitely.
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Top 5 factors attributable to cancer deaths.
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1. Tobacco (33%) 2. Diet (30%) 3. Infection 4. Reproductive factors and hormones 5. Ionizing radiation
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List the 5 main components of the cell cycle in order.
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G0 -> G1 -> S -> G2 -> M
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Describe G0
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G0 is quiescence and can lead to terminal cell cycle arrest.
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Define mitogen.
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Mitogen is a chemical that encourages cells to undergo the replication process.
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Which three factors can send a cell into G0?
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1. cell-cell contact 2. cell differentiation 3. anti-mitogenic factors
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Which three factors take a cell out of G0 state?
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1. mitogens 2. growth factors 3. nutrients
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Describe S
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DNA replication
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Describe G2
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Biosynthesis of microtubules (among other things) necessary for mitosis. RNA and Protein synthesized.
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Describe Mitosis
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Chromosome condensation and segregation. Prophase, metaphase, anaphase, telophase.
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Describe G1
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Gap phase after mitosis that is responsible for biosynthesis of enzymes that are used in S phase. DNA and protein are synthesized.
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How many checkpoints exist in the cell cycle and where are they located?
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4 checkpoints. | 1. Commitment (G1/S) | 2. S/G2 | 3. G2/M | 4. Mitosis
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G2/M Checkpoint
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Entrance to M blocked if replication isn't complete
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M Checkpoint
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Anaphase blocked if chromatids aren't properly assembled on mitotic spindle
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G1/S Checkpoint
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Entrance to S blocked if genome is damaged
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S/G2 Checkpoint
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Entrance to G2 blocked if genome is damaged
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G1/S Checkpoint Mechanism
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DNA damage --> RB protein binds E2F (transcription factor) --> transcription needed for S phase won't occur
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Mechanisms of RB Inactivation
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1. Genetic mutation (lose tumor suppressor f(x)); irreversible 2. Viral inactivation traps RB so it can't suppress E2F (irreversible) 3. Phosphorylation (endogenous inactivation; reversible) 4. Degradation by proteases (irreversible)
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What are CKI's?
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Kinase inhibitors that prevent phosphorylation of RB by CDK's (E2F is suppressed and cell doesn't go to S)
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Explain the "wait anaphase" enzyme system and how it regulates chromatid separation.
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Anaphase is the separation of sister chromatids and it requires the perfect alignment of chromatids. Before the chromatids are aligned the cell is in wait mode. MAD2-CDC20-APC/C is inactive in wait mode. When chromatids are alligned perfectly, MAD2 is released, and CDC20-APC/C is activated and APC/C ubiquinates securin (in complex with separin) and activates the lone separin. Separin, a protease, is now free to cleave the protein connections between the sister chromatids.
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Give two examples of defective chromatid separation checkpoints.
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1. Deficient MAD2: APC/C is active even when chromatids aren't aligned --> uneven separation of DNA --> potential mutations | 2. Securin is not present and separin is largely inactive without securin (securin "primes" separin). The sister chromatids are not separated in anaphase without active separin.
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How prevalent are G1/S regulator mutations among different cancers?
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Extremely prevalent. They are found generally in >70% of all cancer types (>80% and >90% is not uncommon) except for melanoma in which they found only in >20%.
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Name the six hallmarks of cancer.
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1. sustaining proliferating signaling 2. evading growth suppressors 3. activating invasion and metastasis 4. enabling replicative immortality. 5. inducing angiogenesis 6. Resisting cell death
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3 Common molecular strategies for self-sufficiency in growth signals
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1. Extracellular growth signals 2. transcellular signal transduction 3. intracellular signaling pathways
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2 Antigrowth signals
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1. Quiescence (G1 to G0) 2. Terminal differentiation (irreversible G0 arrest)
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3 Components of Apoptotic machinery
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1. Sensors (monitor cellular state) 2. Effectors (survival factors and death factors) 3. Executors
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BCL2
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Responsible for the ability of CA cells to evade apoptosis. Overexpressed in various types of cancer. May be a marker of if patient will respond to tx
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The length of these determine how many cycles of replication a cell can go through.
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Telomeres
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Telomerase
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Active in CA cells to add telomere DNA back to the 5' end to continue replication
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4 Additional hallmarks of cancer
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1. Deregulating cellular energetics 2. Avoiding immune destruction 3. Genome instability 4. Tumor promoting inflammation
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Limitations of early detection of CA
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1. cost and safety (some dx tools increase CA development) 2. sensitivity and specificity of screening methods (need to detect subtle diff.) 3. over dx 4. quality of life (after knowing have CA)
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This extract was shown to decrease tobacco induced lung CA in Fiji.
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Kava. Negative correlation between Kava consumption and CA development.
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4 Challenges to Chemopreventive Agents
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1. Cost and profitability (ins won't cover b/c you don't have CA) 2. Which population(s) should get them? 3. Benefit undetectable in short term 4. Potential SE's associated with all agents
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Gleevec (imatinib)
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The "magic bullet" used to tx CML. Bcr-Abl kinase inhibitor (Bcr-Abl kinase is driving F of CML and not present in normal cells)
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Iressa (gefitinib)
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Targets mutated EGFR (found in various CA's, esp lung CA)
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2 Examples of Combination Therapies
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1. DOX (doxorubicin)-PTX (paclitaxel)-UCN01 kills p53 deficient cells selectively 2. Flavopiridol-Z-DEVD-fmk kills multi drug resistant cells selectively
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MoA of DOX-PTX-UCN01
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DOX causes DNA dmg. p53 and Chk1 (redundant p53 f(x) protein for DNA dmg checkpoint) detect dmg to prevent proliferation. UCN01 inhibits Chk1 so p53 can still prevent proliferation if present. CA cells only have Chk1 --> cell goes into anaphase where is trapped by PTX and can't replicate. Normal cells not killed b/c can't get into M phase (still have p53)
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MoA of Flavopiridol-Z-DEVD-fmk
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Exploit overexpression of Pgp in CA cells.
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2 Ways to create tissue selective therapy.
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Antibodies and Hormone therapies.
