Pharm - Antitumor Abx/Plant Alkaloids Flashcards
Ant-tumor abx
anthracyclines (doxorubicin)
bleomycin, dactinomycin, mitomycin
plant alkaloids
Topoisomerase I inhibitors
Vinca alkaloids
Taxanes
Topoisomerase I inhibitors
irinotecan
topotecan
vinca alkaloids
vinCRistine
vinBLastine
vinorelbine
taxanes
paclitaxel
docetaxel
anthracyclines
MOA
passive diffusion of unionized drug into cells
all nucleated cells can rapidly accumulate drug
intercalate DNA - accumulates in nucleus
topoisomerase II inhibitor
anthracyclines clearance
mostly liver
monitor bilirubin
anthracyclines
major dose-limiting side effect
myelosuppression (neutropenia)
anthracyclines
myelosuppression alopecia N/V Urine Vesicant
cardiotoxicity w/ anthracycline use
undergo 1 or 2 electron reductions to reactive compounds
oxygen radical formation
(semiquinone +O2=O2 free radical)
uses Fe3+ to form reactive species (OH-)
acute: EKG changes, arrhythmias
chronic: cumulative doses LVEF, dilation, congestion, effusions
____ is more susceptible to the oxidative damage caused by anthracyclines
myocardium
has dec endogenous antioxidant enzymes (glutathione)
preventative cardioprotection during anthracycline use
- weekly admin (versus q3week) to avoid high peaks
- chelating agent
- liposomal products
dexrazoxane
hydrolyzed to EDTA-derived analog
chelator, binds intracellular Fe to dec free radical formed w/ anthracycline use
FDA approved - metastatic breast cancer
GIVEN W/I 30 MIN OF DOXORUBICIN
dexrazoxane AE
myelosuppression alopecia mucositis N/V diarrhea
*unsure if via dexrazoxane alone or combo w/ anthracycline
liposomal anthracyclines
Doxil
avoids high peak concentrations of anthracyclines
(avoids free radical damage, cardiotoxicity)
anthracycline resistance
- active efflux from cells (MDRp170)
- altered topoisomerase II
- altered free radical biochem (inc glutathione - antioxidant)
daunorubicin/idarubicin use
leukemias
doxorubicin/epirubicin use
breast
lymphomas
dactinomycin use
Wilm’s
Ewing’s
germ cell
bleomycin use
hodkins
sclerosis for pleural effusions
lung tox
mitomycin-C use
bladder cancer
anal cancer
long nadir (4-6 wks)
camptothecins
irinotecan
topotecan
topotecan use
ovarian
irinotecan use
GI
topotecan AE
- neutropenia
- thrombocytopenia
- GI (mild): mucositis, N/V/D
- alopecia
- rash
- elevated LFTs
irinotecan
AE
- neutropenia
- thrombocytopenia
- eosinophilia
- GI * DIARRHEA (cholinergic)
-N/V, alopecia, asthenia, anorexia, fatigue, inc LFTs, bilirubin, term rxn
irinotecan
2 types of main GI side effect
- early onset=cholinergic syndrome, tx w/ atropine
- late onset=SN-38 metabolite, changes in gut epithelium
topo I inhibitor resistance
- reduced drug accumulation
- altered intracellular drug distribution
- altered carboxyl esterase activity
- dec levels of topo I (dec transcription, mutations)
- low S-phase fraction of cancer cells
topo I
S-phase
-relaxes supercoiled DNA by creating transient single-strand nicks to allow unwinding for DNA replication and RNA transcription.
- promotes movement of the replication fork and provides genomic stability.
- once replication complete, religates DNA strands
vinca alkaloids
vinCRistine
vinBLastine
Vinorelbine
vinca alkaloids MOA
- disturb MT formation
- other mechanisms also prob involved (DNA, RNA, protein synthesis, inhib glycolysis, etc)
vinca alkaloids w/ significant neuropathy
vinCristine
vinca alkaloids w/ significant myelosuppresion
vinBlastin
vincristine uses
non-hodgkins lymphoma
ALL
vinorelbine uses
NSCLC
breast cancer
vinblastin uses
Hodgkin’s disease
testicular cancer
taxanes MOA
enhances MT polymerization
can’t break down, blocks cell cycle @ metaphase/anaphase transition
taxanes
AE
- myelosuppression
- neuropathies
- infusion-related rxns
- hand-foot syndrome (docetaxcel)
