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PHRM 864 > Topoisomerase and Microtubule Inhibs > Flashcards

Topoisomerase and Microtubule Inhibs Flashcards

1
Q

Topoisomerase 1does what

A

single strand cut

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2
Q

topoisomerase I attaches how

A

covalently

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3
Q

how do topo 1 inhibitors work

A

covalently attach to topo 1 and glues it to the DNA, blocks religation

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4
Q

how does topo 1 inhibitors form a physical barrier

A

barrier to replication and transcription
DNA breaks, protein glued, topo 1 inhib

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5
Q
A
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6
Q

cells in what phase are most sensitive to topo 1 cleavage

A

S phase

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7
Q

drug resistance mechanisms with topo 1 inhibs (4)

A

PGP overxpression
MRP overexpression
glutathione S transferase overexpression
topo downregulation

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8
Q

topo 1 inhibitiors

A

topotecan
ironotecan

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9
Q

what is ironotecan

A

topo 1 inhib

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10
Q

ironotecan is a _____

A

prodrug

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11
Q

ironotecan active metabolite metabolized by what

A

SN38 is metabolized by UGT1A1
if polymoprhism pts can have toxicity

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12
Q

UGT1A1 polymorphism could make what drug toxic

A

ironotecan

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13
Q

topo 2 does what

A

double strand cut
relieves torsional stress AND untangles DNA

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14
Q

topoisomerase II is especially important for what

A

replication

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15
Q

how do topoisomerase II inhibs work

A

lock the Topo II after double strand break covalently
double strand dna break
no religation anymore

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16
Q

how does doxorubicin work

A

topo II inhibitor
free radical damages DNA
intercalator

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17
Q

doxorubicin tox

A

cardiac toxicities due to low levels of enzymes that neutralize free radicals

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18
Q

which drug has severe cardiotoxicity

A

doxorubicin, red devil

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19
Q

how is cardiac toxicity from doxorubicin mediated

A

give dexrazoxane

20
Q

what causes cardiac toxicity in doxorubicin, what causes the free radicals?

A

iron catalyzed free radical formation

21
Q

etoposide class

A

topo II inhibitor

22
Q

etoposide cell cycle

A

G2

23
Q

etoposide does what

A

double strand break
does not have free radicals
does not intercalate

24
Q

which topoisomerase inhibitor is not sensitive to glutatione levels?

A

etoposide

25
Q

topo II resistance mechanisms (5)

A

PGP overexpression
MRP overexpression
glutathione S transferase overexpression - doxo only
topo II downregulation
increased DNA damage repair

26
Q

what does bleomycin do?

A

intercalates
generates free iron radicals

27
Q

radical intermediate from bleomycin does what

A

single and double strand breaksb

28
Q

bleomycin side effect

A

pulmonary toxicity

29
Q

bleomycin which side effect not that bad

A

myelosupression

30
Q

bleomycin cell phase

A

G2/M

31
Q

where is bleomycin highest conc

A

skin and lung

32
Q

what do microtubules do

A

move chromosomal material into daughter cells during mitosis part of the spindle

33
Q

what phase are microtubules specific

A

G2/M

34
Q

how do microtubule destabilizers work

A

vinca alkaloids
prevent assembly of microtubules
bind tubulin

35
Q

how do microtubule stabilizers work

A

taxanes
prevent disassembly of microtubules
bind tubulin

36
Q

T/F: microtubule destabilizers and stabilizers bind at the same spot

A

F they bind different sites

37
Q

vinca alkaloids do what

A

inhibit microtubule assembly
destabilizes

38
Q

vincristine toxicity

A

neurotoxicity
peripheral neuropathy

39
Q

vinca alkyloid drug

A

vincristine

40
Q

destabilizer drugs

A

vincristine
erubulin

41
Q

eribulin toxicity

A

lower rate of neurotoxicity

42
Q

microtubule stabilizer drugs

A

paclitaxel
Ixabepilone

43
Q

paclitaxel class

A

stabilizer

44
Q

paclitaxel side effect

A

myelosupression

45
Q

ixabepilone class

A

stabilizer

46
Q

ixabeplilone PGP?

A

poor PGP substrates, not cross resistant with taxanes

PHRM 864 (7 decks)

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