Anthracyclines Flashcards
What are the 3 MOAs of anthracyclines?
- DNA intercalation
- topoisomerase II (-)
- oxygen-based radical-mediated damage of DNA
What is an adverse effect of oxygen-based radical-mediated damage of DNA?
cardiotoxicity
What enzymes function to quench the harmful reactivity of superoxide radical anions?
catalase
superoxide dismutase Cu2+
Cardiotoxicity is a result of the Fenton reaction with ___and ____that results in the formation of superoxide radical anion
Fe 2+ and H2O2 (hydrogen peroxide)
What are the steps of oxygen-based radical-mediated damage of cancer cell DNA?
- H-abstraction from DNA sugar by superoxide radical
- irreversible loss of nucleobase
- irreversible DNA strand cleavage
- cancer cell apoptosis
What enzyme reacts with hydrogen peroxide to prevent superoxide formation in cells?
catalase
What changes does the Fenton reaction make to the heart?
- genomic and mitochondrial DNA damage
- sarcolemma, mitochondrial, and sarcoplasmic reticulum changes
- contractile impairment of heart muscles
- cardiomyopathy–>heart failure–>death
What is a chemical trigger for anthracycline-induced cardiotoxicity?
anthracycline chelation with Fe 2+
What is the risk of cardiotoxicity related to?
cumulative anthracycline dose over a lifetime
What is the lifetime Doxorubicin dose?
450-500 mg/ m2
What must be monitored before and after treatment with an anthracycline?
LVEF with MUGA scan or ECHO
What chemoprotectant is administered with Doxorubicin if the dose exceeds 300 mg/m2?
Dexrazoxane ZINECARD
How does ZINECARD work to reduce cardiotoxicity?
prevents anthracycline-induced oxygen-based radicals that mediate cardiotoxicity without decreasing anti-cancer efficacy
What aspect of pharmacokinetics is responsible for cardiotoxicity?
anthracyclines tend to be distributed to the heart and heart cells have low amounts of catalase
What boxed warnings do anthracyclines have?
cardiotoxicity and vesicant
