Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

therapeutics 864 - exam 1 > topo microtubule inhibitors > Flashcards

topo microtubule inhibitors Flashcards

1
Q

Topoisomerase mechanisms:

DNA must be tightly coiled and packed around ___________ to fit in the nucleus

Transcription and translation induce _______

Topoisomerases provide a mechanism to __increase/reduce__ localized supercoiling and provide access to ___single/double___ stranded DNA by enzymes responsible for replication, transcription and repair

A

DNA must be tightly coiled and packed around nucleosomes to fit in the nucleus

Transcription and translation induce supercoiling

Topoisomerases provide a mechanism to reduce localized supercoiling and provide access to double stranded DNA by enzymes responsible for replication, transcription and repair

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

doxorubicin is a topo __1/2__ ___inhibitor/intercalator

A

2 intercalator

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

etoposide & bleomycin are topo __1/2___ inhibitors that affect ___ cell cycle phase

A

topo 2; G2 (sister chromatid separation)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

irinotecan is a topo __1/2__ inhibitor that affects which cell cycle phase?

A

1; S phase (DNA replication phase)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

type I topoisomerases cut __1/2__ strand(s) of double stranded DNA

A

1

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

while topoisomerases are cutting DNA strands to uncoil & reanneal do they stay covalently attached?

A

yes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

describe how topo 1 inhibitors cause inhibition

A

drug covalently binds to topo 1 & makes it so it cannot detach from DNA. topo 1 is inhibited & DNA is damaged. “camptothecins” act as road block/intercalator

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

t/f topo I inhibition provides a physical barrier to replication & transcription

A

true

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

topo 1 inhibitors overview:

Clinically relevant topoisomerase inhibitors bind to and form a _______drug-enzyme-DNA complex
>Inhibitor binding stabilizes Topo-DNA complex and blocks DNA ________

Cells in ____phase are most sensitive to Topo I induced cleavage

Most topoisomerase inhibitors share a polycyclic aromatic motif for __________
>Polycyclic aromatic motif preferentially stacks with _________

A

Clinically relevant topoisomerase inhibitors bind to and form a ternary drug-enzyme-DNA complex
>Inhibitor binding stabilizes Topo-DNA complex and blocks DNA re-ligation

Cells in S phase are most sensitive to Topo I induced cleavage

Most topoisomerase inhibitors share a polycyclic aromatic motif for intercalation
Polycyclic aromatic motif preferentially stacks with guanine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Describe the 4 drug resistance mechanisms of topo 1 inhibitors

  1. _________overexpression
  2. ___________ (MRP) overexpression
  3. __________ S-transferase overexpression
  4. Topoisomerase ___up/down___regulation or mutation to prevent inhibitor binding
A

P-glycoprotein (PGP) overexpression

Multidrug resistant protein (MRP) overexpression

Glutathione S-transferase overexpression

Topoisomerase downregulation or mutation to prevent inhibitor binding

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

topotecan & irinotecan are semisynthetic analogs of _________

A

camptothecin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

topotecan & irinotecan are potent inhibitors of topo _#__. what structural feature is essential for activity?

A

1; lactone ring

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

t/f topotecan & irinotecan are water soluble

A

true

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

t/f camptothecin is used clinically

A

false; it has potent activity with severe & unpredictable toxicity & low solubility

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

t/f topotecan has low solubility making it a potent and prime clinical candidate

A

false; high water solubility which makes it a good when used clinically –> irinotecan is also water soluble & used clinically

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

irinotecan is metabolized to the active metabolite _________ by what enzyme?

A

SN-38; UGT1A1

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what polymorphism must pts be tested for prior to tx with irinotecan? why?

A

polymorphism of UGT1A1 causing low expression and increased toxicity of irinotecan

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what % of population is affected by UGT1A1 polymorphism

A

10%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Topoisomerase I inhibitors primarily halt cells in which phase of the cell cycle?

A. G0/G1

B. S

C. G2

D. M

A

B. S

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

t/f topo 2 relieves torsional strain AND untangles DNA by catalyzing single-strand DNA breaks

A

false; double strand DNA breaks

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

t/f many compounds inhibit topo 2 but only ones that produce double stranded DNA breaks are cancer chemotherapies

A

true

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

For topo II inhibitors like doxorubicin, the presence of _____ group at R4 confers different clinical properties

A

-OH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

t/f doxorubicin is a topo I inhibitor and intercalator

A

false; topo II inhibitor & intercalator

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

why is doxorubicin non cell cycle dependent?

A

has multiple mechanisms of toxicity beyond intercalator–> also causes DNA damage via free radicals

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

why should someone with a bad heart not be started on doxorubicin?

A

free radical damage causes cardiotoxicity since heart tissue has low levels of enzymes to neutralize radicals

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

how can doxorubucin lead to severe local tissue damage?

A

extravasated (leakage out of vessels)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

what topo II inhibitor has the nickname “red devil”? why?

A

doxorubicin; red color & bad SEs

27
Q

The cardiotoxicity of doxorubicin is believed to be caused by ____ catalyzed free radical formation

A

iron

28
Q

what cyclic analog of metal chelating agent EDTA is used to mediate cardiotoxicity caused by doxorubicin?

