Topoisomerase inhibitors Flashcards
What is the function of topoisomerases?
- regulate the winding states of DNA
- break sugar-phosphate backbone
- reseal sugar posphate backbone
Inhibition of topoisomerases leads to inhibition of what processes?
DNA replication and transcription
What is the order of events for topoisomerase enzymes?
- topoisomerase enzyme nicks DNA backbone
- DNA strands wind/ unwind for replication
- acts as molecular glue and reseals the backbone
What is the MOA of topoisomerase inhibitors?
- inhibit resealing of backbone
- fragmented DNA
- cancer cell apoptosis
What is the difference between topoisomerase I and topoisomerase II?
one strand of DNA is cut and resealed
vs.
2 strands of DNA are cut
What is the MOA of Irinotecan?
topoisomerase I (-)
What natural product class is Irinotecan in?
camptothecins
What is a boxed warning with Irinotecan?
diarrhea (early or late)
What are side effects with Irinotecan?
Irinotecan-induced cholinergic syndrome:
diarrhea
flushing
sweating
cramping
What should Irinotecan-induced early diarrhea be treated with?
Atropine (mAChR antagonist)
What should Irinotecan-induced late diarrhea be treated with?
Loperamide (opioid agonist)
What genetic testing is done to determine the safety of Irinotecan?
UGT1A1 encodes UGP (U- glycuronosyl transferase) that inactivates Irinotecan during phase III drug metabolism
What are people with homozygous UGT1A1*28 and mutated UGT at higher risk for?
diarrhea
neutropenia
What is the MOA of the Epiodphyllotoxins chemical class?
topoisomerase II (-)s; CCS, G2 phase
What side effect is seen more with Etoposide infusion?
infusion rate-related hypotension
How long should Etoposide be infused?
over 30-60 minutes
Why must Etoposide IV have a concentration of <0.4 mg/mL?
to avoid drug precipitation in IV bag/tubing due to limited H2O solubility
Why can PVC-based IV bags and tubing not be used with Etoposide?
causes leaching of DEHP as a plasticizer
What are the advantages of Etoposide phosphate?
More water-soluble:
concentration needs to be >0.4 mg/mL
does not cause leaching of DEHP from PVC based IV bags/tubing