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4 Reasons why DNA is a good anti-CA target
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1. Genetic info. is critical for cell survival and proliferation 2. Most CA cells are highly proliferative (need more DNA replication, transcription, and translation) 3. Well defined primary/secondary/tertiary structures 4. Enough sequence complexity to ensure selectivity and specificity
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Which DNA base pairs pair together?
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G-C (3 H bonds) and A-T (2 H Bonds)
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Difference b/w major and minor grooves.
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Major is wide and shallow while the minor groove is narrow and deep.
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4 Classes of DNA Crosslinking Agents
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1. Nitrogen Mustards 2. Nitrosoureas 3. Hydrazines and Triazines (don't actually form crosslink, but do form covalent bond) 4. Platinum compounds
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Examples of Nitrogen Mustards.
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Mechlorethamine, chlorambucil, melphalan, cyclophosphamide, ifosfamide
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Which Nitrogen Mustards are PD's?
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Cyclophosphamide and ifosfamide
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What's an advantage of melphalan over other Nitrogen Mustards?
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It mimics phenylalalanine so it can be actively transported into cells. CA cells being highly proliferative need even more AA's.
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What nucleophile of DNA do Nitrogen mustards react with?
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Guanine N7 (in major groove) attacks electrophilic 3 member ring of drug.
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What are the steps of activation of cyclophosphamide? What enzyme can decrease efficacy?
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Cyclophosphamide --hydroxylation by CYP450--> unstable opened ring --self decomposition--> active species. Or instead of self decomposition, can be inactivated by aldehyde dehydrogenase (tissues with high conc of this E won't be sensitive to cyclophosphamide)
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Mitomycin C activation
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Reduced to hydroquinone by flavoreductases (overexpressed by some CA cells) --> electron pushing leads to active species
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What nucleophile of DNA does mitomycin C react with?
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Guanine N2 in the minor groove.
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Name 5 nitrosoureas
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Carmustine, lomustine, semustine, nimustine, and streptozotocin (only 1 not capable of forming crosslinks)
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Through what active intermediate do nitrosoureas act?
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Diazonium ion. Nitrogen gas is given off and helps to drive the rxn.
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What kind of strand crosslink can nitrosoureas form?
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Interstrand G-C crosslink
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What kind of strand crosslink can nitrogen mustards and mitomycin C form?
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Interstrand G-G crosslink
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Name 2 examples of triazines
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Decarbazine and Temozolamide
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Name 1 example of a hydrazine
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Procarbazine
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Can triazines form crosslinks?
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Negatory
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Name 4 examples of platinum compounds
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Cisplatin, carboplatin, oxaliplatin, and satraplatin
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Which platinum compound is most reactive?
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Cisplatin
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What 4 kind of DNA adducts can Cisplatin form?
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1. interstrand b/w adjacent base pairs 2. interstrand b/w base pairs that are separated 3. intrastrand crosslinking 4. bind DNA and protein
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4 Mechanisms of resistance to Cisplatin
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1. Reduction of intracellular drug accumulation (selectively pump cisplatin out of cells) 2. Increased inactivation by thiol-containing molecules (ie: glutathione) 3. Increase of DNA dmg repair 4. Inhibition of apoptosis
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What nucleophile of DNA do platinum compounds interact with?
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Guanine N7 in major groove
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What are 4 ways to target Cisplatin resistance?
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1. Increase delivery to tumor (liposomes, co-polymers, intraperitoneal administration) 2. Combination of platinum drugs with molecularly targeted agents (bevacizumab or trastuzumab) 3. Platinum resistance modulators (TLK286 and decitabine) 4. Novel platinum drugs targeting resistance mechanisms (oxaliplatin and satraplatin)
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Toxicities of Crosslinking Agents
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Hematopoietic, gonadal, pulmonary, alopecia, teratogenicity, immunosuppression
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Name 2 examples of DNA intercalators
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Actinomycin and plicamycin
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Which portion of DNA intercalators sits b/w DNA base pairs?
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The aromatic ring systems (flat portion)
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Which part of DNA do dsDNA breaking agents damage?
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The ribose sugar, not the base pairs
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What are 3 examples of dsDNA breaking agents?
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Bleomycin, calicheamicin, and gemtuzumab ozogamicin (recently recalled)
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Which portion of bleomycin can chelate to a metal as part of its MoA? What metal?
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The C-terminus contains N/S rings that can chelate with Fe
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Name examples of code reading agents.
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Netropsin, distamycin A, ET 743
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MoA of ET 743
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It is a code reading agent that recognizes GC base pairs and can form a covalent bond with guanine N2 (minor groove) to form DNA adduct
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This enzyme is responsible for relaxing DNA supercoils prior to replication.
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Topoisomerase. 1 relaxes 1 coil with each rxn, 2 relaxes 2 coils with each rxn.
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Topoisomerase I inhibitors MoA
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Recognize E in complex with DNA (after cleavage) --> binds the cleavable complex so E is trapped and DNA remains broken --> irreversible dsDNA break -> cell death
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What is the first Topoisomerase I inhibitor? (natural product)
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Camptothecin
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What improvement was made to camptothecin? Making what drug?
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Irinotecan has increased H20 solubility
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What enzyme is responsible for activation of irinotecan?
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Carboxylesterase
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What is the naturally occuring Topoisomerase 2 inhibitor?
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Podophyllotoxin
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What is the additional MoA of Topoisomerase 2 inhibitors?
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They are also DNA intercalators (only when topoisomerase is attached to DNA); performed by the flat portion of the molecule (aromatic system)
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Name 4 examples of Topoisomerase 2 inhibitors
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Doxorubicin, daunorubicin, idarubicin, epirubicin
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Name 4 mechanisms of resistance to topoisomerase inhibitors
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1. Decreased cellular accumulation (increased efflux) 2. Mutation of topoisomerase (drug no longer recognizes TP) 3. Subcellular nucleation of topoisomerase inhibitor (deactivate drug molecules) 4. High tolerance to topoisomerase inhibitor damage
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What structure may be in exist in Bcl-2 promoter region that may be a potential drug target?
