DNA & Drugs Flashcards

1
Q

What is HER-2?

A

Epidermal Growth Factor (EGF - cell-cell signaling) targeted in breast cancer

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2
Q

mTOR, Tyrosine Kinases, and VEGF are all examples of what kind of drug targets?

A

These are all important components in signal transduction pathways in the cell (specifically for synthesizing more proteins)

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3
Q

What is the general concept behind using DNA as a chemotherapy target?

A

Cancer cells are dividing at a rate much faster than normal cells so it leaves them more vulnerable to drugs that affect DNA structure and function

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4
Q

What tissues are often most affected by drugs that DNA and why?

A
Cells that naturally proliferate rapidly are slowed down
lining of GI tract
Oral Cavity
Blood 
Hair
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5
Q

What are often the side effects of DNA targeting drugs?

A

Myelosuppression
Mucostis
Gastritis
Alopecia

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6
Q

What are the 3 ways by which drugs can affect existing DNA?

A

Transcription Inhibition
Structure modification
Blocking Cell division

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7
Q

What are 2 ways to prevent new DNA synthesis?

A

DNA assembly

Control of Gene Expression

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8
Q

What are 2 ways that DNA assembly can be affected by DNA targeting drugs?

A

Remove essential coefactors like folate

Provide false precursors

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9
Q

Topioosomerases are an example of what?

A

Targeting existing DNA and inhibiting transcription

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10
Q

What is the job of Topoisomerases?

A

unknot DNA by causing transient breaks

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11
Q

What is the job of Topo-I?

A

removes supercoils by cutting one strand

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12
Q

What is the job of Topo-II?

A

Cuts both strands of DNA helix, allowing one strand to pass through the other

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13
Q

What residue is key in the action of Topo-I/II?

A

Conserved Tyrosine

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14
Q

What are the three ways that Topo inhibitors can work?

A
  1. Direct binding to Topo
  2. Bind to DNA to intercalate between two strands
  3. Catalytic inhibitors
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15
Q

What is the net affect of inhibitors that bind directly to Topo and those that bind to DNA to intercalate the two strands?

A

prevents subsequent re-annealing process to proceed after DNA is cleaved through a DNA-Topo-Enzyme complex

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16
Q

What is the net affect of catalytic inhibitors of Topo?

A

Terminate the DNA replication process without the strand breaking because the entire process is inhibited

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17
Q

What is irinotecan?

A

Topo-I inhibitor

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18
Q

what is topotecan?

A

Topo-I inhibitor

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19
Q

What is etoposide?

A

Topo-II inhibitor

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20
Q

What is mitoxantrone?

A

Topo-II inhibitor

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21
Q

In general how is resistance conferred in cancerous growth?

A

Natural selection - the cells sensitive to the drug die while ones with different enzymes survive and proliferate

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22
Q

What are 3 target based factors that can cause topo inhibitor resistance?

A
  1. Topo I and II are pretty good at subbing for each other
  2. The cell can upregulate topo expression
  3. Sub-clones, some mutants will have favorable genes that code for enzymes resistant to the drug
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23
Q

What are 3 drug bases factors that may cause topo inhibitor resistance?

A
  1. Reduced cellular access - up-regulation of MDR-type efflux pumps
  2. Impaired Drug activation (decreased metabolic activation or increased metabolic degration)
  3. Change in time spent in S-phase (when topos are most active)
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24
Q

What is the major side effect of topo inhibitors?

