Alkylating Agents

Question 1

What are alkylating agents

Answer 1

Add alkyl group to acceptor molecule
From DNA adducts
Can be mono/bifunctional

Question 2

What adducts do alkylating agents form

Answer 2

N7 guanine
O6 guanine
N3 adenine

Are drug specific too

Question 3

Describe the activation of nitrogen mustard related alkylating agents

Answer 3

Initially a strong stable acid
Under physiological conditions = release of Cl-
= form unstable and reactive intermediate
-> reacts with anything nucleophillic
Forms bond with DNA

Question 4

What happens once an alkylating agent binds to DNA

Answer 4

Can undergo further reaction w DNA or form an inactivated monoadduct

Question 5

What are the mechanism of cell death fro alkylating agents

Answer 5

Inhibition of replication
Lethal repair
Induction of apoptotic pathway

Question 6

How does decreased transport cause resistance using melphalan as an example

Answer 6

Has phenylalanine attached to it
= can be substrate for phenylalanine transporters
= decreased uptake of the drug

Question 7

How does GSH have a role in resistance to alkylating agents

Answer 7

GSH can conjugate to the alkylating drugs and then they’re excreted

Question 8

How can resistance occur from the apoptotic pathway

Answer 8

Deficiencies = no cell death despite the damage

Question 9

What is a drug specific organ toxicity associated with alkylating drugs

Answer 9

Bladder toxicity with cyclophosphamide and ifosfamide

Question 10

What are some common general toxicities with alkylating drugs

Answer 10

Hematopoietic and immunosuppression
Nause and vomiting
Alopecia
Infertility