Topoisomerase and Microtubule Inhibs Flashcards
Topoisomerase 1does what
single strand cut
topoisomerase I attaches how
covalently
how do topo 1 inhibitors work
covalently attach to topo 1 and glues it to the DNA, blocks religation
how does topo 1 inhibitors form a physical barrier
barrier to replication and transcription
DNA breaks, protein glued, topo 1 inhib
cells in what phase are most sensitive to topo 1 cleavage
S phase
drug resistance mechanisms with topo 1 inhibs (4)
PGP overxpression
MRP overexpression
glutathione S transferase overexpression
topo downregulation
topo 1 inhibitiors
topotecan
ironotecan
what is ironotecan
topo 1 inhib
ironotecan is a _____
prodrug
ironotecan active metabolite metabolized by what
SN38 is metabolized by UGT1A1
if polymoprhism pts can have toxicity
UGT1A1 polymorphism could make what drug toxic
ironotecan
topo 2 does what
double strand cut
relieves torsional stress AND untangles DNA
topoisomerase II is especially important for what
replication
how do topoisomerase II inhibs work
lock the Topo II after double strand break covalently
double strand dna break
no religation anymore
how does doxorubicin work
topo II inhibitor
free radical damages DNA
intercalator
doxorubicin tox
cardiac toxicities due to low levels of enzymes that neutralize free radicals
which drug has severe cardiotoxicity
doxorubicin, red devil
how is cardiac toxicity from doxorubicin mediated
give dexrazoxane
what causes cardiac toxicity in doxorubicin, what causes the free radicals?
iron catalyzed free radical formation
etoposide class
topo II inhibitor
etoposide cell cycle
G2
etoposide does what
double strand break
does not have free radicals
does not intercalate
which topoisomerase inhibitor is not sensitive to glutatione levels?
etoposide
topo II resistance mechanisms (5)
PGP overexpression
MRP overexpression
glutathione S transferase overexpression - doxo only
topo II downregulation
increased DNA damage repair
what does bleomycin do?
intercalates
generates free iron radicals
radical intermediate from bleomycin does what
single and double strand breaksb
bleomycin side effect
pulmonary toxicity
bleomycin which side effect not that bad
myelosupression
bleomycin cell phase
G2/M
where is bleomycin highest conc
skin and lung
what do microtubules do
move chromosomal material into daughter cells during mitosis part of the spindle
what phase are microtubules specific
G2/M
how do microtubule destabilizers work
vinca alkaloids
prevent assembly of microtubules
bind tubulin
how do microtubule stabilizers work
taxanes
prevent disassembly of microtubules
bind tubulin
T/F: microtubule destabilizers and stabilizers bind at the same spot
F they bind different sites
vinca alkaloids do what
inhibit microtubule assembly
destabilizes
vincristine toxicity
neurotoxicity
peripheral neuropathy
vinca alkyloid drug
vincristine
destabilizer drugs
vincristine
erubulin
eribulin toxicity
lower rate of neurotoxicity
microtubule stabilizer drugs
paclitaxel
Ixabepilone
paclitaxel class
stabilizer
paclitaxel side effect
myelosupression
ixabepilone class
stabilizer
ixabeplilone PGP?
poor PGP substrates, not cross resistant with taxanes
