Cancer ABX (MC) - Block 4

Question 1

What is the general MOA of cancer ABX?

Answer 1

Blocks DNA transcription
* Intially developed as ABX but were too toxic -> used for cancer

Question 2

Describe the mechanism of topoisomerase II?

Answer 2

Cuts the G-segment in half threading the T segment through and reseals breakage

Question 3

What are the drug targets that counter topoisomerase II activity?

Answer 3

1. Drug intercalated into DNA
2. Drug/DNA complex binds
3. Drug shifts slightly to also bind to topo II
4. DNA/Topo II complex can’t complete its cycle
5. DNA repair halts
6. Cancer cell dies

Question 4

What chemical structure contributes to ADRs of red-orange secretions?

Answer 4

Conjugated rings

Question 5

MOA and SAR of anthracyclines?

Answer 5

Poison topoisomerase IIa by stabilizing ternary drug-enzyme DNA cleavable complex:
1. BCD rings intecalate between 2 DNA strands
2. Sugar inserts itself into the minor groove of DNA through ionic interaction
3. Ring A bridges the gap and between DNA and enzyme

Question 6

What type structures are best for DNA intercalation?

Answer 6

Flat ring systems

Question 7

Describe the mechanism of acute antracycline cardiotoxcity?

Answer 7

Superoxide radial anion converts into hydrogen peroxide:
* Most cells metabolize H2O2 to water by catalase, however,
* Cardiac cells don’t have a lot of catalase -> Fe2+ and H2O2 -> Hydroxyl radical that promotes single strand breaks in DNA (Fenton reaction)

Question 8

How can you treat the overproduction of hydroxyl radicals?

Answer 8

Dexrazoxane (antioxidant and iron chelator)

Question 9

Describe the mechanism of chronic antracycline cardiotoxicity?

Answer 9

Rubicinol metabolite concentrated in cardimyocytes (long-lived reservoir) -> inhibits calcium loading and ATPase -> chronic cardiomyopathy

Question 10

How can you combat chronic anthracycline cardiotox?

Answer 10

Large R group provides steric hinderance and slows rx of rubicinol formation

Question 11

Other than cardiotox what are other antracycline ADRs?

Answer 11

1. Severe myelosuppression
2. Highly necrotic to skin

Question 12

Would daunorubicin be considered cardiotoxic?

Answer 12

Small R group -> faster conversion rubicinol -> CHF

Question 13

Better formulation of daunorubicin?

Answer 13

Liposomal formulation that is more tumor selective and less likely to concetrate in the heart, but still can cause CHF

Question 14

How is doxorubicin an improvement from daunorubicin?

Answer 14

Hydroxymethyl at C13 is a slightly bigger R group -> slows aldoketoreductase -> slows conversion to rubicin and provides a longer duration of antineoplastic activity

Question 15

How does the structural changes of epirubicin improve its formulation?

Answer 15

Sterioisomer of doxorubicin: 4’ hydrxyl group of sugar in unnatural b-position changes PK properties:
* Reduce rubicinol formation
* Not susceptable to free radical generating oxidation
* Overall, lower cardio tox -> but greater propensity to accumulate in myocardiocytes

Question 16

Describe the improvements of valrubicin? Disadvantages?

Answer 16

C14-valerate ester and 3’-trifluroacetamide provide more lipophilicity and amine is no longer ionizable -> better penetration into tumor cells

Cons: Water insoluable -> dissolve in water/Cremophor EL/ethanol mixture

Question 17

MOA of valrubicin?

Answer 17

Inhibits incorporation of nucleosides into DNA and RNA, not metabolized, not necrotic to skin

Question 18

What are the improvements of idarubicin? Cons?

Answer 18

Flattening of D rings -> intercalates better:
* orients sugar so better stabilizesDNA-drug enzyme complex
* More lipophilic -> better penetration into tumor cells (more potent)

Cons: Just as active as rubicinol -> found in the plasma for 8 days

Question 19

How does the structure of mitoxantrone differ from other antracyclines?

Answer 19

1. No sugar, bust has cationic nitrogens that can still have ionic interactions with backbone
2. Enhanced stability of quinone ring-? resistnat to NADPH/CYP450 reductase -> limits formation of ROS
3. No active cardiotoxic metabolites (decreased cardiotox)

Question 20

ADRs of mitoxantrone?

Answer 20

Metabolites are very conjugatd -> deep blue -> blue green excrement and turn eyes and fingers bliuish

Question 21

SAR of anthracycline?

Answer 21

Flat ring BCD: intercalation
Larger R-group: decreases chrnic cardiotox
O12: acute hydroxyl free radical
Sugar: Not necessary (i.e. mitoxantrone)
Charged amine: binds to phosphate on DNA backbone

Question 22

MOA of dactinomycin?

Answer 22

Intcalates DNA -> binds between cytosine and guanine residues on a single DNA strand
* Interacts with minor grooze via pentapeptide lactones

Question 23

ADR of dactinomycin

Answer 23

Dose/use-limiting toxicities: myelosuppression, NV and severe blistering agent

Question 24

MOA of bleomycin?

Answer 24

Intercalates in DNA -> positioned for free radical destruction of DNA
* Chelates Fe2+ -> gets oxidized to Fe3+

Question 25

Enzyme that inactivates bleomycin and how does that determine the location of ADRs?

Answer 25

Bleomycin hydrase not found in skin or lungs -> Pulmonary fibrosis (potentially fatal), erythema, hypertrophic skin modifications

No myelosuppression

Question 26

What are the use limiting ADRs of mitomycins?

Answer 26

Myelosuppression

Question 27

MOA of mitomycin?

Answer 27

NADPH/CYP450 reductase generates superoxide radicals -> hydroxyl radial (Fenton rx) -> induce single strand breaks in DNA

Leads to crosslinked DNA

Question 28

What structe undergoes Fenton rx?

Answer 28

Metabolism of quinone

Question 29

Where is bleomycin hydrase not found in?

Answer 29

Skin and lungs

Question 30

Which anticancer agent would intercalate the best between base pairs and DNA

Answer 30

Ring B: flat ring system