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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

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2
Q

doxorubicin is a topo __1/2__ ___inhibitor/intercalator

A

2 intercalator

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3
Q

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

A

topo 2; G2 (sister chromatid separation)

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4
Q

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

A

1; S phase (DNA replication phase)

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5
Q

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

A

1

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6
Q

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

A

yes

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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

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8
Q

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

A

true

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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

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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

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11
Q

topotecan & irinotecan are semisynthetic analogs of _________

A

camptothecin

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12
Q

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

A

1; lactone ring

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13
Q

t/f topotecan & irinotecan are water soluble

A

true

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14
Q

t/f camptothecin is used clinically

A

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

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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

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15
Q

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

A

SN-38; UGT1A1

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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

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17
Q

what % of population is affected by UGT1A1 polymorphism

A

10%

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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

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19
Q

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

A

false; double strand DNA breaks

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20
Q

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

A

true

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21
Q

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

A

-OH

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22
Q

t/f doxorubicin is a topo I inhibitor and intercalator

A

false; topo II inhibitor & intercalator

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23
Q

why is doxorubicin non cell cycle dependent?

A

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

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24
why should someone with a bad heart not be started on doxorubicin?
free radical damage causes cardiotoxicity since heart tissue has low levels of enzymes to neutralize radicals
25
how can doxorubucin lead to severe local tissue damage?
extravasated (leakage out of vessels)
26
what topo II inhibitor has the nickname "red devil"? why?
doxorubicin; red color & bad SEs
27
The cardiotoxicity of doxorubicin is believed to be caused by ____ catalyzed free radical formation
iron
28
what cyclic analog of metal chelating agent EDTA is used to mediate cardiotoxicity caused by doxorubicin?
dexrazoxane--> binds to iron & blocks iron-oxygen induced toxicities
29
etoposide is a topo II inhibitor that is specific to what cell cycle phase
G2
30
t/f etoposide is a topo II inhibitor and intercalator
false; DOES NOT INTERCALATE
31
t/f the resistance mechanisms for topo I and II inhibitors are similar
TRUE
32
t/f glutathione S-transferase overexpression is a resistance mechanism that only effects doxorubicin when compared to other topo II inhibitors
True; etoposide not affected by glutathione
33
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. Doxorubicin
34
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
e. glycopeptide antibiotic
35
what are the 2 essential parts of bleomycin & what do they do?
-bis(thiazole) w charged side chain intercalates into DNA (GpT selective -imidazole coordinates iron oxygen species that generate DNA free radicals
36
t/f bleomycin is unique because its radical intermediate leads to DNA single & double strand breaks
true
37
what drug should NOT be prescribed to someone with poor pulmonary function? A. Bleomycin B. Doxorubicin C. Etoposide D. Irinotecan
A. Bleomycin pulmonary toxicity is dose-limiting
38
bleomycin is inactivated by bleomycin _______, which is in HIGH concentration everywhere except _____ and ______. Because of this ________ toxicity and ____ SE is common
aminohydrolase; skin & lungs pulmonary & rash
39
the B-tubulin side of microtubules is ___+ or -__. the a-tubulin side is __+ or -___
positive; negative
40
________are an essential part of the mitotic spindle and responsible for moving chromosomal material into daughter cells during _____
Microtubules; mitosis
41
microtubule inhibitors affect which phase of the cell cycle?
M (chromosome segregation)
42
In the spindle assembly checkpoint, __________ need to be attached to the spindle microtubules. There also needs to be _______ tension
kinetochores; kinetochore
43
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 ______
interphase & prophase prometaphase & metaphase cell apoptosis; anaploidy
44
_______ alkaloids prevent microtubule assembly ___________ prevent microtubule disassembly
vinca; taxanes
45
what microtubule inhibitors stabilize microtubules, so they can't inappropriately attach to chromosomes --> leads to apoptosis
taxanes
46
what kind of microtubule inhibitor is vincristine
vinca alkaloid
47
what kind of microtubule inhibitor is paclitaxel
taxane
48
t/f erubulin is a vinca alkaloid
false; but it is a microtubule destabilizer/inhibitor of assembly
49
vinca alkaloids are natural products isolated from the _______ plant or semisynthetic analogs
periwinkle
50
vinca alkaloids are large molecules and require a specific ______ to get into cells. they are specifically excellent substrates for the ____________ transporter
transporter; pgp (drugs rapidly pumped out of resistant cells & cross-resistant w other large molecule antitumor agents
51
what do vinca alkaloids bind to?
tubulin
52
do vincas or taxanes inhibit polymerization during mitosis
vincas; polymerization is same as microtubule assembly & vincas inhibit this
53
__________ is a common SE of vinca alkaloids because microtubules are critical to nerve cell axon function
peripheral neuropathy
54
what drug class requires a specific transporter (pgp) to get into cells give example of drug in this class
vinca alkaloids (vincristine)
55
taxanes are natural products derived from the ________ tree
yew paclitaxel from pacific yew docetaxel from european yew
56
t/f taxanes promote microtubule assembly into stable (non-functional) bundles which decreases free tubulin & prevent microtubule formation at spindle
true
57
the stabilization that taxanes cause blocks __________ which leads to mitotic arrest
depolymerization
58
taxanes are excellent substrates for ______ transporter except for ________
pgp transporter; cabaziTAXel
59
resistance to taxanes is attributed to ________- mutations
tubulin
60
paclitaxel is linked to _______- to increase solubility & circulation time of drug
albumin
61
what is the dose-limiting SE of taxanes
myelosuppression neurotoxicity is common, but reversible
62
___________ are naturally occurring macrolides isolated from myxobacterium fermentaion
epothilones (ixabepilone
63
ixabepilone binds to ______ & promotes tubulin polymerization & microtubule stabilization
tubulin
64
t/f epothilones are NOT cross-resistant with taxanes and poor pgp substrates
TRUE
65
Which of the following microtubule inhibitors block the polymerization of tubulin? A. Paclitaxel B. Vincristine C. Ixabepilone
B. Vincristine others block depolymerization

therapeutics 864 - exam 1 (10 decks)

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