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G-quadruplex DNA structure
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What are the 3 classes of antimetabolites?
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1. Purine analogs 2. Pyrimidine analogs 3. Antifolates
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Nucleoside analogs must be activated to what form?
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Triphosphate
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Nucleoside analogs have three mechanisms of inhibition.
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1. DNA/RNA incorporation and damage, direct 2. enzyme inhibition, direct 3. DNA synthesis inhibition (i.e. nucleotide balance is lost and certain bases are used more frequently and inappropriately.
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p 186. Describe how purine analogs are modified from the original base, and give two examples.
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6-mercaptopurine and 6-thioguanine have replaced the 6-carbonyl oxygen with a thiol group. The cancer cell is then killed.
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Describe the structural difference between purine analogs and purine nucleoside analogs
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Nucleoside analogs have the ribose sugar added to the purine base.
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Describe the steps involved in purine nucleobase activation and deactivation.
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Activation
6MP --> MP-RIBOSE-6MP (6-MPMP) --> TP-RIBOSE-6MP Deactivation 6MP --> xanthine oxidase -->6-thioxanthine 6MP --> TPMT / SAM --> 6-Methyl-MP |
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Is 6-MPMP, a precursor to TP-6MP, active? If so, in which ways?
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yes, it inhibits PRPP-AT, preventing the activation of P-RIBOSE for purine addition/synthesis.
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What cancer, in general, are purine nucleoside analogs indicated for?
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Leukemia
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What are the four purine nucleoside analogs?
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cladribine (leustatin), fludarabine phosphate (fludara), pentostatin (Nipent), and clofarabine
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Which purine nucleoside is the most water soluble? What structure was used for this? What situation is this most useful?
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Fludarabine phosphate, the phosphate increases water solubility which is useful for IV administration.
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Describe fludarabine phostphate bioactivation in three steps.
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1. Serum Phosphatases remove phosphate (outside of cell) | 2. Hydrophobic molecule enters the cell | 3. Deoxycytidine kinase (dCK) ads one phosphate per cycle for three cycles to fully activate the molecule.
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Name the enzyme that is inhibited by pentostatin. Explain how this happens.
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ADA - Adenosine DeAminase. Pentostatin mimics ADA's transition state and stabilizes it.
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Name the original pyrimidine analog and three additional drugs that have added constituents to it. Also list the corresponding indications.
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1. Original - 5-fluorouracile (5-FU) - Solid Tumors (variety) | 2. 5-fluorodeoxyuridine - Hepatic metastasis | 3. Capecitabine - Breast and colorectal cancers | 4. Tegafur - Bowel Cancer
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What has been changed on uracil to make 5-FU? pg. 192
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F replaces the methyl group on C-5.
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What is unique about 5-fluorodeoxyuridine, in terms of administration, and why? pg. 192
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Increased H20 solubility because of its 4 available oxygens.
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What is unique about capecitabine and tegafur, in terms of administration, and why?
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Both have PO availability. More hydrophobic? pg 192
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Explain capecitabine's mode of cytotoxic action.
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Selective release of 5-FU in the cancer cell.
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Explain the bioactivation of Capecitabine and then explain which step is selective.
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1. Capecitabine's carboxyester is cleaved by CE | 2. Deaminated (NH2 -> O2) by CyD | 3. Thymidine phosphorylase (TP) cleaves the sugar-base bond because Capacitabine's C5-methyl group cannot be phosphorylated (typically a hydroxy) leaving behind cytotoxic 5-FU | Step 3 is the only selective step because it is in the cancer cells
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5-FU is often converted to what chemical before it is able to enter the cell? Why is this significant?
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Dihydrofluorouracil (DHFR). 80% of 5-FU is converted to DHFR, which is inactive because it is missing a double bond. This double bond is required for a proper electrophilic attack by THIOL-Thymidine-Synthase.
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List three cytotoxic effects of 5-FU and the corresponding 5-FU metabolites
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1. RNA Damage (FUTP) 2. DNA Damage (TdUTP) 3. TS inhibition (5-FdUMP) -> DNA Damage
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In De novo pryimidine biosynthesis, 1 What dUMP constituent is removed? 2. What is it replaced with? 3. List the three molecules involved 4. How does 5-FU Fuck this Up?
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1. C5- Hydrogen | 2. Methyl Group | 3. A. dUMP B. tetrayhydrofolic acid (pmethyl donor) C. thymidine synthase binds to double bond of base and catalyzes this process. | 4. 5-FU has a fluoro at C5 rather than a hydrogen. Tetrahydrofolate's basic N: typically snatches the C5 hydrogen, leaving a Me, and releasing TS, however, the electrophilic C5 fluoro is invincible to such snatchery preventing the release of TS from 5-FdUMP.
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What is the significance of p53 during thymidine synthase therapy?
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Fully functioning p53 (tumor suppressor protein) is required for effective 5-FU therapy.
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Explain 4 chemicals that are additive/synergistic with 5-FU therapy when coadmistered, and why.
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1. DPD substrates (uracil, Eniluracil) act outside of the cell to prevent 5-FU inactivation 2. TS inhibition requires carbon donors - Leucovorin is readily converted to tetrahydrofolic acid 3. Methotrexate acts synergisically by activating enzymes that activate the conversion of 5-FU to FUMP (RNA DAMAGE) 4. Interferon (IFN) enhances inhibition of TS. 5?
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Name the two currently available Deoxycytidine analogs and their corresponding indications.
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1. cytarabine -> acute myelocytic leukemia | 2. gemcitabine -> solid tumors
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Explain cytarabine bioactivation and deactivation processes.
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Activation - 3x deoxycytidine kinase (dCK) Deactivation - dCMP deaminase (12pm NH2->O2)
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How are antifolate drugs transported into the cell?
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Actively, via the reduced folate carrier (RFC) in their free carboxy acid form
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How are antifolate drugs activated inside the cell?
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They are activated by FPGS folypolygylatmyl synthase which the carboxy oh and adds 5 to 7 glutamic acid units.
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List the three antifolate activities.
