Exam 1 Lecture 5

Question 1

What kind of drug is Mitomycin C? (MOA)

Dose limiting

Answer 1

Functions as alkylating agent, although toxicity pattern differs slightly from other alkylating agents.

Myelosuppression is dose limiting

Question 2

MOA of platinum drugs? What is the original prototype?

Answer 2

They are covalent crosslinkers. Cisplatin is the original prototype.

Question 3

What does cisplatin turn into inside of the cell?

Answer 3

Cisplatin turns into aquo form inside of cell.

Aquo form is highly reactive and a potent electrophile

Question 4

What do aquo forms react rapidly with?

Answer 4

Aquo forms react rapidly with other nucleophiles, especially thiols

Question 5

What type of cross links do platinum drugs form? What is the use of this?

Answer 5

Cross links are often intrastrand. Intra strand cis plat cross links impose severe geometrical constraints on DNA

Question 5

What base pairs do aquo forms primarily act on?

Answer 5

Guanine N-7 and adenine N-7 in DNA

Question 6

What are the geometric constraints on DNA platinum drugs impose

Answer 6

Introduce sharp bend in cross linked strand.

lesion not readily repaired by standard DNA repair enzymes

Question 7

What is the major difference between platinum and alkylators?

Answer 7

The type of cross link it forms and side effect profile

Question 8

Side effects of cis platin (dose limiting)

Answer 8

Dose limiting- nephrotoxicity
severe N/V
minimal bone marrow toxicity
peripheral neuropathy

Question 9

drug resistance mechanism of cisplatin (2 main ones)

Answer 9

1. Increased expression of glutathione-s-transferase (GST)
2. increased intracellular concentration of non-protein thiols, especially glutathione

Question 10

Why would increased expression of GST cause resistance to cisplatin

Answer 10

Free thiols have extremely high reactivity toward electrophilic intermediates

Thiols intercept the reactive intermediates of alkylating agents

Free thiol levels > 10-fold higher in alkylating agent-resistant cells

GST catalyzes the reaction of glutathione with alkylating agents (parent
drugs as well as reactive intermediates)

Question 11

Why would increased concentration of non protein thiols cause resistance to cisplatin

Answer 11

Free thiols have extremely high reactivity towards electrophilic intermediates

Thiols intercept the reactive intermediates of alkylating agents
̈ Free thiol levels > 10-fold higher in alkylating agent-resistant cells

Question 12

o block hemorrhagic cystitis, Mesna is coadministered with
which drug?
A. Methotrexate
B. Cyclophosphamide
C. Cisplatin
D. Mitomycin C

Answer 12

cyclophosphamide

Question 13

Which of the following is NOT a crosslinker?
A. Cytarabine
B. Cyclophosphamide
C. Carboplatin
D. Chlorambucil

Answer 13

cytarabine

Question 14

what do topoisomerases do?

Answer 14

topoisomerases provide a mechanism to reduce localized supercoiling and provide access to double stranded DNA by enzymes responsible for replication, transcription and repair.

Question 15

What are the different kinds of topoisomerase inhibitors and Name their drugs (along with what stage they inhibit)

Answer 15

Topo I inhibitor- Irinotecan (targets S phase (DNA replication))

Topo II inhibitor- etoposide and bleomycin (Target G2 phase (sister chromatid separation))

Topo 2 intercalator- doxorubicin- non cell cycle specific

Question 16

Topoisomerase I MOA

Topo I inhibitor MOA

Answer 16

Type I topoisomerase cuts one strand of double stranded DNA, relaxes remaining strand and reanneal.

Topo I inhibition provides a physical barrier to replication and transcription (acts as a road block)

Question 17

Clinically relevant topoisomerase inhibitors bind to and form

Answer 17

a ternary drug-enzyme-DNA complex Inhibitor binding stabilizes Topo-DNA complex and blocks DNA re-
ligation

Question 18

Cells in what phase are most sensitive to Topo I cleavage

Answer 18

Cells in S phase

Question 19

Drug resistance of Topo I inhibitor

Answer 19

P-glycoprotein (PGP) overexpression
̈ Multidrug resistant protein (MRP) overexpression
̈ Glutathione S-transferase overexpression

Question 20

What kind of drug are the camptothecins? Name the camptothecins.

Answer 20

Potent topo I inhbitors

topotecan and irinotecan

Question 21

What is irinotecan broken down into?

Answer 21

SN-38

Question 22

SN-38 is metabolized by

Answer 22

UGT1A1

Question 23

What causes increased risk of toxicity for irinotecan in some people? What portion of population does this occur in?

Answer 23

10% of population has polymorphisms predicting low expression of UGT1A1 leading to increasein toxicity in irinotecan users

(remember irinotecan is broken down to SN 38. SN 38 is metabolized by UGT 1A1.)

Question 24

Topo2 MOA

Answer 24

Topoisomerase II (Top2) relieves torsional strain AND untangles DNA by catalyzing double-stranded DNA breaks

Question 25

Many compounds inhibit Top2 Only ones that produce ________________ are chemotherapies

Answer 25

double strand DNA break

Question 26

What type of drug is doxorubicin? toxicity?