A

Myelosuppression - dose limiting factor

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25
What is Bleomycin's mechanism of action?
causes direct toxicity to DNA - generates free radicals by extracting an H -radicals react with O2 and degrade (works against some enzymes too?)
26
What are the actions of Dactinomycin and Doxorubin?
Bind DNA and Intercalate | - have moeities that are both annular and planar that insert into DNA (between base pairs)
27
What are the most important members of the anthracyclin family?
Dactinomycin, Doxorubin
28
What drug class to the bis-chlorethylnitrosoureas fit into?
- modify existing DNA by modifying DNA structure
29
How does cyclophosphamide work?
- it is a chelating agent that modifies DNA structure - has two highly reactive alkyl armes that react to N7 on guanine's and interlinks them - Has Choroethyl functionality (common to most of these drugs)
30
What are the two main targets for DNA alkylators?
N7 and O6 of guanine
31
What is the difference in monofunctional and bifunctional agents?
monfunctional -Methylating agents Bifunctional agents -cause cross-linking Cross-linking is typically more detrimental to DNA while monofunctional groups may cause DNA pols to mispair, giving increased incidence of cancer
32
How do platinum compounds act on DNA?
Through chelation similar to the sbis-chloroethylnitrosoureas
33
What separates platinum compounds from other alkylating agents?
- It doesn't need to undergo metabolic activation - enters through the Cu2+ pump - also reacts with sulfhyrdrals and various electron rich DNA sites
34
How does the action of p53 relate to the action of alkylating drugs?
-It locks cells in G1/S phase until the alkylation is fixed or the cell dies (induced apoptosis)
35
What is the consequence of a lack of p53 on alkylating drugs?
they are resistant to these drugs because of a lack of cell death signal
36
How may a cell become resistant to alkylating agents?
1. Cell may upregulate DNA repair enzymes 2. decreased metabolic activation of drugs (Pt drugs excluded) 3. Decreased production of reactive products 4. Pumps reducing intracellular conc. of drug
37
What are the side effects of alkylating agents?
myelosuppression (main one) | -alopecia, pulmonary fibrosis, leukogenesis, infertility, teratogenesis
38
What do Topo inhibitors cause and how is this effect counteracted?
- Double strand breaks | - fixed: dS repair
39
What do Pt. agents cause, how is this counteracted?
- Bulky adducs | - Fixed: by nucleotide excision repair
40
What do alkylating agents cause and how are these effects counteracted?
- abasic sites - base modifications - single strand breaks - Fixed: base exicision repair
41
What are two ways that drugs can target the production of new DNA?
- Can be accomplished at the level of the genome itself | - can be done by limiting the number of bona fide purine and pyrimadine components
42
What generally does methotrexate target?
-limits A,C,G,T --> targets production of new DNA
43
How does methotrexate work?
- Folate antagonist - inhibites dihyrofolate reductase (DHFR) [prevents the necessary 1 carbon transfer need to make...] - prevents PURINE dTMP synthesis
44
What drug is often given in conjunction with methotrexate?
leucovorin - reduced folate to reduce toxicity
45
How do 6-mercaptopurine and Thioguanine impair the synthesis of NEW DNA?
Get phosphorylated and incorporated by DNA polymerase, but they are illegitimate
46
How does hydroxyurea impair synthesis of NEW DNA?
- acts on rate limiting enzyme (ribonucleotide reductase) | - acts as a free radical scavenger and ruins the free rad. intermediate in the rxn
47
What are aberrant nucleotides?
ones that are mistaken for real nucleotides and incorporated preventing add'n DNA synth.
48
What are the general methods of resistance for folate antagonists and antimetabolites?
1. Gene amplification - make more enzyme 2. salvage pathways - other cells can recycle bad nucs 3. Damage to p53 4. Increased elimination 5. increased Efflux
49
What are some of the side effects of folate antagonists and antimetabolites?
myelosuppresion muscostitis skin rashes chemical hepitis
50
What are the 4 classes of microtubule inhibiting drugs?
1. Vinca alkaloids - cancer 2. Taxanes - cancer 3. griseoflurin - fungal inf. 4. colchiain - gout
51
What type of cancers to the Vinca alkaloids and Taxanes treat?
Both: breast lung Vinca: Blood and germ Taxanes: Ovarian, head, and neck
52
How do vinca alkaloids work?
prevention of microtubule formation
53
How do taxanes work?
Prevention of disassembly
54
Why might you begin to feel tingling in hands and toes or show loss of deep tendon reflexes when taking microtubule inhibiting drugs?
neural toxicity | -damage to the mircrotubules that carry vessicles to the axons
55
What is the mechanism of action for vincas?
prevent microtubule assembly
56
What is the mechanism of taxol?
prevents microtubule disassembly, nucleus fills with tubules preventing division
57
What is a major side effect of vincas and taxol?
neural toxicity, it can damage microtubules which are needed for vessicle release in axons
58
What do tetracylcine, marolides, and choramphanicol all have in common?
They Inhibit RNA translation
59
How can antisence RNA prevent coding of proteins?
it binds to the mRNA and masks it from polymerases
60
What are some epigenetic writers?
Histone acetyle transferases (HATs), histone methyltransferases (HMTs), Protein arginine methyl transferase (PAMTs)
61
What do epigentic writers do?
Leave marks on histone tails
62
What are some epigenetic erasers?
Histone deacetylases (HDAC), Lysiene demethylases (KDMs), Phosphatases
63
What is the effect of HDAC inhibitors on tumors?
- typically amplify apoptotic processes and increase free radical generation - induce cell cycle arrest - suppress tumor growth