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1. Inhibits DHFR (dihydrofolate reductase). 2. Inhibits TS 3. Inibits GAR Transferase (purine biosynthesis)
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The folic acid pathway is a cancer treatment target for what reason?
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Because folic acid is a precursor to necessary molecules in the synthesis of both purines and pyrimidines.
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What are the four primary enzyme targets of the folic acid pathway?
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1. DHFR - Dihydrofolate reductase (Pur. and Pyr.) | 2. TS - Thymidine synthase (Pry.) | 3. GAR transferase (Pur.) and 4. AICAR transferase (Pur.)
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What antifolate targets does methotrexate inhibit?
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All four. 1. Dihydrofolate reductase 2. Thymidine Synthase 3. Gar Transferase 4. AlCAR Transferase
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Antifolates may or may not undergo: 1. active transport into the cell and 2. polyglutamic activation. What functional groups dictate this characteristic?
|
Antimetabolists with free carboxy groups undergo active transport and polyglutamic activation
|
|
|
Trimetrexate inhibits which folate pathway enzyme? Passive/Active Xport? Activation?
|
DHFR inhibition, Passive Transport / No activation
|
|
|
Pemetrexed inhibits which folate pathway enzyme? Passive/Active Xport? Activation?
|
DHFR, TS, and GAR Tfase inhibition, active transport / activation
|
|
|
edatrexate inhibits which folate pathway enzyme? Passive/Active Xport? Activation?
|
DHFR inhibition, Active transport / activation
|
|
|
Iometrexol inhibits which folate pathway enzyme? Passive/Active Xport? Activation?
|
GAR Tfase inhibitor, active transport / activation
|
|
|
PDX inhibits which folate pathway enzyme? Passive/Active Xport? Activation?
|
DHFR inhibition, active transport / activation
|
|
|
What is unique about Treanda's (bendamustine) mechanism of action?
|
It is a hybrid. 1. purine analog2. alkylator agent. The functional group R-N-(CH2-Cl)2 cross links DNA
|
|
|
What are the two primary characters of cancer?
|
1. An uncontrolled increase of cells ( increased proliferation rate & decreased death rate )
2. Ability to invade or implant (via metastasis) to other tissues. |
|
|
Which two routes are used by cancer cells to metastasize?
|
1. Bloodstream 2. Lymph System
|
|
|
Describe the trend in number of new cancer cases. Why?
|
The number of new cases are growing. As people live longer, cancer cells are more likely to develop into problems.
|
|
|
4 most common cancers men and women?
|
Men 1. Prostate 2. Lung and bronchus 3. Colon and Rectum 4. Urinary Bladder Women 1. Breast 2. Lung and bronchus 3. Colon & Rectum 4. Uterine corpus
|
|
|
4 most deadly cancers men and women?
|
1. Lung and bronchus 2. Men - prostate women - breast 3. colon and rectum 4. pancreas
|
|
|
Men or women, higher cancer incidence and or mortality?
|
Men for both
|
|
|
Which are the general rates of cancer (incidence) in US per 100,000 in 2007.
|
~160 prostate and ~ 120 breast ~70 male lung/bronchus cancer, <60 for the rest
|
|
|
Total number of cancer deaths avoided from 1991 to 2006?
|
550,000 males and 200,000 female
|
|
|
Which two diseases account for 50% of deaths in the USA?
|
Heart Disease and Cancer
|
|
|
Explain the changes in cancer death rate since 1950.
|
There is very minimal decrease. 190.1 from 193.9
|
|
|
How is education associated with death rates from cancer?
|
As education increases death rate from cancer decreases.
|
|
|
Japanese in Japan have high rates of stomach cancer, but when they emmigrate to Hawaii their rates of cancer rates mimmick those of the local culture. What might explain this?
|
It shows how the environment has an important causal role in cancer.
|
|
|
According to the twin study does genetics play a role in cancer?
|
For some cancers yes (up to 40%), for others, not at all.
|
|
|
What six things can cause cancer?
|
1. Viruses 2. Chemicals 3. Physical factors 4. Genetics 5. Therapy 5. Other factors
|
|
|
Which virus is primary in causing cervical cancer? Which two strains cause nearly 70% of all cervical cancer?
|
HPV-16 (53%), HPV-18 (17%)
|
|
|
How does the HPV virus cause cervical cancer?
|
Two oncoproteins that are made by the virus. 1. E6 2. E7
|
|
|
How does oncoprotein E6 promote cancer?
|
Promotes proliferation and inhibits apoptosis activation by p53 and BAK ( apoptosis is often induced by high expression of E7)
|
|
|
How does oncoprotein E7 promote cancer?
|
It promotes proliferation, but if it gets too active, it leads to cell death. It also helps E6 escape death by inhibiting the action of enzyme INK4A.
|
|
|
AIDs patients have how much higher cancer risk? (Men and Women)
|
100% Males 200% Females. Where did this come from?
|
|
|
About how long does it take for lung cancer to develop?
|
20 years
|
|
|
Through what mechanism and chemical does smoking cause cancer?
|
Benzo[a]pyrene undergoes CYP450 oxidation creating an epoxide structure which reacts with an amino group on guanine. (DNA Adduct formation)
|
|
|
What three kinds of agents cause carcinogenesis through adduct formation?
|
1. Alkylating agents 2. arylaminating agents 3. polycyclic aralkylating agents
|
|
|
BBQ causes what kind of mutation via what reaction?
|
Acrylamide is formed via the maillard Reaction between glucose and asparagine at temperatures over 180. Acrylamide is highly reactive towards DNA, causes DNA damage.
|
|
|
In Vitro tests. Example, advantage, limitation.
|
Ames Test :-D. Adv= Rapid/Inexpensive :-D. Lim: False extrapolations (doesn't acct for metabolism)
|
|
|
Animal tests. Example, advantage, limitation.
|
Rodent bioassays. Adv= More predictive than in vitro; Lim= expensive and human extrapolation is imperfect, takes much longer than Ames test.
|
|
|
Human epidemiology. Example, advantage, limitation.
