DNA Alkylating Agents Part 2 Flashcards
What is the harmful metabolite of the prodrug Cyclophosphamide?
Acrolein
What adverse events can happen with Acrolein accumulation?
hemorrhagic cystitis (bleeding/ inflamed cysts in the bladder/ kidney)
What allows Cyclophosphamide more time to find DNA as the desired drug target?
prodrug undergoes metabolic oxidation to active metabolite
What enzyme is responsible for the conversion of Cyclophosphamide to its active metabolite?
ALDH (aldehyde dehydrogenase)
Why does Cyclophosphamide not have “typical” chemotherapy toxicities?
bone marrow stem cells, liver cells, and intestinal epithelium have relatively high concentrations of ALDH
Why is Cyclophosphamide not typically used in combination with anthracyclines?
- can potentiate cardiotoxicity
- both CCNS drugs
What adverse effects are seen with Acrolein accumulation in the bladder?
- dysuria
- hematuria (red/orange urine)
- potentially fatal bleeding
How can hemorrhagic cystitis risk be reduced?
- increase fluid intake >2 L/day
- take cyclophosphamide in the morning to adequately hydrate during the day
- coadminister MESNA
How do bladder/ kidney proteins interact with acrolein to become toxic?
Cys-SH alkylation with acrolein
Which agent has similar but worse effects than Cyclophosphamide?
Ifosfamide
What additional toxic metabolite is formed by the oxidation of Ifosfamide?
Chloroacetylaldehyde
What kind of toxicities are seen with chloroacetylaldehyde?
nephro/neurotoxic
What dose-limiting side effect does the chloroacetylaldehyde metabolite cause? Why does this happen?
- syndrome of global brain dysfunction (encephalopathy)
- can cross the BBB and react covalently with brain proteins
How can encephalopathy be managed?
methylene blue
How can hemorrhagic cystitis with Ifosfamide be prevented?
MESNA given with every dose
How does MESNA work to provide chemoprotective effects?
functional mimic of Glutathione-SH concentrates in the bladder/ kidneys and forms an inactive complex with acrolein
Why can MESNA not protect against encephalopathy seen with chloroacetylaldehyde?
does not cross the BBB or concentrate in neurons
What are the symptoms of heavy metal toxicity seen with platinum-containing agents?
- ototoxicity
- nephrotoxicity
- peripheral sensory neuropathy
How are platinum-containing prodrugs activated inside the cancer cell?
aquation
How do platinum-containing agents enter cancer cells?
copper transporting protein (CRT1) and/or passive diffusion
How does Cisplatin cause ototoxicity?
concentrates in the cochlear of the ear
How is nephrotoxicity reduced when using Cisplatin?
1-2 L/day IV hydration
why is oxaliplatin associated with sensory neuropathy?
oxalic acid dianion chelates intracellular Ca2+ and alters nerve signaling
what can exacerbate oxaliplatin-associated sensory neuropathy?
cold temperatures
why should organoplatinum compounds not be administered with aluminum-containing needles/ IV sets?
chemically reacts to form a discolored precipitate and loss of drug potency (aluminum incompatibility)
What is the BBW for all platinum-containing compounds?
anaphylactic-like reaction that risk increases with repeat doses
When are anaphylactic-like reactions with platinum-containing agents most likely to occur?
> 6 cycles
What agent is the “penicillin of cancer drugs” because it is the most widely used treatment?
Cisplatin
