Mechanistic Basis of Chemotherapy 1

Question 1

Describe alkylating agents MoA
Drugs acting directly on nucleic acids

Answer 1

Form highly reactive aziridinium ion that can be attacked by nucleophilic DNA bases, guanine
Alkyl groups are transferred to nucleophilic sites of DNA bases
Can occur twice leading to cross-linked DNA
Damage caused cannot be repaired = cancer cells can no longer proliferate

Question 2

What are the limitations of alkylating agents?
Drugs acting directly on nucleic acids

Answer 2

Reaction fast = no tissue or cell specificity = SE/toxicity
H2O/Nu- may inactivate aziridinium/mustard
Decomposition may be inhibited if buffered to slightly acidic pH

Question 3

Describe if the R group is aliphatic in the alkylating agent
Drugs acting directly on nucleic acids

Answer 3

Increase nucleophilic character on N lone pair = increase speed of aziridinium formation
Can be attacked by nucleophiles in healthy or cancer cells
= increased toxicity

Question 4

Describe if the R group is aromatic in the alkylating agent
Drugs acting directly on nucleic acids

Answer 4

Stabilises the lone pair on N through resonance = N becomes less nucleophilic = decreases Aziridinium ion formation
Higher stability = enhanced tissue selectivity = greater time to interact with cancer cells before aziridinium ion formed

Question 5

Describe resistance mechanism of alkylating agent
Drugs acting directly on nucleic acids

Answer 5

Decreased cellular uptake OR increased cellular efflux
Cells may develop “agent specific” DNA repair processes

Question 6

Describe the MoA of intercalating agents
Drugs acting directly on nucleic acids

Answer 6

Able to insert themselves into space between successive DNA base pairs
= slight unwinding of DNA helix alternating DNA structure
= causes cells to die

Question 7

What is important about the chemical structure of intercalating agents for its MoA?
Drugs acting directly on nucleic acids

Answer 7

Need planar aromatic rings to insert themselves in space between successive DNA base pairs

Question 8

Describe the role of Topoisomerase I
Drugs acting directly on nucleic acids

Answer 8

Breaks + rejoins single stranded DNA

Question 9

Describe the role of Topoisomerase II
Drugs acting directly on nucleic acids

Answer 9

Breaks + rejoins double stranded DNA
Inhibitors stabilise the protein-DNA complex leading to double strand breaks
= targets complex

Question 10

What is an example of a Topoisomerase II inhibitor?
Drugs acting directly on nucleic acids

Answer 10

Mitoxantrone
Excretion primarily biliary

Question 11

How do anthracyclines work?
Drugs acting directly on nucleic acids

Answer 11

DNA intercalation
Topoisomerase II poison
Generation of reactive oxygen species (ROS) = lead to cardiotoxicity

Question 12

How does anthracyclines chemical structure relate to function?
Drugs acting directly on nucleic acids

Answer 12

Polycyclic, aromatic + planar = able to intercalate

Question 13

What is an example of anthracycline?
Drugs acting directly on nucleic acids

Answer 13

Doxorubicin

Question 14

How does non-intercalating Topoisomerase inhibitors (poison) work?
Drugs acting directly on nucleic acids

Answer 14

Stabilise covalent intermediate between DNA + Topoisomerase II
= drugs prolong transition state = DNA breakage

Question 15

What are examples of non-intercalating Topoisomerase inhibitors (poison)?
Drugs acting directly on nucleic acids

Answer 15

Etoposide

Question 16

What are Camptothecins?
Drugs acting directly on nucleic acids

Answer 16

Topoisomerase I inhibitors = Irinotecan + Topotecan

Question 17

Describe MoA of Irinotecan
Drugs acting directly on nucleic acids

Answer 17

Complex disables the relegation of nicked strand + prevents topoisomerase release
Lethal double-strand break
= DNA damage = cell death