|
Prospective cohort, case-control. Adv= direct measurement; Lim= Causation may be hard to determine; Confounding variables.
|
|
|
What are the three carcinogenic physical factors?
|
1. Ionization radiation (x-rays, gamma rays) 2. UV radiation A, B, C (240 to 400nm) 3. asbestos
|
|
|
What are the sources of ionizing radiation?
|
1. Earth - inherent to environment 2. Nuclear plants 3. X-Rays
|
|
|
Which tissues are most sensitive to ionization radiation?
|
Highly proliferating cells - blood and bone marrow. Most likely to cause leukemia.
|
|
|
What is the mechanism of ionization damage?
|
Base pair deletions leading to dsDNA breaks.
|
|
|
UV light originates from where and causes what?
|
The sun causing skin cancer
|
|
|
UV light mechanism (two)?
|
1. UVC/UVB (shorter wavelengths) -> pyrimidine dimers -> squamos and basal cell carcinomas || 2. UVA (longer wavelength) -> reactive oxygen species -> melanoma
|
|
|
Asbestos mechanism is what?
|
dsDNA breaks, reactive oxygen species generation, and cytokine induction
|
|
|
Asbestos causes which two types of cancer?
|
1. Malignant mesothelioma 2. bronchogenic cancer
|
|
|
What three types of genes are involved in cancer?
|
1. Tumor supressor genes 2. Tumor Oncogenes 3. DNA repair genes
|
|
|
Name two tumor suppressor genes
|
RB1 & p53
|
|
|
CDK4 oncogene promotes what cancer?
|
Melanoma
|
|
|
RET oncogene promotes what cancer?
|
multiple endocrine neoplasia type 2
|
|
|
MET oncogene promotes what cancer?
|
papillary renal cell carcinoma
|
|
|
KIT oncogene promotes what cancer?
|
gastrointestinal stromal tumors
|
|
|
BRCA1 is what?
|
tumor suppressor protein. 1. Repairs DNA breaks/adducts 2. modulates gene expression during cell stress 3. Arrests cell replication at checkpoints (G1/S, S, and G2/M) 4. Protein ubiquitination
|
|
|
Why are carcinogenesis and cancer therapy two sides of the same coin?
|
Because many agents that induce cancer are also used to treat cancer.
|
|
|
Upon curing a primary tumor, what may happen to the RR of developing another type of malignancy?
|
RR of other malignancies may increase depending on type of therapy.
|
|
|
How does BMI affect cancer risk?
|
Cancer risk is generally increased, except for lung CA in which an increased BMI --> decreased RR of CA
|
|
|
Does stress cause cancer?
|
Yes, there is an association, definitely.
|
|
|
Top 5 factors attributable to cancer deaths.
|
1. Tobacco (33%) 2. Diet (30%) 3. Infection 4. Reproductive factors and hormones 5. Ionizing radiation
|
|
|
List the 5 main components of the cell cycle in order.
|
G0 -> G1 -> S -> G2 -> M
|
|
|
Describe G0
|
G0 is quiescence and can lead to terminal cell cycle arrest.
|
|
|
Define mitogen.
|
Mitogen is a chemical that encourages cells to undergo the replication process.
|
|
|
Which three factors can send a cell into G0?
|
1. cell-cell contact 2. cell differentiation 3. anti-mitogenic factors
|
|
|
Which three factors take a cell out of G0 state?
|
1. mitogens 2. growth factors 3. nutrients
|
|
|
Describe S
|
DNA replication
|
|
|
Describe G2
|
Biosynthesis of microtubules (among other things) necessary for mitosis. RNA and Protein synthesized.
|
|
|
Describe Mitosis
|
Chromosome condensation and segregation. Prophase, metaphase, anaphase, telophase.
|
|
|
Describe G1
|
Gap phase after mitosis that is responsible for biosynthesis of enzymes that are used in S phase. DNA and protein are synthesized.
|
|
|
How many checkpoints exist in the cell cycle and where are they located?
|
4 checkpoints. | 1. Commitment (G1/S) | 2. S/G2 | 3. G2/M | 4. Mitosis
|
|
|
G2/M Checkpoint
|
Entrance to M blocked if replication isn't complete
|
|
|
M Checkpoint
|
Anaphase blocked if chromatids aren't properly assembled on mitotic spindle
|
|
|
G1/S Checkpoint
|
Entrance to S blocked if genome is damaged
|
|
|
S/G2 Checkpoint
|
Entrance to G2 blocked if genome is damaged
|
|
|
G1/S Checkpoint Mechanism
|
DNA damage --> RB protein binds E2F (transcription factor) --> transcription needed for S phase won't occur
|
|
|
Mechanisms of RB Inactivation
|
1. Genetic mutation (lose tumor suppressor f(x)); irreversible 2. Viral inactivation traps RB so it can't suppress E2F (irreversible) 3. Phosphorylation (endogenous inactivation; reversible) 4. Degradation by proteases (irreversible)
|
|
|
What are CKI's?
|
Kinase inhibitors that prevent phosphorylation of RB by CDK's (E2F is suppressed and cell doesn't go to S)
|
|
|
Explain the "wait anaphase" enzyme system and how it regulates chromatid separation.
|
Anaphase is the separation of sister chromatids and it requires the perfect alignment of chromatids. Before the chromatids are aligned the cell is in wait mode. MAD2-CDC20-APC/C is inactive in wait mode. When chromatids are alligned perfectly, MAD2 is released, and CDC20-APC/C is activated and APC/C ubiquinates securin (in complex with separin) and activates the lone separin. Separin, a protease, is now free to cleave the protein connections between the sister chromatids.
|
|
|
Give two examples of defective chromatid separation checkpoints.
|
1. Deficient MAD2: APC/C is active even when chromatids aren't aligned --> uneven separation of DNA --> potential mutations | 2. Securin is not present and separin is largely inactive without securin (securin "primes" separin). The sister chromatids are not separated in anaphase without active separin.
|
|
|
How prevalent are G1/S regulator mutations among different cancers?
|
Extremely prevalent. They are found generally in >70% of all cancer types (>80% and >90% is not uncommon) except for melanoma in which they found only in >20%.
