lecture 6 topoisomerase and microtubules Flashcards
what is topoisomerase mechanism?
DNA must be tightly coiled and packed around nucleosomes to fit in nucleus
relieve stress
what is TOPO1 inhibitors mechanism?
binds to and form tertenary drug-enzyme DNA complex
cells in S phase are most sensitive to TOPO 1 induced cleavage
what are drug resistance mechanisms for TOPO1 inhibitors?
GST overexpression
PGP, MRP overexpression
topo downregulation or mutation
what are the TOPO1 inhibitors?
irinotecan and topotecan
what phase of the cell cycle do TOPO1s target?
S-phase
what is important about irinotecan?
SN-38 (active metabolite)
is metabolized to inactive form by uridine diphosphate glucosyltransferase (UGT1A1)
10% of population has polymorphism, leading to toxicity of irinotecan
what is topoisomerase 2?
produces dsDNA breaks and are in cancer chemotherapies
what drugs are TOPO2 inhibitors?
doxorubicin
etoposide
what stage in the cell cycle do TOPO2 target?
doxorubicin is non cell specific
etoposide is g2 block
what is doxorubicin MOA?
intercalctor and free radical causes DNA damage, inhibits TOPO2
what is an important side effect of doxorubicin?
free radical damage is cardiotoxic since heart tissue has low enzymes that neutralize free radicals
what is resistance for doxorubicin?
GST overexpression
what is etoposide?
inhibits TOPO2, but does not intercalate
g2 specific block
what is bleomycin?
cytotoxic agent
what is bleomycin toxicity?
pulmonary toxicity bc bleomycin aminohydrolase is high everywhere besides the lungs