Answer 26

It is a topo II inhibitor that is non cell cycle dependent biggest toxicity is cardiotoxicity severe local tissue damage if extravasated

Question 27

Why is there cardiotoxicity with doxorubicin

Answer 27

doxorubicin is an intercalator that causes free radical damage. free radical damage causes cardiotoxicity. This is because the heart tissue has low levels of enzymes that neutralize free radicals. (Cardiotoxicity of doxorubicin believed to be caused by iron-catalyzed free radical formation)

Question 28

What is a drug that mediates toxicity to doxorubicin

Answer 28

dexrazoxane

Question 29

MOA of how dexrazoxane mediates doxorubicin toxicity

Answer 29

MOA- enters cell and binds to iron, blocks iron-oxygen induced toxicity

Question 30

Does dexrazoxane interfere with the anti tumor effect of doxorubicin?

Answer 30

No

Question 31

What type of drug is etoposide? MOA? What cell cycle does it inhibit?

Answer 31

Etoposide is a Topo II inhibitor. It inhibits religation of double stranded breaks induced by topo II, but does not intercalate G2 block- cell cycle specific

Question 32

What is resistance to Topo II inhibitors caused by?

Answer 32

Glutathione-S-transferase overexpression in doxorubicin only PGP overexpression MRP overexpression increased DNA damage repair Topo II downregulation or mutation

Question 33

What type of drug is bleomycin? MOA? toxicity (dose limiting)? What cell cycle does it affect?

Answer 33

Bleomycin is a topo II inhibitor It intercalates into DNA and generates free radicals. Radical intermediate leads to DNA single strand break and double strand break. greatest effect is on G2 and M phase toxicity- pulmonary toxicity is dose limiting effect

Question 34

Why does bleomycin cause pulmonary and skin side effects

Answer 34

Bleomycin is inactivated by bleomycin aminohydrolase, which is in high concentration everywhere, but skin and lung

Question 35

What is the role of microtubule during cell division

Answer 35

Microtubules are an essential part of mitotic spindle It is responsible for moving chromosomal material into daughter cell during mitosis

Question 36

What phase in cell cycle do microtubules act on?

Answer 36

M phase

Question 37

Name microtubule inhibitor drugs

Answer 37

Vincristine and paclitaxel

Question 38

Describe the requirements for spindle assemble checkpoint? Compare normal cells and cancerous cell

Answer 38

Kinetochores need to be attached to spindle microtubules. There needs to be kinetochore tension. Cancer cells do not have checkpoints, if a normal cell has a good checkpoint, it will not start dividing until there is kinetochore tension. In a cancer cell, you are unable to reach checkpoint that leads to cell death or messed up cell division.

Question 39

What are two major classes of microtubule inhibitors drug ?

Answer 39

Vinca alkaloids taxanes

Question 40

Difference in MOA between the two classes of microtubule inhibitor drugs? Why do they work?

Answer 40

Vinca alkaloids prevent microtubule assemble taxanes prevent microtubule disassembly Even though they have opposite effects, microtubules need dynamic instability. Microtubules need to elongate and shorten and these drugs prevent that

Question 41

Name microtubule destabilizers

Answer 41

Vinca alkaloid Erubulin

Question 42

vinca alkaloid MOA, toxicity, resistance

Answer 42

Vinca alkaloids bind to tubulin. This binding leads to inhibition of microassembly (polymerization) peripheral neuropathy is a toxic side effect excellent substrate for PGP

Question 43

name a vinca alkaloid

Answer 43

Vincristine

Question 44

Vincristine toxicity (dose limiting)

Answer 44

Neurotoxicity is the dose limiting toxicity extravasation causes SEVERE local inflammation neurologic assessment prior to each dose

Question 45

compare eribulin and vinca alkaloids in terms of MOA and toxicity

Answer 45

different MOA than vinca alkaloids. Eribulin MOA is it is a microtubule polymerization inhibitor that binds at microtubule ends and prevents elongation. Vinca alkaloids inhibit elongation and shortening at + end Eribulin has a lower rate of neurotoxicity

Question 46

What are the microtubule stabilizers?

Answer 46

Taxanes Epothilones

Question 47

taxanes bind to tubulin with two consequences, what are they

Answer 47

1. promotion of microtubule assembly into stable (non-functional) bundles decreases free tubulin and prevents microtubule formation at spindle 2. stabilization of existing microtubules blocks depolymerization this leads to mitotic arrest

Question 48

Taxane drug resistant mechanism

Answer 48

it is an excellent substrate for pGP. Drug rapidly pumped out of resistant cells. It is also cross resistant with other large molecule antitumor agents

Question 49

Name a taxane drug. What is its toxicity (dose limiting)

Answer 49

Paclitaxel it is linked to albumin to increase stability and circulation time toxicity- myelosuppression is dose limiting neurotoxicity is also common

Question 50

Epothilones MOA, toxicity and name a drug

Answer 50

Toxicity- neurotoxicity (reversible) Binds to tubulin and promotes tubulin polymerization and microtubule stabilization ixabepilone

Question 51

are epothilones cross resistant with taxanes? Are epothilones good PGP substrates

Answer 51

Epothilones are not cross resistant with taxanes. Poor pgp substrate