Alkylators and platinum compounds

Question 1

summary about alkylating agents

Answer 1

-These generate reactive electrophilic intermediates
-attack an alkyl group to DNA and protein
- Not cell cycle phase specific
- can effect replicating cells and non-replicating cells since they affect transcription and DNA replication

Question 2

Side effects of alkylation

Answer 2

myelosuppression,N/V, hairloss

Unique: Measurable incidence of second malignancies with use of these agents

Question 3

Cyclophosphamide

Answer 3

Most commonly used alkylator
Prodrug 9 requires activation by CYPP450 (benefit to prodrug strategy is that because its inactivated by aldehyde dehydrogenase this decreases the myeloid suppression in bone marrow since aldehyde dehydrogenase levels are high in the bone)
- not active until it is inside the cell
- produces a byproduct acrolein (Toxicity to the bladder mucosa due to acrolein)
- inactivated by aldehyde dehydrogenase
SE: Mild bone marrow toxicity, Hemorrhagic cystitis

Question 4

Mesna

Answer 4

THIS IS NOT TREATING CANCER
Given with Cyclophosphamide to decrease the toxicity in the bladder due to byproduct acrolein
- acts as a nucleophile to inactivate acrolein (because its charged it does not go out of the blood it goes directly to the bladder waiting to inactivate the byproduct)

Question 5

Chlorambucil

Answer 5

• has a aryl group attached which decreases nucleophilicity of the nitrogen on the compound

Question 6

Mitomycin C

Answer 6

commonly used
acts as alkylating agent that forms bifunctional crosslinks
Myelosuppression

Question 7

Drug resistance

Answer 7

1. increased expression of DNA repair enzymes (glutathione which will pair to compounds and make them inactive)
2. Increase cellular glutathione S-transferase (catalyzes the reaction between glutathione and these compounds making them inactive)

Question 8

Cisplatin

Answer 8

Platinum Drug (doesn’t have alkyl group)
Has a CIS conformation so creates an intrastrand crosslink
Cisplatin has a chemical transformation so inside the cell where Cl levels are low it is turned into the active form but outside the cell where Cl levels are high so it stays inactive
- dose limiting nephrotoxicity, N/V, minimal bone marrow toxicity (NO MYELOSUPPRESSION)