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Therapeutics > exam 1 lecture 4 > Flashcards

exam 1 lecture 4 Flashcards

1
Q

Which of the following drugs targets a kinase that is produced by
formation of the Philadelphia chromosome?
a) Alectinib
b) Gefitinib
c) Imatinib
d) binimetinib

A

imatinib

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2
Q

Which compound below is not a covalent kinase inhibitor?
A. Gefitinib
B. Osimertinib
C. Afatinib
D. Acalabrutinib

A

Gefitinib

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3
Q

Describe how T315I prevents the efficacy of imatinib?

A

T315I mutation prevents binding of imatinib to BCR-abl

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4
Q

What drug is indicated upon identification of T315I mutation

A

Ponatinib

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5
Q

Which drugstarget DNA replication (S-cell cycle)

A

5-fluorouracil
Cytarabine
6-mercaptopurine
methotrexate
Irinotecan

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6
Q

What do antimetabolites target?

A

They target intermediary metabolic pathways involved in synthesis of essential molecules in proliferating cells

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7
Q

What is dose limiting to antimetabolites

A

It targets rapidly proliferating cells (myelosuppression)

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8
Q

What are antimetabolites analogs of? WHat do they mimic?

A

Naturally occuring metabolites.

cofactor mimics and substrate mimics

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9
Q

What is adenine paired with? WHat are the pyramidines? WHich ones have two hydrogen bonds?

A

Adenine with thyamine.

Pyramidines are CUT

Adenine and thyamine both have 2 bonds.

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10
Q

What are some pyramidine analogs that interfere with pyramidine nucleotides synthesis?

A

5-FU and capecitabine

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11
Q

What are some pyramidine analogs that inhibit DNA polymerase

A

Gemcitabine and Ara-C

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12
Q

WHat are some uridine analogs? How do they work?

A

5-fluorouracil.

Primarily inhibit thymidine synthesis from uracil

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13
Q

WHat type of analog is 5-flurouracil? WHat is it converted to?

A

it is a fluorinated uracil analog

5-FU is converted to fDUMP via a two step transformation

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14
Q

What happens to dUMP in the presence of folates

A

Thymidylate synthase synthesizes thymidine monophosphate (TMP) from dUMP

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15
Q

How is the ternary complex formed? WHat does this entail?

A

fDUMP mimics DUMP and binds active site of thymidylate synthase.

forms ternary complex with enzyme and tetrahydrofolate

this makes reaction unable to proceed to completion and thymidylate synthase is trapped in ternary complex

TMP can not be produced, results in inhibition of DNA synthesis.

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16
Q

how to rescue fdump-enzyme-folate toxicity

A

thymidine treatment

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17
Q

source of resistance to 5-FU

A

Downregulation of activating enzymes that convert 5-FU to fDUMP

upregulation of thymidylate synthase

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18
Q

describe the susceptability of 5-FU in the population

A

5% of the population has a gene polymorphism resulting in the deficiency of enzyme DPD. Which breaks down 5-FU. Results in increased toxicity with 5-FU

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19
Q

5-FU drug rescue during overdose

A

Thymidine

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20
Q

What drug increases the efficacy of 5-FU

A

leucovorate

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21
Q

what is leucovorate converted to in the cell?

A

folate

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22
Q

How does higher tetrahydrofolate affect the efficacy of 5-FU

A

increases

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23
Q

Name a cytosine analog

A

Cytarabine

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24
Q

What happens to cytarabine in the cell

A

Converted to Ara-CTP intracellularly

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25
Q

What is Ara-CTP

A

Ara-CTP is a competitive inhibitor of DNA polymerase a

Ara-CTP is also incorporated into DNA and inhibits further DNA synthesis

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26
Q

What does cytidine deaminase do? What happens if there is decreased levels of cytidine deaminase in CNS?

A

Converts cytarabine to non toxic uracil arabinoside.

decreased levels of cytidine deaminase in CNS makes Ara-C highly toxic in leukemia and lymphoma

27
Q

What are some resistance mechanisms of cytarabine

A

Downregulation of activating enzymes
upregulation of cytidine deaminase
downregulation of transporter

28
Q

cytarabine is deactivated by

A

cytidine deaminase

29
Q

What is given with cytarabine to increase efficacy and decrease resistance (synergy)

A

Tetrahydrouridine

30
Q

Name a purine analog

A

6-mercaptopurine

31
Q

6-mercaptopurine is an analog of?

