Anthracyclines

Question 1

How many rings are chained in the anthracycline structure?

Answer 1

Four

Question 2

What drug class is mitoxantrone? How many rings are chained in its structure?

Answer 2

Anthracendione; three

Question 3

Which anthracycline is the prototype and most frequently used in the class?

Answer 3

Doxorubicin

Question 4

What is doxorubicin’s brand name?

Answer 4

Adriamycin

Question 5

What is a nickname for doxorubicin? Why is it called that?

Answer 5

“The Red Devil”; bright red coloring

Question 6

What is the predominant mechanism of action of anthracyclines?

Answer 6

Toperisomerase II inhibition

Question 7

How does toperisomerase II inhibition work in anthracyclines?

Answer 7

Covalently binds to toperisomerase II and DNA, but ultimately prevents re-ligation (like etoposide)

Question 8

Is toperisomerase II inhibition in anthracyclines cell cycle specific or cell cycle non-specific?

Answer 8

Cell cycle specific

Question 9

What are the other two mechanisms of action for anthracyclines?

Answer 9

DNA intercalation and free radical production

Question 10

What is DNA intercalation?

Answer 10

The insertion of a drug (or something else) in between DNA base pairs. Results in single and double strand DNA breaks

Question 11

Is DNA intercalation in anthracyclines cell cycle specific or cell cycle non-specific?

Answer 11

Cell cycle non-specific

Question 12

What is free radical production?

Answer 12

Free radical production mediated by both enzymes and iron complexes. Reactive intermediates are then capable of damaging intracellular proteins and metabolites that can covalently bind to DNA. Historically believed to be a driving mechanism of the class’ cardiotoxicity and vesicant properties.

Question 13

Is free radical production in anthracyclines cell cycle specific or cell cycle non-specific?

Answer 13

Cell cycle non-specific

Question 14

What are the hallmark toxicities seen in anthracyclines?

Answer 14

Fair amount of myelosuppression and N/V, mucositis, and alopecia

Question 15

What side effect of anthracyclines are you expected to know?

Answer 15

Cardiotoxicity. Decreased left ventricular ejection fraction (LVEF). This is a class effect, and risk increases with cumulative exposure (lifetime maximum exposure)

Question 16

What is another significant side effect of anthracycline?

Answer 16

Vesicant - causes tissue necrosis with extravasation

Question 17

What is a side effect caused only by doxorubicin and daunorubicin?

Answer 17

Red-colored urine/tears following administration

Question 18

What anthracycline side effects are more likely if given via bolus?

Answer 18

Myelosuppression and cardiotoxicity

Question 19

Secondary leukemia is associated with anthracyclines. Which gene is typically mutated?

Answer 19

MLL gene mutations (same as etoposide)

Question 20

What is the approximate standard dose of doxorubicin and daunorubicin?

Answer 20

50-60 mg/m2

Question 21

What is the maximum cumulative lifetime maximum for doxorubicin and daunorubicin?

Answer 21

400-550 mg/m2

Question 22

What is the approximate standard dose of idarubicin?

Answer 22

12 mg/m2

Question 23

What is the maximum cumulative lifetime maximum of idarubicin?

Answer 23

150 mg/m2

Question 24

What is the approximate standard dose of epirubicin?

Answer 24

100 mg/mg2

Question 25

What is the maximum cumulative lifetime maximum of epirubicin?

Answer 25

900 mg/m2

Question 26

What dose range should be considered as the danger zone for anthracycline cardiotoxicity?

Answer 26

The cumulative lifetime max dose range

Question 27

True or false. Use beyond the max lifetime dose is never indicated.

Answer 27

False. Use beyond may be indicated at times, such as when the patient was once treated for one cancer and now has a secondary cancer. Risk of death from cancer outweighs the risk of heart failure.

Question 28

What is the brand name of liposomal doxorubicin?

Answer 28

Doxil

Question 29

How does liposomal doxorubicin differ from conventional doxorubicin?

Answer 29

* Leads to lower Cmax but longer exposure * Different toxicity profile - less N/V, myelosuppression, and cardiotoxicity, but more dermatologic toxicity such as mucositis and hand-foot syndrome (hand-foot can be dose limiting)

Question 30

How are the MOAs of mitoxantrone and anthracyclines similar?

Answer 30

Primarily toperisomerase II inhibitors; DNA intercalation

Question 31

How are the MOAs of mitoxantrone and anthracyclines different?

Answer 31

Mitoxantrone has less free radical production than anthracyclines

Question 32

How is the toxicity profile of mitoxantrone different than anthracyclines'?

Answer 32

* Less cardiotoxicity (still has some!) * Less severe vesicant properties

Question 33

What is considered the antidote of anthracyclines?

Answer 33

Dexrazoxane

Question 34

How does dexrazoxane work?

Answer 34

Has chelating properties to prevent iron-mediated free radical production

Question 35

What are the two different brand name formulations of dexrazoxane?

Answer 35

Zinecard and Totect

Question 36

What is Zinecard approved for?

Answer 36

Limit cardiotoxicity of doxorubicin (cardioprotective) - considered in patients with 300 mg/m2 lifetime exposure - does appear to decrease the effectiveness of doxorubicin, so not used often (usually only in pediatric formulations)

Question 37

What is Totect approved for?

Answer 37

Treat anthracycline extravasation - extravasation is initially treated with ice (slows free radical cascade and decreases blood flow to the area) - remove ice at least 15 minutes before administration to increase blood flow to the area

Question 38

What should be monitored in patients taking anthracyclines?

Answer 38

* LVEF assessment at baseline (to ensure don't have HF) - can be done via echocardiogram or multi-gated acquisition study (MUGA) * Signs/symptoms of extravasation - treat with ice then dexrazoxane * CBC (done will all myelosuppressive agents) - typical WBC nadir (lowest point) - 10 to 14 days * LFTs - dose reductions for t. billi > 1.2 (normal = 1) per package insert ((elevated bilirubin means not excreted as well in the feces))