Wk 13: Anthracyclines

Question 1

What are examples of anthracyclines?

Answer 1

• Doxorubicin
• Daunorubicin
• Idarubicin
• Epirubicin
• Mitoxantrone + pixantrone

Question 2

What are the general features of anthracyclines?

Answer 2

• Intercalators are planar
• Polycyclic aromatics
• Positively charged: ionised amine induces stability, more water sol + binds strongly to DNA
• H bonding site: -OH, >NH, >C=O

Question 3

What are the effects of intercalation?

Answer 3

• More rigid: viscosity + melting temp inc
• DNA breathing reduced
• H-bonding fails at point of intercalation
• DNA structure partially unwinds + enlongates

Question 4

What are the types of intercalation?

Answer 4

• Parallel: most stable
• Perpendicular: most common

Question 5

How is the DNA stabilised after intercalation?

Answer 5

• Ring D of anthracycline protrudes into major groove of double helix + ring A reaches out into minor groove
• Amino sugar, linked to ring A interacts w/ groups in minor groove serving as anchor to stabilise anthracycline DNA complex

Question 6

What are the properties of doxorubicin?

Answer 6

• Photosensitive
• Extravasation: wear gloves
• Fast flowing vien causes rapid dilution by blood vol
• IM/SC = tissue necrosis
• Cardiotoxic

Question 7

What are the side effects of liposomal doxorubicin?

Answer 7

• Nausea + vom
• Alopecia
• Stomatitis
• Hand + foot (red by red dose + inc cycle duration)

Question 8

What is the mechanism of action of doxorubicin?

Answer 8

• Intercalation of DNA, inhibiting topoisomerase II
• Produces free radicals
• Alkylation by quinone

Question 9

What is the mechanism of action of topoisomerase II?

Answer 9

• Interacts w/ DNA forming binary covalent complex
• Breaks both DNA strand
• Ends separated + 2nd duplex passed through break
• Cut DNA reconnected
• Inc/dec linking no. of loop by 2 units

Question 10

What are the effects of doxorubicin on topoisomerase II?

Answer 10

Stabilises topoisomerase II:
- Forms rigid ternary complex

• Cannot cleave
• Inhibits DNA replication
• Apoptotic response - inhibiting cell replication

Question 11

How does doxorubicin form free radicals?

Answer 11

• Redox of quinone
• CYP450 reductase catalyses reduction to semiquinone radicals
• Generates: superoxide + hydroxyl radical

Question 12

What are the consequences of free radicals?

Answer 12

Cardiotoxicity:
- Tumour + cardiac have low superoxide dismutase

• Superoxide radical accumulation
• Cardiac tissue has low levels of catalase: unable to metabolise H2O2, producing hydroxyl radicals

Question 13

What can be given alongside doxorubicin to prevent cardiotoxic effects?

Answer 13

Dexrazoxane - removes iron

Question 14

What are the pharmacokinetics of doxorubicin?

Answer 14

• Extensively plasma bround tf doesn’t pass BBB
• Hepatically excreted
• Red urine

Question 15

Which anthracycline is used if heart muscles are damaged through doxorubicin treatment?

Answer 15

Mitoxantrone:
- Dark blue

• Lack ability to produce free radicals (less cardiotoxic)

Question 16

What is the difference between doxorubicin + epirubicin?

Answer 16

• Two isomers differ in configuration at 1 stereogenic centre
• Epirubicin: Better tolerated, less nausea, vomiting + cardiac toxicity

Question 17

What is the mechanism of action of bleomycins?

Answer 17

Intercalator - stabilised by H bonding:
- Forms complex w/ Fe(II)

• Formation of hydroxyl + superoxide radicals
• Cleavage of phosphodiester bond

Question 18

What are the regions of bleomycins?

Answer 18

• C terminal domain: DNA binding affinity by minor groove binding + intercalation
• N-terminus domain: metal chelating + oxygen activation domain
• Flexible central linker: provides flexibility to cleave both strands w/o dissociation from DNA
• Glycoside region