DNA Alkylating Agents Part 2

Question 1

What is the harmful metabolite of the prodrug Cyclophosphamide?

Answer 1

Acrolein

Question 2

What adverse events can happen with Acrolein accumulation?

Answer 2

hemorrhagic cystitis (bleeding/ inflamed cysts in the bladder/ kidney)

Question 3

What allows Cyclophosphamide more time to find DNA as the desired drug target?

Answer 3

prodrug undergoes metabolic oxidation to active metabolite

Question 4

What enzyme is responsible for the conversion of Cyclophosphamide to its active metabolite?

Answer 4

ALDH (aldehyde dehydrogenase)

Question 5

Why does Cyclophosphamide not have “typical” chemotherapy toxicities?

Answer 5

bone marrow stem cells, liver cells, and intestinal epithelium have relatively high concentrations of ALDH

Question 6

Why is Cyclophosphamide not typically used in combination with anthracyclines?

Answer 6

1. can potentiate cardiotoxicity
2. both CCNS drugs

Question 7

What adverse effects are seen with Acrolein accumulation in the bladder?

Answer 7

1. dysuria
2. hematuria (red/orange urine)
3. potentially fatal bleeding

Question 8

How can hemorrhagic cystitis risk be reduced?

Answer 8

1. increase fluid intake >2 L/day
2. take cyclophosphamide in the morning to adequately hydrate during the day
3. coadminister MESNA

Question 9

How do bladder/ kidney proteins interact with acrolein to become toxic?

Answer 9

Cys-SH alkylation with acrolein

Question 10

Which agent has similar but worse effects than Cyclophosphamide?

Answer 10

Ifosfamide

Question 11

What additional toxic metabolite is formed by the oxidation of Ifosfamide?

Answer 11

Chloroacetylaldehyde

Question 12

What kind of toxicities are seen with chloroacetylaldehyde?

Answer 12

nephro/neurotoxic

Question 13

What dose-limiting side effect does the chloroacetylaldehyde metabolite cause? Why does this happen?

Answer 13

1. syndrome of global brain dysfunction (encephalopathy)
2. can cross the BBB and react covalently with brain proteins

Question 14

How can encephalopathy be managed?

Answer 14

methylene blue

Question 15

How can hemorrhagic cystitis with Ifosfamide be prevented?

Answer 15

MESNA given with every dose

Question 16

How does MESNA work to provide chemoprotective effects?

Answer 16

functional mimic of Glutathione-SH concentrates in the bladder/ kidneys and forms an inactive complex with acrolein

Question 17

Why can MESNA not protect against encephalopathy seen with chloroacetylaldehyde?

Answer 17

does not cross the BBB or concentrate in neurons

Question 18

What are the symptoms of heavy metal toxicity seen with platinum-containing agents?

Answer 18

1. ototoxicity
2. nephrotoxicity
3. peripheral sensory neuropathy

Question 19

How are platinum-containing prodrugs activated inside the cancer cell?

Answer 19

aquation

Question 20

How do platinum-containing agents enter cancer cells?

Answer 20

copper transporting protein (CRT1) and/or passive diffusion

Question 21

How does Cisplatin cause ototoxicity?

Answer 21

concentrates in the cochlear of the ear

Question 22

How is nephrotoxicity reduced when using Cisplatin?

Answer 22

1-2 L/day IV hydration

Question 23

why is oxaliplatin associated with sensory neuropathy?

Answer 23

oxalic acid dianion chelates intracellular Ca2+ and alters nerve signaling

Question 24

what can exacerbate oxaliplatin-associated sensory neuropathy?

Answer 24

cold temperatures

Question 25

why should organoplatinum compounds not be administered with aluminum-containing needles/ IV sets?

Answer 25

chemically reacts to form a discolored precipitate and loss of drug potency (aluminum incompatibility)

Question 26

What is the BBW for all platinum-containing compounds?

Answer 26

anaphylactic-like reaction that risk increases with repeat doses

Question 27

When are anaphylactic-like reactions with platinum-containing agents most likely to occur?

Answer 27

> 6 cycles

Question 28

What agent is the “penicillin of cancer drugs” because it is the most widely used treatment?

Answer 28

Cisplatin