Anthracyclines Flashcards
What are the MOA of doxorubicin?
1) Topoisomerase II inhibition –> the complex that forms can lead to DBS
2) DNA intercalation
3) Free radicals (ROS)
4) Membrane perturbations –> changes the membrane density
5) Stimulating apoptosis
6) Signal transduction inhibition –> protein kinase C –> PI3K; can also activate AKT (antagonism by PTEN)
7) Inhibition of DNA and RNA polymerase
8) DNA alkylation
9) changes in Ca2+ homeostasis
10) inhibition of thioredoxin reductase
How is doxorubicin eliminated”?
Biliary
- marked hyperbilurubinemia = decreased clearance
- marked hepatic tumour burden = decreased clearance
What are the mechanisms of resistance of doxorubicin?
1) Enhanced drug efflux –> steroids, PGP substrates
2) Altered topoisomerase II activity
3) Intracellular free radicals detoxifying
4) Resistance to apoptosis
5) Decreased MMR
6) Increased DNA repair
What kind of interaction does doxorubicin have with:
heparin, phenobarbital, morphine, paclitaxel, and traztuzumab?
-Heparin: forms aggregates, increases clearance
- Phenobarbital: increases clearance
- Morphine: decreases clearance
- Paclitaxel and trastuzumab: cardiotoxicity
What are the main toxicities of doxorubicin?
- Myelosuppression
- GI
= Extravasation injury - Cardiac toxicity –> Acute:
Arrhythmias, Pericarditis-myocarditis syndrome;
Chronic (cumulative dose of > 180mg/m2): DCM - Anaphylactic reactions
- Radiation recall
RT –> moist desquamation –> moist desquamation resolves –> gives doxorubicin –> moist desquamation comes back just as bad
How does the ABCB1 deficiency effect doxorubicin metabolism in dogs?
- DOX exposures in the ABCB1(null) population were increased in all simulated tissues including serum (24%) and gut (174%)
- GI toxicosis would be dose limiting in ABCB1(null) populations
- Dosage reductions necessary to prevent GI toxicosis likely result in subtherapeutic concentrations, thereby reducing DOX efficacy in ABCB1(null) dogs
What are some hematologic effect of doxorubicin in cats?
- 30mg/m2 IV q3w x 10
- Poikilocytosis
- No anemia
- No clinical heart disease
- Though changes noted on necropsy
- Dose used in this study is higher than clinical use so not usually seen as a cardiotoxic drug
- Pre-existing heart condition in cats –> if already has DCM –> then should be more worried
What are some systemic toxicities associated with doxorubicin in cats?
- Partial or complete anorexia occurred in all cats with significant weight loss after a cumulative dose of 150 mg/m2
- Clinical heart disease and electrocardiographic changes were not observed
- Renal dysfunction in two cats
- At necropsy, all cats had histological evidence of renal disease
What’s the difference in toxicity between 1mg/kg & 25mg/m2 dosing for doxorubicin in cats?
Only post-treatment neutrophils - significantly lower in the BSA group
What’s the response rate and duration of remission of CHOP in canine rescue LSA?
78%
remission = 159 days
What’s the MST for single agent doxorubicin for canine R atrial HSA?
116-139 days
What’s the MST for single agent doxorubicin SQ HSA?
RR 38.8%, 1CR
What’s the MST for single agent doxorubicin for canine OSA
MST = 8 months
1y, 2y and 3y survival rates 35%, 17%, and 9%
What’s the MST for doxorubicin/CCNU combo for canine histiocytic sarcoma?
MST = 185m, similar to single agent doxorubicin
What’s the outcome for canine high grade STS treated with Sx +/- doxorubicin?
No significant difference in outcome
DFI = 724 days, MST = 856
50% had metastasis
What’s the outcome for single agent doxorubicin for cats with high grade LSA?
- 32% CR, 32% PR, 36% PD
- another study found 42% RR median duration 64 days; 26% CR median duration of 92 days
What’s the outcome of UW-25 for cats with LSA?
- MPFI 56 days and MST 97 days
- CR longer PFI and MST than those with partial or no response:
PFI 205 versus 54 versus 21 days
MST 318 versus 85 versus 27 days
What’s the outcome of feline high grade GI LSA treated with Sx and CHOP?