|
|
|
Name the six hallmarks of cancer.
|
1. sustaining proliferating signaling 2. evading growth suppressors 3. activating invasion and metastasis 4. enabling replicative immortality. 5. inducing angiogenesis 6. Resisting cell death
|
|
|
3 Common molecular strategies for self-sufficiency in growth signals
|
1. Extracellular growth signals 2. transcellular signal transduction 3. intracellular signaling pathways
|
|
|
2 Antigrowth signals
|
1. Quiescence (G1 to G0) 2. Terminal differentiation (irreversible G0 arrest)
|
|
|
3 Components of Apoptotic machinery
|
1. Sensors (monitor cellular state) 2. Effectors (survival factors and death factors) 3. Executors
|
|
|
BCL2
|
Responsible for the ability of CA cells to evade apoptosis. Overexpressed in various types of cancer. May be a marker of if patient will respond to tx
|
|
|
The length of these determine how many cycles of replication a cell can go through.
|
Telomeres
|
|
|
Telomerase
|
Active in CA cells to add telomere DNA back to the 5' end to continue replication
|
|
|
4 Additional hallmarks of cancer
|
1. Deregulating cellular energetics 2. Avoiding immune destruction 3. Genome instability 4. Tumor promoting inflammation
|
|
|
Limitations of early detection of CA
|
1. cost and safety (some dx tools increase CA development) 2. sensitivity and specificity of screening methods (need to detect subtle diff.) 3. over dx 4. quality of life (after knowing have CA)
|
|
|
This extract was shown to decrease tobacco induced lung CA in Fiji.
|
Kava. Negative correlation between Kava consumption and CA development.
|
|
|
4 Challenges to Chemopreventive Agents
|
1. Cost and profitability (ins won't cover b/c you don't have CA) 2. Which population(s) should get them? 3. Benefit undetectable in short term 4. Potential SE's associated with all agents
|
|
|
Gleevec (imatinib)
|
The "magic bullet" used to tx CML. Bcr-Abl kinase inhibitor (Bcr-Abl kinase is driving F of CML and not present in normal cells)
|
|
|
Iressa (gefitinib)
|
Targets mutated EGFR (found in various CA's, esp lung CA)
|
|
|
2 Examples of Combination Therapies
|
1. DOX (doxorubicin)-PTX (paclitaxel)-UCN01 kills p53 deficient cells selectively 2. Flavopiridol-Z-DEVD-fmk kills multi drug resistant cells selectively
|
|
|
MoA of DOX-PTX-UCN01
|
DOX causes DNA dmg. p53 and Chk1 (redundant p53 f(x) protein for DNA dmg checkpoint) detect dmg to prevent proliferation. UCN01 inhibits Chk1 so p53 can still prevent proliferation if present. CA cells only have Chk1 --> cell goes into anaphase where is trapped by PTX and can't replicate. Normal cells not killed b/c can't get into M phase (still have p53)
|
|
|
MoA of Flavopiridol-Z-DEVD-fmk
|
Exploit overexpression of Pgp in CA cells.
|
|
|
2 Ways to create tissue selective therapy.
|
Antibodies and Hormone therapies.
|
|
|
4 Reasons why DNA is a good anti-CA target
|
1. Genetic info. is critical for cell survival and proliferation 2. Most CA cells are highly proliferative (need more DNA replication, transcription, and translation) 3. Well defined primary/secondary/tertiary structures 4. Enough sequence complexity to ensure selectivity and specificity
|
|
|
Which DNA base pairs pair together?
|
G-C (3 H bonds) and A-T (2 H Bonds)
|
|
|
Difference b/w major and minor grooves.
|
Major is wide and shallow while the minor groove is narrow and deep.
|
|
|
4 Classes of DNA Crosslinking Agents
|
1. Nitrogen Mustards 2. Nitrosoureas 3. Hydrazines and Triazines (don't actually form crosslink, but do form covalent bond) 4. Platinum compounds
|
|
|
Examples of Nitrogen Mustards.
|
Mechlorethamine, chlorambucil, melphalan, cyclophosphamide, ifosfamide
|
|
|
Which Nitrogen Mustards are PD's?
|
Cyclophosphamide and ifosfamide
|
|
|
What's an advantage of melphalan over other Nitrogen Mustards?
|
It mimics phenylalalanine so it can be actively transported into cells. CA cells being highly proliferative need even more AA's.
|
|
|
What nucleophile of DNA do Nitrogen mustards react with?
|
Guanine N7 (in major groove) attacks electrophilic 3 member ring of drug.
|
|
|
What are the steps of activation of cyclophosphamide? What enzyme can decrease efficacy?
|
Cyclophosphamide --hydroxylation by CYP450--> unstable opened ring --self decomposition--> active species. Or instead of self decomposition, can be inactivated by aldehyde dehydrogenase (tissues with high conc of this E won't be sensitive to cyclophosphamide)
|
|
|
Mitomycin C activation
|
Reduced to hydroquinone by flavoreductases (overexpressed by some CA cells) --> electron pushing leads to active species
|
|
|
What nucleophile of DNA does mitomycin C react with?
|
Guanine N2 in the minor groove.
|
|
|
Name 5 nitrosoureas
|
Carmustine, lomustine, semustine, nimustine, and streptozotocin (only 1 not capable of forming crosslinks)
|
|
|
Through what active intermediate do nitrosoureas act?
|
Diazonium ion. Nitrogen gas is given off and helps to drive the rxn.
|
|
|
What kind of strand crosslink can nitrosoureas form?
|
Interstrand G-C crosslink
|
|
|
What kind of strand crosslink can nitrogen mustards and mitomycin C form?
|
Interstrand G-G crosslink
|
|
|
Name 2 examples of triazines
|
Decarbazine and Temozolamide
|
|
|
Name 1 example of a hydrazine
|
Procarbazine
|
|
|
Can triazines form crosslinks?
|
Negatory
|
|
|
Name 4 examples of platinum compounds
|
Cisplatin, carboplatin, oxaliplatin, and satraplatin
|
|
|
Which platinum compound is most reactive?
