Antineoplastics IV Flashcards
1
Q
Vinca alkaloids
A
Vinblastine, vincristine, vinorelbine
2
Q
Taxanes
A
Paclitaxel (cabazitaxel, docetaxel)
3
Q
Epilone
A
Ixabepilone
4
Q
Vinca alkaloids MOA
A
-Bind tubulin at forming end of microtubules and TERMINATE spindle assembly
5
Q
Vinca alkaloids resistance
A
- decreased accumulation via increased P-glycoprotein expression –>MDR
- Changes in target proteins (mutations in tubulin).
- Cross reactivity among vinca alkaloids not absolute
6
Q
Vincristine therapeutic uses
A
MOPP for Hodgkin’s disease
CHOP for non-Hodgkin’s lymphoma
7
Q
Vinblastine therapeutic uses
A
ABVD for Hodgkin’s disease.
PVB for testicular cancer.
8
Q
Vinca alkaloid toxicity
A
-Bone marrow suppression
-Neurotoxicity
(Vincristine has more CNS toxicity–fatal if given intrathecally) (Vinblastine more bone marrow suppression)
-Nausea and vomiting (greater for vinblastine)
-Vesicant
-Alopecia
9
Q
What is used as an indication of sufficicent dose of vinca alkaloids?
A
Depression of deep tendon reflexes within 2-3 weeks in 100% of patients
10
Q
What is an indication to decrease dose of vinca alkaloids?
A
Severe paresthesias and mild to moderate sensory loss
11
Q
Taxane MOA
A
Binds to tubulin to ENHANCE AND STABILIZE spindle assembly
12
Q
Taxane resistance
A
Decreased accumulation via increased P-glycoprotein expression –> MDR
13
Q
Taxane pharmacokinetics
A
Extensive CYP450 metabolism
14
Q
Taxane toxicity
A
- Bone marrow suppression
- Hypersensitivity/allergic reactions
- Peripheral neuropathy
- Nausea and vomiting
- Hypotension, arrhythmias
15
Q
What form of paclitaxel has reduced toxicity
A
albumin-bound
16
Q
Epilone (Ixabepilone)MOA
A
Binds tubulin to ENHANCE AND STABILIZE spindle assembly.
17
Q
Ixabepilone used with capecitabine for 3rd line treament of what? Why 3rd line?
A
Breast cancer. Used in patients who have failed anthracycline antibiotic and taxane treatments (Ixabepilone doesn’t cause MDR resistance)
18
Q
Where is ixabepilone metabolized?
A
Liver
19
Q
Ixabepilone toxicity
A
- Bone marrow suppression
- Peripheral neuropathy
- Cardiac arrhythmias
- Hypersensitivity
20
Q
Glucocorticoids
A
Dexamethasone and prednisone
21
Q
Antibiotics
A
Cyclosporine and tacrolimus
22
Q
mTOR inhibitors (also antibiotics)
A
Everlolimus, temsirolimus
23
Q
Antibodies and fusion proteins
A
Alemtuzumab, denileukin diftitux, ibritumomab, rituximab, tositumomab
24
Q
Glucocorticoids MOA
A
- Interfere with concentration, distribution and function of leukocytes (increase neutrophils, decrease T and B lymphocytes, monocytes etc.)
- Causes decrease in cytokine release *including decrease in IL-2 and TNF-alpha
- Decrease size of lymph nodes and spleen
25
Antibiotics used to prevent rejection following bone marow transplants
Cyclosporine and tacrolimus
26
Angiogenesis inhibitors
Everolimus and temsirolimus
27
Immunosuppressive antibiotic functions
- NFAT mediated regulation of IL synthesis
| - mTOR regulation of cell growth and angiogenesis
28
Immunosuppressive antibiotic MOA
- interfere with intracellular processes that are key for cell proliferation and cytokine production and release.
- interfere with one of two intracellular signaling cascades
29
Immunosuppressive antibiotic MOA pathway 1
Antirejection
| -Bind to cytoplasmic proteins and inhibit calcineurin
30
Calcineurin
needed for activation of NFAT to decrease release of IL-2 and decreased cell proliferation
31
Cyclosporine binds what?
Cyclophilin
32
Tacrolimus binds what?
FK-binding protein
33
Immunosuppressive antibiotic MOA pathway 2
Anti-angiogenesis and anti-proliferation
| -Everolimus and temsirolimus function as mTOR inhibitors
34
Drugs that target CD20
- Rituximab
- Ibritumomab
- Tositumomab
35
CD20 drug target use
B-cell non-hodgkin's lymphoma
36
Drug that targets CD52
Alemtuzumab
37
CD52 drug target use
B cell chronic lympocytic leukemia
38
Denileukin diftitux
- fusion protein that has diphtheria toxin coupled to Il-2
- goal to kill cells expressing IL-2 receptors
- Approved for use in cutaneous T-cell lymphoma
39
What does the diphtheria toxin do?
