Topoisomerase

Question 1

Irnotecan

Answer 1

TopoI inhibitor
Commonly used Prodrug activated by esterases to form SN-38
SN-38 (the active form) is metabolized by UGT1A1 so if patient with low expression of UGT1A1 they have more toxicities

Question 2

Doxorubicin

Answer 2

Most widely used anthracycline
Topoisomerase II inhibitor
act as intercalators which causes additional toxicities

• Forms free radical which cause damage specifically causes CARDIOTOXICITY because the heart tissue has low levels of enzymes that neutralize these free radicals

Question 3

DEXRAZOCANE

Answer 3

inhibitor that helps to manage cardiotoxicity due to free radical formation from doxorubicin

• Binds to iron and chelates it so the free radicals cannot form due to low iron concentrations

Question 4

Etoposide

Answer 4

Topoisomerase II inhibitor - G2 specific
Blocks religation of double strand breaks induced by topoisomerase II but does not intercalate

Question 5

Bleomycin

Answer 5

G2 and M phase specific
Topoisomerase inhibitor - causes single and double stranded breaks
intercalates into DNA and generates free radicals that cause DNA damage

dose limiting: Pulmonary toxicity (lung probs), rash
this is because bleomycin is inactivated by bleomycin aminohydrolase which is at low concentration in the skin and lungs (explains side effects)

Question 6

Vincristine

Answer 6

Microtubule inhibitor
inhibit microtubule assembly
dose limiting: neurotoxicity

Question 7

Paclitaxel

Answer 7

Microtubule inhibitor - prevents degradation and binding of microtubule so division is messed up or mitotic arrest (decreases the amount of free tubule)
dose limiting: myelosupression

Question 8

Erubulin

Answer 8

Microtubule inhibitor - Destabilizers
prevents the assembly of microtubules
lower rate of neurotoxicity (commonly used)

Question 9

Ixabepilone

Answer 9

Microtubule inhibitor - prevents depolymerization and decreases the amount of free tubule leading to mitotic arrest
neurotoxicity

Question 10

Topoisomerase I inhibitors

Answer 10

Single break bind to topoisomerase I and form a ternary complex These are intercalators that covalently react
Cells in S phase are most effected
Drug resistance: glutathione S-Transferase over-expression, over-expression of efflux pumps

Question 11

Topoisomerase II inhibitors

Answer 11

inhibits topoisomerase II, causes double stranded breaks, and covalently attaches topoII to DNA
Drug resistance: overexpression of efflux pumps that push drug out of the cell, (overexpression of glutathione S-Transferase - Doxorubicin only)