|
Cisplatin
|
|
|
What 4 kind of DNA adducts can Cisplatin form?
|
1. interstrand b/w adjacent base pairs 2. interstrand b/w base pairs that are separated 3. intrastrand crosslinking 4. bind DNA and protein
|
|
|
4 Mechanisms of resistance to Cisplatin
|
1. Reduction of intracellular drug accumulation (selectively pump cisplatin out of cells) 2. Increased inactivation by thiol-containing molecules (ie: glutathione) 3. Increase of DNA dmg repair 4. Inhibition of apoptosis
|
|
|
What nucleophile of DNA do platinum compounds interact with?
|
Guanine N7 in major groove
|
|
|
What are 4 ways to target Cisplatin resistance?
|
1. Increase delivery to tumor (liposomes, co-polymers, intraperitoneal administration) 2. Combination of platinum drugs with molecularly targeted agents (bevacizumab or trastuzumab) 3. Platinum resistance modulators (TLK286 and decitabine) 4. Novel platinum drugs targeting resistance mechanisms (oxaliplatin and satraplatin)
|
|
|
Toxicities of Crosslinking Agents
|
Hematopoietic, gonadal, pulmonary, alopecia, teratogenicity, immunosuppression
|
|
|
Name 2 examples of DNA intercalators
|
Actinomycin and plicamycin
|
|
|
Which portion of DNA intercalators sits b/w DNA base pairs?
|
The aromatic ring systems (flat portion)
|
|
|
Which part of DNA do dsDNA breaking agents damage?
|
The ribose sugar, not the base pairs
|
|
|
What are 3 examples of dsDNA breaking agents?
|
Bleomycin, calicheamicin, and gemtuzumab ozogamicin (recently recalled)
|
|
|
Which portion of bleomycin can chelate to a metal as part of its MoA? What metal?
|
The C-terminus contains N/S rings that can chelate with Fe
|
|
|
Name examples of code reading agents.
|
Netropsin, distamycin A, ET 743
|
|
|
MoA of ET 743
|
It is a code reading agent that recognizes GC base pairs and can form a covalent bond with guanine N2 (minor groove) to form DNA adduct
|
|
|
This enzyme is responsible for relaxing DNA supercoils prior to replication.
|
Topoisomerase. 1 relaxes 1 coil with each rxn, 2 relaxes 2 coils with each rxn.
|
|
|
Topoisomerase I inhibitors MoA
|
Recognize E in complex with DNA (after cleavage) --> binds the cleavable complex so E is trapped and DNA remains broken --> irreversible dsDNA break -> cell death
|
|
|
What is the first Topoisomerase I inhibitor? (natural product)
|
Camptothecin
|
|
|
What improvement was made to camptothecin? Making what drug?
|
Irinotecan has increased H20 solubility
|
|
|
What enzyme is responsible for activation of irinotecan?
|
Carboxylesterase
|
|
|
What is the naturally occuring Topoisomerase 2 inhibitor?
|
Podophyllotoxin
|
|
|
What is the additional MoA of Topoisomerase 2 inhibitors?
|
They are also DNA intercalators (only when topoisomerase is attached to DNA); performed by the flat portion of the molecule (aromatic system)
|
|
|
Name 4 examples of Topoisomerase 2 inhibitors
|
Doxorubicin, daunorubicin, idarubicin, epirubicin
|
|
|
Name 4 mechanisms of resistance to topoisomerase inhibitors
|
1. Decreased cellular accumulation (increased efflux) 2. Mutation of topoisomerase (drug no longer recognizes TP) 3. Subcellular nucleation of topoisomerase inhibitor (deactivate drug molecules) 4. High tolerance to topoisomerase inhibitor damage
|
|
|
What structure may be in exist in Bcl-2 promoter region that may be a potential drug target?
|
G-quadruplex DNA structure
|
|
|
What are the 3 classes of antimetabolites?
|
1. Purine analogs 2. Pyrimidine analogs 3. Antifolates
|
|
|
Nucleoside analogs must be activated to what form?
|
Triphosphate
|
|
|
Nucleoside analogs have three mechanisms of inhibition.
|
1. DNA/RNA incorporation and damage, direct 2. enzyme inhibition, direct 3. DNA synthesis inhibition (i.e. nucleotide balance is lost and certain bases are used more frequently and inappropriately.
|
|
|
p 186. Describe how purine analogs are modified from the original base, and give two examples.
|
6-mercaptopurine and 6-thioguanine have replaced the 6-carbonyl oxygen with a thiol group. The cancer cell is then killed.
|
|
|
Describe the structural difference between purine analogs and purine nucleoside analogs
|
Nucleoside analogs have the ribose sugar added to the purine base.
|
|
|
Describe the steps involved in purine nucleobase activation and deactivation.
|
Activation
6MP --> MP-RIBOSE-6MP (6-MPMP) --> TP-RIBOSE-6MP Deactivation 6MP --> xanthine oxidase -->6-thioxanthine 6MP --> TPMT / SAM --> 6-Methyl-MP |
|
|
Is 6-MPMP, a precursor to TP-6MP, active? If so, in which ways?
|
yes, it inhibits PRPP-AT, preventing the activation of P-RIBOSE for purine addition/synthesis.
|
|
|
What cancer, in general, are purine nucleoside analogs indicated for?
|
Leukemia
|
|
|
What are the four purine nucleoside analogs?
|
cladribine (leustatin), fludarabine phosphate (fludara), pentostatin (Nipent), and clofarabine
|
|
|
Which purine nucleoside is the most water soluble? What structure was used for this? What situation is this most useful?
|
Fludarabine phosphate, the phosphate increases water solubility which is useful for IV administration.
|
|
|
Describe fludarabine phostphate bioactivation in three steps.
|
1. Serum Phosphatases remove phosphate (outside of cell) | 2. Hydrophobic molecule enters the cell | 3. Deoxycytidine kinase (dCK) ads one phosphate per cycle for three cycles to fully activate the molecule.
