topo microtubule inhibitors Flashcards
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
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
doxorubicin is a topo __1/2__ ___inhibitor/intercalator
2 intercalator
etoposide & bleomycin are topo __1/2___ inhibitors that affect ___ cell cycle phase
topo 2; G2 (sister chromatid separation)
irinotecan is a topo __1/2__ inhibitor that affects which cell cycle phase?
1; S phase (DNA replication phase)
type I topoisomerases cut __1/2__ strand(s) of double stranded DNA
1
while topoisomerases are cutting DNA strands to uncoil & reanneal do they stay covalently attached?
yes
describe how topo 1 inhibitors cause inhibition
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
t/f topo I inhibition provides a physical barrier to replication & transcription
true
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 _________
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
Describe the 4 drug resistance mechanisms of topo 1 inhibitors
- _________overexpression
- ___________ (MRP) overexpression
- __________ S-transferase overexpression
- Topoisomerase ___up/down___regulation or mutation to prevent inhibitor binding
P-glycoprotein (PGP) overexpression
Multidrug resistant protein (MRP) overexpression
Glutathione S-transferase overexpression
Topoisomerase downregulation or mutation to prevent inhibitor binding
topotecan & irinotecan are semisynthetic analogs of _________
camptothecin
topotecan & irinotecan are potent inhibitors of topo _#__. what structural feature is essential for activity?
1; lactone ring
t/f topotecan & irinotecan are water soluble
true
t/f camptothecin is used clinically
false; it has potent activity with severe & unpredictable toxicity & low solubility
t/f topotecan has low solubility making it a potent and prime clinical candidate
false; high water solubility which makes it a good when used clinically –> irinotecan is also water soluble & used clinically
irinotecan is metabolized to the active metabolite _________ by what enzyme?
SN-38; UGT1A1
what polymorphism must pts be tested for prior to tx with irinotecan? why?
polymorphism of UGT1A1 causing low expression and increased toxicity of irinotecan
what % of population is affected by UGT1A1 polymorphism
10%
Topoisomerase I inhibitors primarily halt cells in which phase of the cell cycle?
A. G0/G1
B. S
C. G2
D. M
B. S
t/f topo 2 relieves torsional strain AND untangles DNA by catalyzing single-strand DNA breaks
false; double strand DNA breaks
t/f many compounds inhibit topo 2 but only ones that produce double stranded DNA breaks are cancer chemotherapies
true
For topo II inhibitors like doxorubicin, the presence of _____ group at R4 confers different clinical properties
-OH
t/f doxorubicin is a topo I inhibitor and intercalator
false; topo II inhibitor & intercalator
why is doxorubicin non cell cycle dependent?
has multiple mechanisms of toxicity beyond intercalator–> also causes DNA damage via free radicals
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
how can doxorubucin lead to severe local tissue damage?
extravasated (leakage out of vessels)
what topo II inhibitor has the nickname “red devil”? why?
doxorubicin; red color & bad SEs
The cardiotoxicity of doxorubicin is believed to be caused by ____ catalyzed free radical formation
iron
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
etoposide is a topo II inhibitor that is specific to what cell cycle phase
G2
t/f etoposide is a topo II inhibitor and intercalator
false; DOES NOT INTERCALATE
t/f the resistance mechanisms for topo I and II inhibitors are similar
TRUE
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
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
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
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
t/f bleomycin is unique because its radical intermediate leads to DNA single & double strand breaks
true
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
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
the B-tubulin side of microtubules is ___+ or -__. the a-tubulin side is __+ or -___
positive; negative
________are an essential part of the mitotic spindle and responsible for moving chromosomal material into daughter cells during _____
Microtubules; mitosis
microtubule inhibitors affect which phase of the cell cycle?
M (chromosome segregation)
In the spindle assembly checkpoint, __________ need to be attached to the spindle microtubules. There also needs to be _______ tension
kinetochores; kinetochore
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
_______ alkaloids prevent microtubule assembly
___________ prevent microtubule disassembly
vinca; taxanes
what microtubule inhibitors stabilize microtubules, so they can’t inappropriately attach to chromosomes –> leads to apoptosis
taxanes
what kind of microtubule inhibitor is vincristine
vinca alkaloid
what kind of microtubule inhibitor is paclitaxel
taxane
t/f erubulin is a vinca alkaloid
false; but it is a microtubule destabilizer/inhibitor of assembly
vinca alkaloids are natural products isolated from the _______ plant or semisynthetic analogs
periwinkle
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
what do vinca alkaloids bind to?
tubulin
do vincas or taxanes inhibit polymerization during mitosis
vincas; polymerization is same as microtubule assembly & vincas inhibit this
__________ is a common SE of vinca alkaloids because microtubules are critical to nerve cell axon function
peripheral neuropathy
what drug class requires a specific transporter (pgp) to get into cells
give example of drug in this class
vinca alkaloids (vincristine)
taxanes are natural products derived from the ________ tree
yew
paclitaxel from pacific yew
docetaxel from european yew
t/f taxanes promote microtubule assembly into stable (non-functional) bundles which decreases free tubulin & prevent microtubule formation at spindle
true
the stabilization that taxanes cause blocks __________ which leads to mitotic arrest
depolymerization
taxanes are excellent substrates for ______ transporter except for ________
pgp transporter; cabaziTAXel
resistance to taxanes is attributed to ________- mutations
tubulin
paclitaxel is linked to _______- to increase solubility & circulation time of drug
albumin
what is the dose-limiting SE of taxanes
myelosuppression
neurotoxicity is common, but reversible
___________ are naturally occurring macrolides isolated from myxobacterium fermentaion
epothilones (ixabepilone
ixabepilone binds to ______ & promotes tubulin polymerization & microtubule stabilization
tubulin
t/f epothilones are NOT cross-resistant with taxanes and poor pgp substrates
TRUE
Which of the following microtubule inhibitors block the polymerization of tubulin?
A. Paclitaxel
B. Vincristine
C. Ixabepilone
B. Vincristine
others block depolymerization
