Topoisomerase inhibitors

Question 1

Topoisomerase 1

Answer 1

Topo1 senses supercoiling–> cut one strand of the double stranded DNA to relax the remaining strand–> stays covalently bound and religates–>releases

Question 2

Topoisomerase 2

Answer 2

Topo2 senses supercoiling–> cuts both strands of double stranded DNA to relax and relieve torsional stress

Topo2 can decatenate two 2 DNA pieces that are linked together after replication

Question 3

Irinotecan, Topotecan

Answer 3

Topo inhibitors

MOA: Binds to topoisomerase 1 through intercalation and forms a ternary complex that stabilizes the complex and blocks DNA relegation

Ternary complex prevents DNA replication and transcription

S PHASE

Question 4

Irinotecan, topotecan resistance

Answer 4

Increased PgP and MRP efflux transporter expression

Increased expression of GST

Topoisomerase downregulation and mutation

Question 5

Irinotecan toxicity

Answer 5

Irinotecan–>carboxylesterases–> SN-38

SN-38 is metabolized by UGT1A1

10% of population have gene polymorphism of UGT1A1 leading to a low expression and increased toxicity

Question 6

Doxorubicin

Answer 6

Topo 2

MOA: binds to topo2 after DNA strand breaks through intercalation and blocks DNA relegation

Forms free radicals that cause DNA damage

NON-CELL CYCLE DEPENDENT

Question 7

Doxorubicin toxicity

Answer 7

Cardiotoxicity

Free radicals damage cardiac muscle that contains low levels of enzymes that neutralize free radicals

SOLUTION: Dexrazoxane

Cardiotoxicity is caused by iron-catalyzed free radical formation

Dexrazoxane is a EDTA analog that binds to iron blocking formation of free radicals

Local tissue damage if extravasated

Question 8

Doxorubicin resistance

Answer 8

Increased PgP and MRP efflux transporter expression

Increased expression of GST

Topoisomerase downregulation and mutation

Increased DNA repair enzymes

Question 9

Etoposide

Answer 9

MOA: binds to topo 2 and blocks DNA relegation

NOT BY INTERCALATION

NOT SENSITIVE TO GLUTATHIONE

Cell cycle: G2 PHASE

Resistance: Increased PgP and MRP expression
Topo downregulation and mutation
Increased DNA repair enzymes

Question 10

Bleomycin

Answer 10

MOA: Thiazole with a charged side chain that intercalates into DNA

Imidazole coordinate with Fe+ generating DNA free radicals

Forms a radical intermediate leading to DNA single strand and double strand breaks

Cell cycle: G2/ M PHASE

Question 11

Bleomycin toxicity

Answer 11

Pulmonary toxicity

Bleomycin is inactivated by bleomycin amidohydrolase that are low concentration in skin and lung

Mild myelosuppression

Question 12

Microtubules in cell division

Answer 12

Responsible for moving chromosomal material into daughter cells during mitosis

Dynamic instability: If attached to a chromosome at the right section, the microtubule stops falling apart and attaches

Spindle assembly checkpoint: Kinetochores need to be attached to the spindle microtubules with kinetochore tension

Question 13

Types of Microtubule inhibitors

Answer 13

Microtubule assembly inhibitors: Vinca alkaloids

Prevent polymerization of tubulin by tubulin monomers

Question 14

Microtubule disassembly inhibitors

Answer 14

taxanes

microtubules cannot grow to attach to the chromosomes

microtubules, once attached to chromosome, cannot shrink to pull chromosome apart

Without depolymerization, run out of tubulin monomers to build more microtubules

Question 15

Vincristine

Answer 15

assembly inhibitor

MOA: bind to tubulin to inhibit microtubule assembly (polymerization) and inhibition shortening

leads to mitotic arrest

Question 16

Vincristine toxicity

Answer 16

NEUROTOXICITY

Peripheral neuropathy

microtubules are critical to nerve cell axon function

local tissue damage when extravasation

Question 17

Vincristine resistance

Answer 17

Increased PgP and MRP expression

decrease in drug importers

Question 18

Eribulin

Answer 18

MOA: binds to the ends of microtubules and prevents elongation

LOWER RATE OF NEUROTOXICITY

Question 19

Paclitaxel

Answer 19

bound to albumin to increase half-life

MOA: Bind to tubulin

Promotes assembly into a stable bundle that decreased free tubulin to prevent microtubule formation

Stabilization of microtubules blocks depolymerization and segregation into daughter cells

leads to mitotic arrest

Toxicity: myelosuppression

Resistance: increased Pgp and MRP expression
Increased tubulin mutations