Brainscape's Knowledge GenomeTM

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


See full index

PHRM 864 > Lecture 6 - Topo-microtubule Inhibitors > Flashcards

Lecture 6 - Topo-microtubule Inhibitors Flashcards

1
Q

Topoisomerase mechanisms

A

transcription and translation induce supercoiling
topoisomerases provide 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

Topo1 inhibitors

A

irinotecan

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

Topo2 intercalator

A

doxorubicin

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

Topo2 inhibitors

A

etoposide
bleomycin

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

Topoisomerase 1

A

type I topoisomerase cut one strand of double stranded DNA, relax remaining strand and reanneal

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

Topoisomerase I inhibitor mechanism

A

inhibitor covalently attached to enzyme that is covalently attached to DNA, blocks religation from occurring
provides physical barrier to replication and transcription, prevent DNA from being functional

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

Topoisomerase I inhibitors

A

S phase specific! - cells in S phase are most sensitive to Topo I induced cleavage
bind to and form a ternary drug-enzyme-DNA complex, glues topoisomerase to DNA
inhibitor binding stabilizes Topo-DNA complex and blocks DNA religation

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

Topoisomerase I inhibitor drug resistance

A

PGP overexpression, multidrug resistant protein overexpression, topoisomerase downregulation or mutation to prevent inhibitor binding

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

Topoisomerase I inhibitors - camptothecins

A

topotecan and irinotecan

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

Irinotecan

A

is a prodrug, irinotecan converted to SN-38 (active metabolite) by carboxylesterases
SN-38 is metabolized by uridine diphospate glucosyltransferase (UGT1A1)
~10% of the pop has polymorphisms predicting low expression of UGT1A1, leading to increased toxicity of irinotecan

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

Topoisomerase II relieves

A

torsional strain and untangles DNA by catalyzing double-stranded DNA breaks

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

Topoisomerase II inhibitors

A

doxorubicin
etoposide
non-cell cycle dependent, although activity is greater in G2/M

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

Doxorubicin

A

toxicity: cardiotoxicity - damage to cardiac muscle dependent on cumulative dose; severe local tissue damage if extravastated
free radical damage causes cardiotoxicity since heart tissue has low levels of enzymes that neutralize free radicals

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

Dexrazoxane

A

drug to mediate toxicity, helps to manage cardiac damage; protects against anthracycline-induced cardiotoxicity
cyclic analog of metal chelating agent EDTA
enters cell and converts to ring-opened chelating agent - binds to iron, blocks iron-oxygen induced toxicities; cardiotoxicity of doxorubicin believed to be caused by iron-catalyzed free radical formation

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

Etoposide

A

inhibits religation of double stranded breaks induced by topoII but does not intercalate
G2 block-cell cycle specific
produces G2/M block

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

Resistance to topo II inhibitors

A

PGP overexpression, MRP overexpression, glutathione S-transferase overexpression (doxorubicin only), topoisomerase II downregulation or mutation, increased DNA damage repair

17
Q

Bleomycin

A

charged side chain, intercalates into DNA, generates free radicals from imidazole, causes Fe++ iron oxygen species to generate DNA free radical
radical intermediate leads to DNA single strand and double strand breaks
greatest effect on cells in G2 and M phases of cell cycle

18
Q

Bleomycin toxicity

A

pulmonary toxicity is dose-limiting and cumulative - pulmonary inflammation progressing to pulmonary fibrosis
myelosuppression is minimal

19
Q

Bleomycin inactivated by

A

bleomycin aminohydrolase, which is in high concentrations everywhere but skin and lung
increased levels of aminohydrolase in resistant cancers

20
Q

Dynamic instability

A

proteins cap tubulins, build up, then fall apart
growing and shrinking microtubules

21
Q

Microtubules during cell division

A

responsible for moving chromosomal material into daughter cells during mitosis

22
Q

Microtubule inhibitors

A

vincristine
paclitaxel

23
Q

Spindle assembly checkpoint

A

kinetochores need to be attached to spindle microtubules; needs to be kinetochore tension

24
Q

Spindle assembly checkpoint with inhibitors

A

microtubule assembly inhibitors –> in cancer cells, you never get to checkpoint, if it can’t get to checkpoint –> apoptosis
microtubule de-assembly inhibitors lead to sustained checkpoint activation –> cell death
defective spindle assembly checkpoint –> chromosomes skrewed up

25
Q

Vinca alkaloids

A

prevent microtubule assembly - prevent tubular monomer from forming microtubules

26
Q

Taxanes

A

prevent microtubule disassembly
these stabilize microtubules

27
Q

Microtubule destabilizers and stabilizers bind

A

different sites on tubulin
this is how they have their different functions

28
Q

Microtubule destabilizers

A

vinca alkaloids (vincristine and analogs)
erubulin

29
Q

Vinca alkaloids

A

large molecules require a specific transporter to get into cells
excellent substrates for PGP transporter: drugs rapidly pumped out of resistant cells, cross-resistant with other large molecule antitumor agents

30
Q

Vinca alkaloids bind to

A

tubulin
binding leads to inhibition of microtubule assembly (polymerization) and inhibition of microtubule shortening
no attachment of microtubules to mitotic spindle, leads mitotic arrest because no spindle checkpoint activation
SE: peripheral neuropathy

31
Q

Vinca alkaloids - vincristine

A

toxicity - extravasation causes severe local inflammation
neurotoxicity

32
Q

Vinca alkaloids - vinblastine and vinorelbine

A

neurotoxicity less severe than with vincristine

33
Q

Eribulin

A

microtubule polymerization inhibitor - binds at microtubule ends and prevents elongation
lower rate of neurotoxicity

34
Q

Microtubule stabilizers

A

taxanes (paclitaxel)
epothilones (ixabepilone)

35
Q

Taxanes

A

paclitaxel, docetaxel, cabazitaxel

36
Q

Taxanes bind to

A

tubulin with two consequences: promotion of microtubule assembly into stable (non-functional) bundles decreases free tubulin and prevents microtubule formation at spindle; stabilization of existing microtubules blocks depolymerization (shortening) and segregation of sister chromatids to daughter cells
leads to mitotic arrest
excellent substrates for PGP transporter - drugs rapidly pumped out of resistant cells, cross-resistant with other large molecule antitumor agents

37
Q

Paclitaxel

A

linked to albumin to increase solubility and circulation time of drug
toxicity: myelosuppression and neurotoxicity

38
Q

Epothilones

A

binds to tubulin and promotes tubulin polymerization and microtubule stabilization
not cross-resistant with taxanes, poor PGP substrate
toxicity: neurotoxicity

PHRM 864 (20 decks)

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