lecture 5 alkylating agents

Question 1

what are alkylating agents MOA?

Answer 1

drugs that are reactive electrophiles that bind to DNA nucleophiles
create inter+intrastrand crosslinks to inhibit DNA replication

Question 2

what phase of cell cycl are alkylating agents?

Answer 2

non cell-cycle specific

Question 3

what are the side effects of alkylators?

Answer 3

myelosuppression
monoadducts are mutagenic + carcinogenic
measurable incidence of second malignancies

Question 4

what is the prodrug alkylating agent?

Answer 4

cyclophosphamide

Question 5

what is the most commonly used alkylating agent?

Answer 5

cyclophosamide

Question 6

what are the side effects of cyclophosamide?

Answer 6

mild bone marrow toxicity
hemorrhagic cystitis due to acrolein to bladder mucosa

Question 7

what is given with cyclophosamide?

Answer 7

mesna to decrease bladder toxicity

Question 8

how does mesna function?

Answer 8

charged sulfonate group that does not penetrate –> inactives acrolein accumulates in urine

Question 8

what is mitomycin C?

Answer 8

alkyalting agent
myelosuppresion is dose limiting

Question 8

what is important about cisplatin?

Answer 8

intrastrand crosslinks
dose-limiting nephrotoxicity

Question 8

what are the resistance mechanisms to alkylating agents?

Answer 8

increased intracellular conc. of free thiols (glutathione) bc they bind to electrophiles
increased express of glutathione s transferease bc that catalyzes rxn of glutathione with alkylating agents