|
|
|
Name the enzyme that is inhibited by pentostatin. Explain how this happens.
|
ADA - Adenosine DeAminase. Pentostatin mimics ADA's transition state and stabilizes it.
|
|
|
Name the original pyrimidine analog and three additional drugs that have added constituents to it. Also list the corresponding indications.
|
1. Original - 5-fluorouracile (5-FU) - Solid Tumors (variety) | 2. 5-fluorodeoxyuridine - Hepatic metastasis | 3. Capecitabine - Breast and colorectal cancers | 4. Tegafur - Bowel Cancer
|
|
|
What has been changed on uracil to make 5-FU? pg. 192
|
F replaces the methyl group on C-5.
|
|
|
What is unique about 5-fluorodeoxyuridine, in terms of administration, and why? pg. 192
|
Increased H20 solubility because of its 4 available oxygens.
|
|
|
What is unique about capecitabine and tegafur, in terms of administration, and why?
|
Both have PO availability. More hydrophobic? pg 192
|
|
|
Explain capecitabine's mode of cytotoxic action.
|
Selective release of 5-FU in the cancer cell.
|
|
|
Explain the bioactivation of Capecitabine and then explain which step is selective.
|
1. Capecitabine's carboxyester is cleaved by CE | 2. Deaminated (NH2 -> O2) by CyD | 3. Thymidine phosphorylase (TP) cleaves the sugar-base bond because Capacitabine's C5-methyl group cannot be phosphorylated (typically a hydroxy) leaving behind cytotoxic 5-FU | Step 3 is the only selective step because it is in the cancer cells
|
|
|
5-FU is often converted to what chemical before it is able to enter the cell? Why is this significant?
|
Dihydrofluorouracil (DHFR). 80% of 5-FU is converted to DHFR, which is inactive because it is missing a double bond. This double bond is required for a proper electrophilic attack by THIOL-Thymidine-Synthase.
|
|
|
List three cytotoxic effects of 5-FU and the corresponding 5-FU metabolites
|
1. RNA Damage (FUTP) 2. DNA Damage (TdUTP) 3. TS inhibition (5-FdUMP) -> DNA Damage
|
|
|
In De novo pryimidine biosynthesis, 1 What dUMP constituent is removed? 2. What is it replaced with? 3. List the three molecules involved 4. How does 5-FU Fuck this Up?
|
1. C5- Hydrogen | 2. Methyl Group | 3. A. dUMP B. tetrayhydrofolic acid (pmethyl donor) C. thymidine synthase binds to double bond of base and catalyzes this process. | 4. 5-FU has a fluoro at C5 rather than a hydrogen. Tetrahydrofolate's basic N: typically snatches the C5 hydrogen, leaving a Me, and releasing TS, however, the electrophilic C5 fluoro is invincible to such snatchery preventing the release of TS from 5-FdUMP.
|
|
|
What is the significance of p53 during thymidine synthase therapy?
|
Fully functioning p53 (tumor suppressor protein) is required for effective 5-FU therapy.
|
|
|
Explain 4 chemicals that are additive/synergistic with 5-FU therapy when coadmistered, and why.
|
1. DPD substrates (uracil, Eniluracil) act outside of the cell to prevent 5-FU inactivation 2. TS inhibition requires carbon donors - Leucovorin is readily converted to tetrahydrofolic acid 3. Methotrexate acts synergisically by activating enzymes that activate the conversion of 5-FU to FUMP (RNA DAMAGE) 4. Interferon (IFN) enhances inhibition of TS. 5?
|
|
|
Name the two currently available Deoxycytidine analogs and their corresponding indications.
|
1. cytarabine -> acute myelocytic leukemia | 2. gemcitabine -> solid tumors
|
|
|
Explain cytarabine bioactivation and deactivation processes.
|
Activation - 3x deoxycytidine kinase (dCK) Deactivation - dCMP deaminase (12pm NH2->O2)
|
|
|
How are antifolate drugs transported into the cell?
|
Actively, via the reduced folate carrier (RFC) in their free carboxy acid form
|
|
|
How are antifolate drugs activated inside the cell?
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They are activated by FPGS folypolygylatmyl synthase which the carboxy oh and adds 5 to 7 glutamic acid units.
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List the three antifolate activities.
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1. Inhibits DHFR (dihydrofolate reductase). 2. Inhibits TS 3. Inibits GAR Transferase (purine biosynthesis)
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The folic acid pathway is a cancer treatment target for what reason?
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Because folic acid is a precursor to necessary molecules in the synthesis of both purines and pyrimidines.
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What are the four primary enzyme targets of the folic acid pathway?
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1. DHFR - Dihydrofolate reductase (Pur. and Pyr.) | 2. TS - Thymidine synthase (Pry.) | 3. GAR transferase (Pur.) and 4. AICAR transferase (Pur.)
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What antifolate targets does methotrexate inhibit?
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All four. 1. Dihydrofolate reductase 2. Thymidine Synthase 3. Gar Transferase 4. AlCAR Transferase
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Antifolates may or may not undergo: 1. active transport into the cell and 2. polyglutamic activation. What functional groups dictate this characteristic?
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Antimetabolists with free carboxy groups undergo active transport and polyglutamic activation
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Trimetrexate inhibits which folate pathway enzyme? Passive/Active Xport? Activation?
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DHFR inhibition, Passive Transport / No activation
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Pemetrexed inhibits which folate pathway enzyme? Passive/Active Xport? Activation?
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DHFR, TS, and GAR Tfase inhibition, active transport / activation
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edatrexate inhibits which folate pathway enzyme? Passive/Active Xport? Activation?
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DHFR inhibition, Active transport / activation
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Iometrexol inhibits which folate pathway enzyme? Passive/Active Xport? Activation?
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GAR Tfase inhibitor, active transport / activation
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PDX inhibits which folate pathway enzyme? Passive/Active Xport? Activation?
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DHFR inhibition, active transport / activation
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What is unique about Treanda's (bendamustine) mechanism of action?
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It is a hybrid. 1. purine analog2. alkylator agent. The functional group R-N-(CH2-Cl)2 cross links DNA
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