Topoisomerase inhibitors Flashcards
How do Topoisomerase I inhibitors work?
Topoisomerase cuts the DNA phosphate backbone of 1 strand to allow for unwinding -> decreases tension
-the inhibitor prevents Topoisomerase I from religating the broken strand –> causing single DNA strand break
What is the brand name of Irinotecan and what is the active metabolite?
Camptothecin analog
Camptosar
active metabolite: SN-38
What is the unique side effect of Irinotecan?
-early diarrhea -> cholinergic storm (SLUD: salivation, lacrimation (tears), urination, defecation)
-late diarrhea (12-24h after infusion)
also:
-Myelosuppression, nausea
Which drugs are used for early and late-onset diarrhea associated with Irinotecan (cancer) therapy?
-early onset (during infusion):
treat with anticholinergic atropine 0.25 to 1 mg IV (can be used as prophylaxis)
-late onset (12-14h after infusion)
treat with Loperamide 4mg, then 2 mg q2h until no loose stools for 12h
may exceed the OTC max dose (16mg/day)
Other Topoisomerase I inhibitor
FYI
Topotecan (Hycamtin)
What is the active and inactive metabolite of Irinotecan?
active: SN-38
inactive: SN-38G (can be converted back into active metabolite in the intestine -> causing DIARRHEA -> then reabsorbed into the body)
Which hepatic enzyme converts the active metabolite of Irinotecan into the inactive form?
UGT1A1
homozygote genotype for UGT1A1*28 need dose reduction
Which lab is monitored to determine if patients need a dose reduction for Irinotecan?
Bilirubin levels
the drug is excreted through the bile
-high bilirubin means impaired liver function or biliary obstruction -> low metabolism of the drug
-patients with Hepatic dysfunction, Gilbert syndrome
How does UGT inducer affect toxicity
Carbamaezpine, Phenytoin, Phenobarbital, smoking
-> need higher doses of Irinotecan
How does Topoisomerase II inhibition work?
Which cell cycle is affected?
prevents ligation of DNA after Topoisomerase II has cut into DNA (double-strand break)
-arrest in the S/G2 phase (also Irinotecan)
The two Epipodophyllotoxins are…
-Etoposide
-Teniposide
both are Topoisomerase II inhibitors
What is the brand name for Etoposide?
Toposar, VP-16
What is the advantage of Etoposide phosphate?
brand name: Topophos
the phosphate allows the drug to get into the solution faster
What is a rate-limiting factor of Etoposide?
Hypotension
when given too fast it can cause Hypotension
What is the unique toxicity of Etoposide?
secondary leukemia
often a mutation in chromosome 11 in the MLL gene
What are the 3 MOA of Doxorubucin?
-Topoisomerase II inhibition !!! -> binds covalently to Topo II and DNA and prevents religation !!!
Cell cycle-specific!!!
-DNA intercalation (insertion) -> ss and ds DNA break
-free radical production
What is the brand name of Doxorubicin “The Red Devil”?
Adriamycin
(one of the most used antineoplastics)
What is the unique toxicity in Anthracyclines?
NAPLEX !!!
-Cardiotoxicity through free radicals -> decreased LVEF (heart failure)
-Vesicant (tissue damage when it leaks to the blood vessels)
-colors urine/tears red (doxorubicin and Daunorubicin)
also has the Hallmark toxicities:
-Myelosuppression
-Mucositis
-N/V
-Alopecia
Topoisomerase II inhibition causes which unique side effect?
Secondary leukemia
-Epotoposide (Topo II inhibitor)
-Anthracyclines (Doxorubicin)
What is a Vesicant extravasation?
Vesicant are drugs
-they cause tissue damage when leaking into tissue
An elderly patient with low LVEF has acute leukemia. The drug of choice for acute leukemia is an Anthracycline. How should the drug be administered to reduce toxicity? Which toxicity?
Continuous infusion (over 72h) -> less cardiotoxic (less risk for a decrease in LVEF)
(Secondary leukemia is one of the side effects, 1%)
Which gene is commonly mutated in secondary leukemia?
MLL gene
What is the standard dose of Doxorubicin and how is the cumulative lifetime dose calculated?
50 mg/m2
cumulative life time dose = all doses received
example:
a patient receives 6 cycles * 50 mg/m2 = 300 mg/m2
Which Anthracyclines are less Cardiotoxic?
-Liposomal doxorubicin (doxorubicin in a liposome, therefore released slowly like continuous infusion)
-Mitoxantrone (anthracene-dione)
A patient with an LVEF of 50% needs treatment for acute leukemia. Anthracycline is the drug of choice but it is cardiotoxic (decrease in LVEF).
The oncologist chose Mitoxantrone due to its low cardiotoxicity profile. What is the downside of less toxic Anthracyclines?
It is less effective and has a higher risk of relapse
Why is Liposomal Doxorubicin (Doxil) less cardiotoxic?
lower Cmax, longer exposure
-less N/V myelosuppression, cardiotoxic
-more mucositis
-Hand-foot syndrome
Which of the 3 MOAs of Mitoxantrone is different than in Anthracyclines?
less free radical production than anthracyclines (due to different structure)
-Topo II inhibition
-DNA intercalation
Compare the toxicity profile between Mitoxantrone and Anthracylines
Mitoxantrone is…
-less cardiotoxic
-less severe vecisant properties
Which drug has chelating properties to prevent Fe-mediated free radical production?
Dexrazoxane
(Topo II inhibitor but doesn’t kill cancer cells)
What are the 2 brand names and indications of Dexrazoxane?
Zinecard: limits cardiotoxicity of doxorubicin
Totect: treats anthracycline extravasation (tissue damage from leaking)
-> free-radical scavenger to prevent tissue damage
When is cancer treatment (Doxorubicin) with Zinecard considered?
consider in patients with 300 mg/m2 lifetime exposure BUT also decreases the effectiveness of doxorubicin
What should be monitored during treatment with Doxorubicin or other Anthracyclines?
-ECHO or MUGA (more accurate) (to check LVEF at baseline)
-signs of extravasation: tx with ice
-CBC (as with all myelosuppressive agents)
-LFTs: dose reduction for bilirubin >1.2 (normal =1)
-> also with Irinotecan
What is the first thing to do if someone experiences anthracycline extravasation injury?
-stop the drug
-ICE compress -> it slows down the free radical chain reaction
-remove the ICE for 15 min (it has caused vasoconstriction preventing Totect from getting there)
-treat with Totect
