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MBOD Week 5 > DNA & Drugs > Flashcards

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
Q

What is Bleomycin’s mechanism of action?

A

causes direct toxicity to DNA
- generates free radicals by extracting an H
-radicals react with O2 and degrade
(works against some enzymes too?)

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26
Q

What are the actions of Dactinomycin and Doxorubin?

A

Bind DNA and Intercalate

- have moeities that are both annular and planar that insert into DNA (between base pairs)

27
Q

What are the most important members of the anthracyclin family?

A

Dactinomycin, Doxorubin

28
Q

What drug class to the bis-chlorethylnitrosoureas fit into?

A
  • modify existing DNA by modifying DNA structure
29
Q

How does cyclophosphamide work?

A
  • 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
Q

What are the two main targets for DNA alkylators?

A

N7 and O6 of guanine

31
Q

What is the difference in monofunctional and bifunctional agents?

A

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
Q

How do platinum compounds act on DNA?

A

Through chelation similar to the sbis-chloroethylnitrosoureas

33
Q

What separates platinum compounds from other alkylating agents?

A
  • It doesn’t need to undergo metabolic activation
  • enters through the Cu2+ pump
  • also reacts with sulfhyrdrals and various electron rich DNA sites
34
Q

How does the action of p53 relate to the action of alkylating drugs?

A

-It locks cells in G1/S phase until the alkylation is fixed or the cell dies (induced apoptosis)

35
Q

What is the consequence of a lack of p53 on alkylating drugs?

A

they are resistant to these drugs because of a lack of cell death signal

36
Q

How may a cell become resistant to alkylating agents?

A
  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
Q

What are the side effects of alkylating agents?

A

myelosuppression (main one)

-alopecia, pulmonary fibrosis, leukogenesis, infertility, teratogenesis

38
Q

What do Topo inhibitors cause and how is this effect counteracted?

A
  • Double strand breaks

- fixed: dS repair

39
Q

What do Pt. agents cause, how is this counteracted?

A
  • Bulky adducs

- Fixed: by nucleotide excision repair

40
Q

What do alkylating agents cause and how are these effects counteracted?

A
  • abasic sites
  • base modifications
  • single strand breaks
  • Fixed: base exicision repair
41
Q

What are two ways that drugs can target the production of new DNA?

A
  • 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
Q

What generally does methotrexate target?

A

-limits A,C,G,T –> targets production of new DNA

43
Q

How does methotrexate work?

A
  • Folate antagonist
  • inhibites dihyrofolate reductase (DHFR)
    [prevents the necessary 1 carbon transfer need to make…]
  • prevents PURINE dTMP synthesis
44
Q

What drug is often given in conjunction with methotrexate?

A

leucovorin - reduced folate to reduce toxicity

45
Q

How do 6-mercaptopurine and Thioguanine impair the synthesis of NEW DNA?

A

Get phosphorylated and incorporated by DNA polymerase, but they are illegitimate

46
Q

How does hydroxyurea impair synthesis of NEW DNA?

A
  • acts on rate limiting enzyme (ribonucleotide reductase)

- acts as a free radical scavenger and ruins the free rad. intermediate in the rxn

47
Q

What are aberrant nucleotides?

A

ones that are mistaken for real nucleotides and incorporated preventing add’n DNA synth.

48
Q

What are the general methods of resistance for folate antagonists and antimetabolites?

A
  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
Q

What are some of the side effects of folate antagonists and antimetabolites?

A

myelosuppresion
muscostitis
skin rashes
chemical hepitis

50
Q

What are the 4 classes of microtubule inhibiting drugs?

A
  1. Vinca alkaloids - cancer
  2. Taxanes - cancer
  3. griseoflurin - fungal inf.
  4. colchiain - gout
51
Q

What type of cancers to the Vinca alkaloids and Taxanes treat?

A

Both:
breast
lung

Vinca:
Blood and germ

Taxanes:
Ovarian, head, and neck

52
Q

How do vinca alkaloids work?

A

prevention of microtubule formation

53
Q

How do taxanes work?

A

Prevention of disassembly

54
Q

Why might you begin to feel tingling in hands and toes or show loss of deep tendon reflexes when taking microtubule inhibiting drugs?

A

neural toxicity

-damage to the mircrotubules that carry vessicles to the axons

55
Q

What is the mechanism of action for vincas?

A

prevent microtubule assembly

56
Q

What is the mechanism of taxol?

A

prevents microtubule disassembly, nucleus fills with tubules preventing division

57
Q

What is a major side effect of vincas and taxol?

A

neural toxicity, it can damage microtubules which are needed for vessicle release in axons

58
Q

What do tetracylcine, marolides, and choramphanicol all have in common?

A

They Inhibit RNA translation

59
Q

How can antisence RNA prevent coding of proteins?

A

it binds to the mRNA and masks it from polymerases

60
Q

What are some epigenetic writers?

A

Histone acetyle transferases (HATs), histone methyltransferases (HMTs), Protein arginine methyl transferase (PAMTs)

61
Q

What do epigentic writers do?

A

Leave marks on histone tails

62
Q

What are some epigenetic erasers?

A

Histone deacetylases (HDAC), Lysiene demethylases (KDMs), Phosphatases

63
Q

What is the effect of HDAC inhibitors on tumors?

A
  • typically amplify apoptotic processes and increase free radical generation
  • induce cell cycle arrest
  • suppress tumor growth

MBOD Week 5 (9 decks)

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