Alkylating Agents

Question 1

alkylating agents are potent _____

Answer 1

electrophiles

Question 2

alkyl agents alkylate what compounds

Answer 2

purine bases in DNA
(guanine and adenine)

Question 3

most common place for alkylating agents to add

Answer 3

Guanine N7

Question 4

what is a bifunctional alkylating agent

Answer 4

produces both intra and inter strand linkages

Question 5

cell cycle phase that alkylating agents target

Answer 5

non cell cycle specific

Question 6

if DNA tries to replicate with modification what happens

Answer 6

cell death
could add the wrong bases

Question 7

agents other than DNA bases that alkylating agents react with?

Answer 7

thiols
cysteine / lysine residues
glutathione (quenches activity)

Question 8

what happens in long term survivors taking alkylating agents?

Answer 8

second malignancies due to so many mutations

Question 9

most second malignancies are located where?

Answer 9

bone marrow (leukemia)

Question 10

cyclophosphamide is activated by what

Answer 10

CYP450

Question 11

cyclophosphamide becomes what

Answer 11

phorphoramide mustard

Question 12

what is cyclophosphamide inactivated by

Answer 12

aldehyde dehydrogenase

Question 13

cyclophosphamide is less toxic why

Answer 13

increased aldehyde dehydrogenase in bone marrow = less bone marrow supression

Question 14

cyclophosphamide by product

Answer 14

acrolein

Question 15

acrolein toxicity in cyclophosphamide

Answer 15

hemorragic cyctitis

Question 16

cyclophosphamide given with what to avoid acrolein toxicity

Answer 16

mesna

Question 17

mesna accumulates where

Answer 17

urine, bladder

Question 18

which alkylating agent is a prodrug

Answer 18

cyclophosphamide

Question 19

mitomycin C dose limiting side effect

Answer 19

myelosupression

Question 20

mitomycin C mechanism

Answer 20

bifunctional cross links

Question 21

are platinum compounds alkylating agents?

Answer 21

no, covalent crosslinkers

Question 22

platinum compounds cross link ____

Answer 22

intrastrand

Question 23

platinum compound geometry effect onDNA

Answer 23

can create sharp bends in strands that make DNA repair difficult

Question 24

cisplatin produces what types of cross links

Answer 24

intrastrand

Question 25

cisplatin dose limiting se

Answer 25

nephrotoxicity

Question 26

cisplatin side effect with bone marrow

Answer 26

minimal toxicity

Question 27

resistance mechanims of alkylating agents and platinum compounds

Answer 27

inc expression DNA repair enzymes
inc intracellular conc of thiols especially glutathione
inc exporession of glutathione S transferase (GST)

Question 28

how do thiols create drug resistance

Answer 28

high reactivity towards electrophillic intermediates