MDFI 357 days and MST 417 days
What’s the role of adjuvant doxorubicin in FISS?
uncertain, doesn’t seem to change the MST if already had Sx and RT (674 vs. 842)
What’s the role of dexrazoxane?
- it’s an iron chelator
- blocks apoptosis in ventricular myocytes
- if there is an extravasation, should use within 6 h (though optimal timing is unknown)
What’s the MTD for idarubicin in cats?
2mg/cat/day PO X 4 days every 3 weeks
What are the side effects of idarubicin in cats?
- anorexia (DLT)
- leukopenia (DLT)
- vomiting
What’s idarubicn?
it’s a daunorubicin analogue
What’s epirubicin?
It’s a doxorubicin analogue
- less cardiotoxic
- but also less potent
What’s the most common AE for epirubicin in dogs?
GI
What other toxicities have been reported with epirubicin?
dog - cardiomyopathy
cat - hypersensitivity
What’s the outcome for epiuribicin instead of doxorubicin for CEOP-25
96% RR
DFI 216 days
MST 342 days
What’s the role of epirubicin in canine splenic HSA?
seems to be as effective as single agent doxorubicin, but more GI side effects
What’s the efficacy of epirubicin for FISS in neoadjuvant/ adjuvant setting?
- 14% local recurrence (264-1573 days)
- Median follow up 1072 day, 80% alive at the end of the study
What’s the main advantage of using Doxil?
less cardiotoxicity compared to doxorubicin
What are some reported side effects of Doxil and how is it treated?
- Dogs: Plantar-palmar dysesthesia, can used vitamin B6 (pyridoxine).
- Cats: nephrotoxicity and cutaneous toxicity noted
What’s the route of elimination for mitoxantrone?
hepatic
How does mitoxantrone affect smaller dogs?
<15kg, more likely to have neutropenia. <10kg, more likely to be hospitalized for neturopenia.
How do cats do with combined mitoxantrone and cyclophosphamide?
- Side effects limited to transient appetite suppression in one cat and loose stools in two cats
- Myelosuppression and gastrointestinal side effects comparable to single-agent mitoxantrone
What’s the outcome of CHOP based protocol with mitoxantrone substituted for doxorubicin in dogs with LSA?
Comparable, numerically looks less but still has good RR and DFI/MST
CMOP MPFI 162-165 days and MST 234-248 days
CHOP MPFI 208-222 days and MST 318-348 days
What’s the efficacy of mitoxantrone as a single agent for canine LSA resuce?
CR = 47%, median duration 84 days
What’s the outcome of mitoxantrone + piroxicam for canine iUC?
MTTP = 194d
MST = 350 days
similar outcome when combined with CO2 laser ablation and palliative RT
What’s the outcome of mitoxantrone in post-op, RT dogs with AGASACA?
MDFI - 287 days
MST - 956 days
What’s the outcome of single agent mitoxantrone for feline mammary carcinoma?
MDFI = 360 days
MST = 480 days
What was the RR for DMAC for canine relapsed LSA? What was the most common side effect?
72%
Thrombocytopenia (56%)
What is the DMAC protocol?
Actinomycin D 0.75 mg/m2 IV week 1
Cytarabine 300 mg/m2 SQ or IV over 8 hours week 1
Dexamethasone 1 mg/kg week 1 and week 2
Melphalan 20 mg/m2 PO week 2
Repeat every 2 weeks x 5-8
What’s the acute DLT for doxorubicin?
GI and myelosuppression
dogs- cardiotoxicity
cats - nephrotoxicity
What’s the MOA for mitoxantrone?
- DNA intercalation
- inhibition of DNA and RNA polymerase
- inhibition of topoisomerase II
What are sone advantage of mitoxatrone?
- no oxidative damage to the cells
- less ROS
What’s the DLT of mitoxantrone?
myelosuppression
no cardiotoxicity reported in the dog
What’s the MOA of actinomycin-D
- inhibits DNA transcription –> inhibit RNA and protein synthesis
What’s the DLT of actinomycin D?
GI and myelosuppression
What’s the MOA of epipodophyllotoxins?
Ex. etoposide and teniposide
- topoisomerase II inhibitors by stabilizing the protein-DNA cleavage complex –> SSB or DSB
What’s the DLT of IV etoposide in dogs?
severe anaphylaxis, likely due to the polysorbate 80 vehicle (same as docetaxel)
What’s the oral bioavailability of etoposide in dogs?
low, and highly variable