A

adenine

32
Q

what does 6-mercaptopurine block the synthesis of?

A

Purine nucleotides

33
Q

Resistance of 6-mercaptopurine is caused by

A

HGPRT

34
Q

What is 6-mercaptopurine inactivated by

A

TPMT

35
Q

What percent of children have TPMY in US

A

10%

36
Q

Drug interaction of 6-mercaptopurine

A

6-MP has a drug interaction with allopurinol

37
Q

Describe the interaction between allopurinol and 6-MP

A

allopurinol is a xanthine oxidase inhibitor.

Xanthine oxidase breaks down 6-MP. Those taking allopurinol are at risk for 6-mp toxicity

38
Q

what are folates essential for?

A

It is an essential cofactor for many enzymatic reactions.

39
Q

Describe the MOA of folic acid and how DHFR comes into play.

A

Folic acid enters the folate pool as dihydrofolate (FH2)

reduction to tetrahydrofolate happens by DHFR

40
Q

What does DHFR inhibition do? What drugs target DHFR?

A

DHFR inhibition reduces FH4 pools.

The major effect is the inhibition of TMP synthesis

Antifolates target DHFR

41
Q

cpds that bind to and inhibit DHFR are

A

folate mimics 1) folic acid
2) methotrexate

42
Q

WHat causes resistance to methotrexate?

A

amplification of DHFR gene or mutation of DHFR to resistant form of enzyme

decreased polyglutamation results in decreased intracellulat mtx accumulation

43
Q

What is overdose rescue for methotrexate? How does it work?

A

Leucovorin

it increases intracellular pools of tetrahydrofolate and reverses toxic effects of DHFR inhibition

44
Q

Leucovorin enhances which substances

A

5-FU and capcitabine

45
Q

what rescues 5-fu toxic effects

A

thymidine

46
Q

What are alkylating agents? What do they result in?

A

Alkylating agents generate reactive electrophilic intermediates that react with nucleophilic groups. They result in attachment of alkyl to DNA and protein

47
Q

What is the most common site of alkylation

A

alkylation of purine bases in DNA (most commonly guanine)

48
Q

What do we mean when we say alkylating agents are bifunctional

A

They produce intra and inter strand linkages

49
Q

Are alkylating agents cell cycle specific?

A

No

50
Q

Repair of cross links in normal cell vs cancer cell

A

Repair of crosslink in cancer is not good

51
Q

are alkylating agents potent nucleophiles or electrophiles

A

electrophiles

52
Q

side effects of alkylation

A

some rapidly proliferating cells are sensitive to effects of DNA alkylation and cross linking (bone marrow, gut mucosa)

measurable incidence of 2nd malignancy in long term survivors. Usually in bone marrow.

(myelosuppression, N/V, carcinogenic)

53
Q

side effects of all alkylators

A

(myelosuppression, N/V, carcinogenic)

54
Q

What are two strategies to decrease reactivity of nitrogen mustard gas

A
  1. decrease nucleophilicity of nitrogen by adding aryl group
  2. prodrug strategy
55
Q

describe the prodrug strategy to decrease reactivity of mustard gas and the role PM plays in this

A

PM- Phosphoramide mustard- is a metabolite that crosslinks DNA

hydroxylated metabolite must be converted to PM into tumor cell because PM is highly polar and does not readily diffuse into cell and has short half life.

56
Q

PM is inactivated by

A

aldehyde dehydrogenase

57
Q

Most useful and commonly used alkylating agent

A

cyclophosphamide

58
Q

side effects of cyclophosphamide

A

mild bone marrow toxicity
hemorrhagic cystitis

59
Q

why does cyclophosphamide have mild bone marroe toxicity

A

sparing to marrow stem cell because of high ADH levels in these cell types

60
Q

why does cyclophosphamide have hemorrhagic cycstitis (toxic to bladder)

A

acrolein is toxic to bladder mucosa

acrolein accumulates in urine and damages bladder mucosa

61
Q

how to block hemorrhagic cystitis

A

use mesna

62
Q

how does mesna work

A

mesna contains charged sulfonate group so it does not penetrate cells. mesna accumulates in the urine

63
Q

what inactivates cyclophosphamide

A

aldehyde dehydrogenase

64
Q
A

Therapeutics (38 decks)

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