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Fall 2021: Therapeutics III > Topoisomerase Inhibitors (Dykhuizen) > Flashcards

Topoisomerase Inhibitors (Dykhuizen) Flashcards

1
Q

What does topoisomerase I do?

A

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

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2
Q

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

A

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

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3
Q

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

A

S phase

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4
Q

What four factors contribute to topoisomerase I inhibitor resistance?

A
  • PGP overexpression
  • MRP overexpression
  • Glutathione S-transferase overexpression
  • Topoisomerase downregulation/mutation to prevent inhibitor binding
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5
Q

Give two examples of drugs in the camptothecin class.

A

Irinotecan (Camptosar) and Topotecan (Hycamtin)

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6
Q

Which topoisomerase type do camptothecins inhibit?

A

topoisomerase I

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7
Q

What is the water-soluble analog of camptothecin?

A

Topotecan (Hycamtin)

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8
Q

True or false: camptothecin is still used clinically today.

A

no; low solubility and severe/unpredictable toxicity

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9
Q

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

A

UGT1A1 (uridine diphosphate glucosyltransferase)

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10
Q

Which topoisomerase II isoform is the major target for chemotherapies?

A

topoisomerase 2A

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11
Q

What does topoisomerase II do?

A

cuts both strands of the DNA helix simultaneously

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12
Q

Which topoisomerase type does doxorubicin inhibit?

A

topoisomerase II

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13
Q

What are doxorubicin’s three mechanisms of toxicity?

A
  1. intercalator
  2. free radical formation = DNA damage
  3. topoisomerase II inhibition
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14
Q

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

A

cardiotoxicity

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15
Q

True or false: doxorubicin is cell cycle-dependent.

A

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

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16
Q

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

A
  • cardiac muscle damage
  • local tissue damage if extravasated
17
Q

What drug has been nicknamed “the red devil”?

A

doxorubicin

18
Q

Doxorubicin is classified structurally as an ____________.

A

anthracycline

19
Q

What was the original natural anthracycline to be discovered?

A

Daunorubicin (Daunomycin, Cerubidin**e)

20
Q

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

A

epirubicin

21
Q

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

A

idarubicin

22
Q

Dexrazoxane is the cyclic analog of which metal chelating agent?

A

EDTA

23
Q

Dexrazoxane is known to have a protective effect against what?

A

anthracycline-induced cardiotoxicity

24
Q

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

A

iron

25
Q

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

A

iron

26
Q

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

A

false

27
Q

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

A

Mitoxantrone (Novantrone)

28
Q

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

A

mitoxantrone does not cause free radical formation

29
Q

What class of topoisomerase II inhibitors does NOT intercalate?

A

etoposides

30
Q

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

A

G2

31
Q

Is etoposide clinically cross-resistant?

A

yes

32
Q

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

A
  • PGP overexpression
  • MRP overexpression
  • Glutathione S-transferase overexpression
  • Topoisomerase II downregulation/mutation
  • Increased DNA damage repair
33
Q

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

A

Doxorubicin

34
Q

Give an example of a glycopeptide antibiotic.

A

Bleomycin (Blenoxane)

35
Q

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

A

G2/M

36
Q

What is the primary dose-limiting toxicity of bleomycin?

A

pulmonary toxicity (pneumonitis progressing to pulmonary fibrosis)

37
Q

What enzyme is known to deactivate bleomycin?

A

aminohydrolase

38
Q

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

A

skin and lungs

39
Q

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

A

aminohydrolase

Fall 2021: Therapeutics III (25 decks)

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