A

dexrazoxane–> binds to iron & blocks iron-oxygen induced toxicities

29
Q

etoposide is a topo II inhibitor that is specific to what cell cycle phase

A

G2

30
Q

t/f etoposide is a topo II inhibitor and intercalator

A

false; DOES NOT INTERCALATE

31
Q

t/f the resistance mechanisms for topo I and II inhibitors are similar

A

TRUE

32
Q

t/f glutathione S-transferase overexpression is a resistance mechanism that only effects doxorubicin when compared to other topo II inhibitors

A

True; etoposide not affected by glutathione

33
Q

A patient has a history of heart disease and poor cardiac function. Which topoisomerase inhibitor should not be prescribed?

A. Doxorubicin

B. Etoposide

C. Irinotecan

A

A. Doxorubicin

34
Q

what drug class does bleomycin belong to?
a. topo I inhibitor
b. topo II inhibitor
c. alkylator
d. kinase inhibitor
e. glycopeptide antibiotic
f. immunotherapy

A

e. glycopeptide antibiotic

35
Q

what are the 2 essential parts of bleomycin & what do they do?

A

-bis(thiazole) w charged side chain intercalates into DNA (GpT selective
-imidazole coordinates iron oxygen species that generate DNA free radicals

36
Q

t/f bleomycin is unique because its radical intermediate leads to DNA single & double strand breaks

A

true

37
Q

what drug should NOT be prescribed to someone with poor pulmonary function?
A. Bleomycin
B. Doxorubicin
C. Etoposide
D. Irinotecan

A

A. Bleomycin

pulmonary toxicity is dose-limiting

38
Q

bleomycin is inactivated by bleomycin _______, which is in HIGH concentration everywhere except _____ and ______.

Because of this ________ toxicity and ____ SE is common

A

aminohydrolase; skin & lungs

pulmonary & rash

39
Q

the B-tubulin side of microtubules is ___+ or -__. the a-tubulin side is __+ or -___

A

positive; negative

40
Q

________are an essential part of the mitotic spindle and responsible for moving chromosomal material into daughter cells during _____

A

Microtubules; mitosis

41
Q

microtubule inhibitors affect which phase of the cell cycle?

A

M (chromosome segregation)

42
Q

In the spindle assembly checkpoint, __________ need to be attached to the spindle microtubules. There also needs to be _______ tension

A

kinetochores; kinetochore

43
Q

microtubule assembly inhibitors act in b/t which phases of mitosis?

de-assembly?

this leads to _______. if a cell is able to overcome this, it can lead to ______

A

interphase & prophase

prometaphase & metaphase

cell apoptosis; anaploidy

44
Q

_______ alkaloids prevent microtubule assembly

___________ prevent microtubule disassembly

A

vinca; taxanes

45
Q

what microtubule inhibitors stabilize microtubules, so they can’t inappropriately attach to chromosomes –> leads to apoptosis

A

taxanes

46
Q

what kind of microtubule inhibitor is vincristine

A

vinca alkaloid

47
Q

what kind of microtubule inhibitor is paclitaxel

A

taxane

48
Q

t/f erubulin is a vinca alkaloid

A

false; but it is a microtubule destabilizer/inhibitor of assembly

49
Q

vinca alkaloids are natural products isolated from the _______ plant or semisynthetic analogs

A

periwinkle

50
Q

vinca alkaloids are large molecules and require a specific ______ to get into cells. they are specifically excellent substrates for the ____________ transporter

A

transporter; pgp (drugs rapidly pumped out of resistant cells & cross-resistant w other large molecule antitumor agents

51
Q

what do vinca alkaloids bind to?

A

tubulin

52
Q

do vincas or taxanes inhibit polymerization during mitosis

A

vincas; polymerization is same as microtubule assembly & vincas inhibit this

53
Q

__________ is a common SE of vinca alkaloids because microtubules are critical to nerve cell axon function

A

peripheral neuropathy

54
Q

what drug class requires a specific transporter (pgp) to get into cells

give example of drug in this class

A

vinca alkaloids (vincristine)

55
Q

taxanes are natural products derived from the ________ tree

A

yew

paclitaxel from pacific yew
docetaxel from european yew

56
Q

t/f taxanes promote microtubule assembly into stable (non-functional) bundles which decreases free tubulin & prevent microtubule formation at spindle

A

true

57
Q

the stabilization that taxanes cause blocks __________ which leads to mitotic arrest

A

depolymerization

58
Q

taxanes are excellent substrates for ______ transporter except for ________

A

pgp transporter; cabaziTAXel

59
Q

resistance to taxanes is attributed to ________- mutations

A

tubulin

60
Q

paclitaxel is linked to _______- to increase solubility & circulation time of drug

A

albumin

61
Q

what is the dose-limiting SE of taxanes

A

myelosuppression

neurotoxicity is common, but reversible

62
Q

___________ are naturally occurring macrolides isolated from myxobacterium fermentaion

A

epothilones (ixabepilone

63
Q

ixabepilone binds to ______ & promotes tubulin polymerization & microtubule stabilization

A

tubulin

64
Q

t/f epothilones are NOT cross-resistant with taxanes and poor pgp substrates

A

TRUE

65
Q

Which of the following microtubule inhibitors block the polymerization of tubulin?

A. Paclitaxel

B. Vincristine

C. Ixabepilone

A

B. Vincristine

others block depolymerization

therapeutics 864 - exam 1 (10 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions