Alkylating agents

Question 1

Chlorambucil

Answer 1

MOA: Alkylates nucleophiles that will prevent DNA replication and DNA transcription by DNA cross-links

Question 2

Strategy to reduce reactivity and increase selectivity for Chlorambucil

Answer 2

Decrease nucleophilicity of nitrogen by adding aryl groups

Pulls the electron density away from nitrogen through resonance to decrease how fast you form the electrophile and how reactive the electrophile is

Question 3

Resistance

Answer 3

Upregulation of DNA repair enzymes

Increased intracellular concentration of glutathione

Increased expression of cellular glutathione S-transferase (GST)

Question 4

Cyclophosphamide

Answer 4

MOA: Alkylates nucleophiles that will prevent DNA replication and DNA transcription by DNA crosslinks

Question 5

Strategy to reduce reactivity and increase selectivity for Cyclophosphamide

Answer 5

Prodrug strategy

Requires hydroxylation by CYP450s

Cyclophosphamide–>phosphoramide mustard (PM) + acrolein

PM is a metabolite that cross-links DNA when activated in the tumor cell: Highly polar and cannot diffuse into cells, short half life

PM is inactivated by aldehyde dehydrogenase
High levels of ADH in bone marrow reduce myelosuppression toxicity in this agent

Question 6

Acrolein

Answer 6

Byproduct

Accumulates in the urine and damages bladder mucosa

Treatment: Mesna

Mesna contains a charged group that doesn’t allow to penetrate cells–>accumulates in the urine–>thiol group reacts with and inactivates acrolein

Question 7

SE of Cyclophosphamide

Answer 7

Bone marrow toxicity: due to high levels of ADH

Hemorrhagic cystitis: due to acrolein

Question 8

Mitomycin C

Answer 8

MOA: Alkylates agents that will prevent DNA replication and transcription by DNA cross links

FORMS BIFUNCTIONAL CROSS-LINKS

Cell-cycle: non-cell cycle dependent

SE: myelosuppression–> dose limiting

Resistance

Question 9

Platinum drugs

Answer 9

Covalent crosslinkers but they DO NOT alkylate agents

Leaving groups (chloride ions) are in CIS position

NON-CELL SPECIFIC: most effects in G1

Question 10

Cisplatin

Answer 10

MOA: undergoes reversible hydrolysis in aqueous solution

Equilibrium favors cisplatin in plasma where there is a high chloride concentration

Equilibrium favors aquo form inside the cell where this is a low chloride concentration

Aquo form is a potent electrophile that reacts rapidly with nucleophiles

Aquo form reacts primarly at the guanine N7 and adenine N7 that forms INTRASTRAND crosslinks due to their small bond lengths

cannot be repaired by standard DNA repair enzymes