Topoisomerase Inhibitors (Dykhuizen) Flashcards
What does topoisomerase I do?
cuts one strand of double-stranded DNA, relaxes and reanneals it
Beyond the prevention of re-ligation, what other aspect of topoisomerase I inhibition prevents replication and transcription?
intercalation; there is basically a blob of protein stuck between DNA bases
What cell cycle phase is most sensitive to topoisomerase I inhibition?
S phase
What four factors contribute to topoisomerase I inhibitor resistance?
- PGP overexpression
- MRP overexpression
- Glutathione S-transferase overexpression
- Topoisomerase downregulation/mutation to prevent inhibitor binding
Give two examples of drugs in the camptothecin class.
Irinotecan (Camptosar) and Topotecan (Hycamtin)
Which topoisomerase type do camptothecins inhibit?
topoisomerase I
What is the water-soluble analog of camptothecin?
Topotecan (Hycamtin)
True or false: camptothecin is still used clinically today.
no; low solubility and severe/unpredictable toxicity
Low expression of what enzyme will result in increased toxicity of irinotecan?
UGT1A1 (uridine diphosphate glucosyltransferase)
Which topoisomerase II isoform is the major target for chemotherapies?
topoisomerase 2A
What does topoisomerase II do?
cuts both strands of the DNA helix simultaneously
Which topoisomerase type does doxorubicin inhibit?
topoisomerase II
What are doxorubicin’s three mechanisms of toxicity?
- intercalator
- free radical formation = DNA damage
- topoisomerase II inhibition
Besides DNA damage, what is another consequence of free radical damage from doxorubicin?
cardiotoxicity
True or false: doxorubicin is cell cycle-dependent.
false (even though activity is greater in G2/M)
What two side effects are associated with doxorubicin (Adriamycin) toxicity?
- cardiac muscle damage
- local tissue damage if extravasated
What drug has been nicknamed “the red devil”?
doxorubicin
Doxorubicin is classified structurally as an ____________.
anthracycline
What was the original natural anthracycline to be discovered?
Daunorubicin (Daunomycin, Cerubidin**e)
Which anthracycline is noted to have less severe cardiotoxicity than doxorubicin due to its faster elimination?
epirubicin
Which anthracycline is known to have increased fat solubility and cellular uptake?
idarubicin
Dexrazoxane is the cyclic analog of which metal chelating agent?
EDTA
Dexrazoxane is known to have a protective effect against what?
anthracycline-induced cardiotoxicity
Cardiotoxicity of doxorubicin is believed to be caused by _____-catalyzed free radical formation.
iron
After dexrazoxane (Zinecard) enters the cell and is converted to ring-opened EDTA, what does it bind to?
iron
True or false: there is evidence that dexrazoxane creates some interference with the antitumor effect of doxorubicin.
false
What drug is considered to be a synthetic attempt at reducing anthracycline toxicity?
Mitoxantrone (Novantrone)
Besides modest structural variances, what is a key difference between mitoxantrone and the anthracyclines?
mitoxantrone does not cause free radical formation
What class of topoisomerase II inhibitors does NOT intercalate?
etoposides
Which, if any, part of the cell cyle is blocked by etoposides?
G2
Is etoposide clinically cross-resistant?
yes
Describe the five ways in which one can develop resistance to topoisomerase II inhibitors.
- PGP overexpression
- MRP overexpression
- Glutathione S-transferase overexpression
- Topoisomerase II downregulation/mutation
- Increased DNA damage repair
A patient has a history of heart disease and poor cardiac function. Which topoisomerase inhibitor should NOT be prescribed?
Doxorubicin
Give an example of a glycopeptide antibiotic.
Bleomycin (Blenoxane)
Where in the cell cycle does bleomycin have the greatest effect?
G2/M
What is the primary dose-limiting toxicity of bleomycin?
pulmonary toxicity (pneumonitis progressing to pulmonary fibrosis)
What enzyme is known to deactivate bleomycin?
aminohydrolase
Aminohydrolase exists in high concentration everywhere in the body except for which two places?
skin and lungs
What enzyme exists in high levels in bleomycin-resistant patients?
aminohydrolase
