Topoisomerase Inhibitors (Dykhuizen)

Question 1

What does topoisomerase I do?

Answer 1

cuts one strand of double-stranded DNA, relaxes and reanneals it

Question 2

Beyond the prevention of re-ligation, what other aspect of topoisomerase I inhibition prevents replication and transcription?

Answer 2

intercalation; there is basically a blob of protein stuck between DNA bases

Question 3

What cell cycle phase is most sensitive to topoisomerase I inhibition?

Answer 3

S phase

Question 4

What four factors contribute to topoisomerase I inhibitor resistance?

Answer 4

• PGP overexpression
• MRP overexpression
• Glutathione S-transferase overexpression
• Topoisomerase downregulation/mutation to prevent inhibitor binding

Question 5

Give two examples of drugs in the camptothecin class.

Answer 5

Irinotecan (Camptosar) and Topotecan (Hycamtin)

Question 6

Which topoisomerase type do camptothecins inhibit?

Answer 6

topoisomerase I

Question 7

What is the water-soluble analog of camptothecin?

Answer 7

Topotecan (Hycamtin)

Question 8

True or false: camptothecin is still used clinically today.

Answer 8

no; low solubility and severe/unpredictable toxicity

Question 9

Low expression of what enzyme will result in increased toxicity of irinotecan?

Answer 9

UGT1A1 (uridine diphosphate glucosyltransferase)

Question 10

Which topoisomerase II isoform is the major target for chemotherapies?

Answer 10

topoisomerase 2A

Question 11

What does topoisomerase II do?

Answer 11

cuts both strands of the DNA helix simultaneously

Question 12

Which topoisomerase type does doxorubicin inhibit?

Answer 12

topoisomerase II

Question 13

What are doxorubicin’s three mechanisms of toxicity?

Answer 13

1. intercalator
2. free radical formation = DNA damage
3. topoisomerase II inhibition

Question 14

Besides DNA damage, what is another consequence of free radical damage from doxorubicin?

Answer 14

cardiotoxicity

Question 15

True or false: doxorubicin is cell cycle-dependent.

Answer 15

false (even though activity is greater in G₂/M)

Question 16

What two side effects are associated with doxorubicin (Adriamycin) toxicity?

Answer 16

• cardiac muscle damage
• local tissue damage if extravasated

Question 17

What drug has been nicknamed “the red devil”?

Answer 17

doxorubicin

Question 18

Doxorubicin is classified structurally as an ____________.

Answer 18

anthracycline

Question 19

What was the original natural anthracycline to be discovered?

Answer 19

Daunorubicin (Daunomycin, Cerubidin**e)

Question 20

Which anthracycline is noted to have less severe cardiotoxicity than doxorubicin due to its faster elimination?

Answer 20

epirubicin

Question 21

Which anthracycline is known to have increased fat solubility and cellular uptake?

Answer 21

idarubicin

Question 22

Dexrazoxane is the cyclic analog of which metal chelating agent?

Answer 22

EDTA

Question 23

Dexrazoxane is known to have a protective effect against what?

Answer 23

anthracycline-induced cardiotoxicity

Question 24

Cardiotoxicity of doxorubicin is believed to be caused by _____-catalyzed free radical formation.

Answer 24

iron

Question 25

After dexrazoxane (*Zinecard*) enters the cell and is converted to ring-opened EDTA, what does it bind to?

Answer 25

iron

Question 26

True or false: there is evidence that dexrazoxane creates some interference with the antitumor effect of doxorubicin.

Answer 26

false

Question 27

What drug is considered to be a synthetic attempt at reducing anthracycline toxicity?

Answer 27

Mitoxantrone (*Novantrone*)

Question 28

Besides modest structural variances, what is a key difference between mitoxantrone and the anthracyclines?

Answer 28

mitoxantrone does not cause free radical formation

Question 29

What class of topoisomerase II inhibitors does NOT intercalate?

Answer 29

etoposides

Question 30

Which, if any, part of the cell cyle is blocked by etoposides?

Answer 30

G₂

Question 31

Is etoposide clinically cross-resistant?

Answer 31

yes

Question 32

Describe the five ways in which one can develop resistance to topoisomerase II inhibitors.

Answer 32

* PGP overexpression * MRP overexpression * Glutathione S-transferase overexpression * Topoisomerase II downregulation/mutation * Increased DNA damage repair

Question 33

A patient has a history of heart disease and poor cardiac function. Which topoisomerase inhibitor should NOT be prescribed?

Answer 33

Doxorubicin

Question 34

Give an example of a glycopeptide antibiotic.

Answer 34

Bleomycin (*Blenoxane*)

Question 35

Where in the cell cycle does bleomycin have the greatest effect?

Answer 35

G₂/M

Question 36

What is the primary dose-limiting toxicity of bleomycin?

Answer 36

pulmonary toxicity (pneumonitis progressing to pulmonary fibrosis)

Question 37

What enzyme is known to deactivate bleomycin?

Answer 37

aminohydrolase

Question 38

Aminohydrolase exists in high concentration everywhere in the body except for which two places?

Answer 38

skin and lungs

Question 39

What enzyme exists in high levels in bleomycin-resistant patients?

Answer 39

aminohydrolase