Catalyzes ADP-ribosylation of elongation factor-2--> inhibits protein translation by inactivating EF2
40
Antibodies and fusion protein resistance
-Changes in target protein that prevent Ab from recognizing antigen
41
Antibodies and fusion protein pharmacokinetics
IV admin
| long half lives
42
Antibodies and fusion protein toxicity
```
Infusion reactions (common)
Hypersensitivity reactions (fever, muscle aches, headache, rashes, anaphylaxis)
Infections
```
43
Specific toxicities for anti-CD Ab
- cardiac arrhythmias
- tumor lysis syndrome
- Alemtuzumab: cough, tightness in chest, suspicion that radiolabelled ab (ibritumomoab, tositumomab) may be more likely to cause birth defects
44
Cytokines
IFN-alpha
IL-2
TNF-A
45
IL-2 general characteristics
- not directly cytotoxic (induces and expands T cell response cytolytic for tumor cells)
- used alone or with adoptive cellular therapy
- short half-life (continuously infused or multiple daily doses)
46
IL-2 side effects
Cytokine storm--activating a ton of cascades.
Fever/chills, diarrhea, weight gain, hand foot syndrome.
Can cause shock, thrombocytopenia, respiratory distress, FATAL HYPOTENSION
47
IFN-A MOA (3)
1. Decreases fibroblast growth factor (FGF) production
2. Inhibtion of cell division of both normal and tumor cells.
3. Increases MHC-I expression on tumor cells
48
IFN-A side effects
- flu-like symptoms
- hypotension
- myelosuppression
- DEPRESSION
49
TNF-alpha general info
- Cause fibroblast proliferation, chemokine induction, T and B cell activation.
- Effects on many cell types
- INTRA-ARTERIAL ADMIN due to extremely short half-life!
- MALAISE AND FLU-LIKE SYMPTOMS that can cause HEMORRHAGIC NECROSIS
50
Hematopoietic agents
erythropoietin (RBC) , filgrastim (G-CSF), IL-11 (platelets), romiplostim, sargramostim (GM-CSF)
51
Drugs that target protein function
- Tyrosine kinase inhibitors
| - Drugs targeting altered intracellular processes
52
Bcr-Abl tyrosine kinase inhibitors and the cancer type they treat
BOSUTINIB, DASATINIB, IMATINIB, NILOTINIB
| -Chronic myeloid leukemia (CML)
53
EGFR tyrosine kinase inhibitors and cancer types they treat
CETUXIMAB, ERLOTINIB, GEFITINIB, PANITUMUMAB
| -Epithelially derived cancer
54
HER2 tyrosine kinase inhibitors and cancer type that they treat
PERTUZUMAB, TRASTUZUMAB [ADO-TRASTUZUMAB EMTANSINE]
| -Breast cancer
55
PDGF-R and VEGF-R tyrosine kinase inhibitors
PAZOPANIB, SORAFENIB, SUNITINIB
56
tyrosine kinase
- regulators of intracellular signal transduction pathways responsible for development of multicellular communication
- phosphorylate tyrosine residues
57
Signal transduction inhibitor ending
-NIB
58
c-kit tyrosine kinase inhibitor and cancer type they treat
DASATANIB, IMATINIB, NILOTINIB, SUNITINIB,
| -GIST
59
Inhibitors of EGFR (Cetuximab and panitumumab) MOA
Prevent actions of EGFR and identify cells expressing the receptor as foreign (targets of cell mediated immunity)
60
Side effects of Cetuximab and Panitumumbab
- infusion, hypersensitivity reactions
- Infections
- Rash, photosensitivity, lung (interstitial lung disease)
61
Trastuzumab MOA
-Binds Ab and interferes with HER2 singnaling, identifying cells as foreign so they can be destroyed by the immune system
62
Pertuzumab MOA
- DIMERIZATION INHIBITOR
| - prevents HER2 from dimerizing with other HER receptors
63
Ado-trastuzumab emtansine MOA
-Internalized and undergoes lysosomal degradation to form 2 component (trastuzumab and DM1)
64
DM1 function
small molecule inhibitor that disrupts microtubule networks by binding to tubulin
65
Resistance to HER2 inhibitors
Altering HER2 so that Ab doesn't recognize its target
66
Trastuzumab side effects
- Infusion/hypersensitivity reactions
- Infections
- Birth defects/fetal loss
- VENTRICULAR DYSFUNCTION and CHF
67
Drugs that target altered intracellular processes general concepts
- Less selective
| - Greater # of side effects
68
Drug that depletes asparagine
L-asparaginase
69
L-asparaginase MOA
Deprives tumor cells of asparagine and causes selective toxicity
70
L-asparaginase side effects
Hypersensitivity reactions
71
Caveats when using L-asparaginase in combination
- Sequence of drug admin is critical!!!
- MTX given first, have synergistic cytotoxicity (higher cell kill)
- if L-asparaginase first, see reduction in toxicity (MTX depends on the enzymes needed for being DNA synthesis)
72
Drugs that inhibit proteosome
Bortezomib (reversible) and carfilzomib (irreversible)
73
MOA of drugs that inhibit proteosome (bortezomib and carfilzomib)
- Inhibitors of 26S proteasome (complex that degrades ubiquitinated proteins)
- Inhibitons affects multiple signaling cascades and triggers apoptosis
74
Side effects of drugs that inhibit proteosome (bortezomib and carfilzomib)
- Thrombocytopenia, neutropenia, and/or anemia
| - Peripheral neuropathy
75
Drugs that inhibit HDAC
Romidepsin, vorinostat
76
MOA of drugs that inhibit HDAC (romidepsin, vorinostat)
-Increase transcription and lead to cell cycle arrest and apoptosis.
77
HDACs (histone deacetylases)
-work with histone acetyltransferases to regulate gene expression (acetylation associated with euchromatin and deacetylation associated with heterochromatin)
78
What can cancer cells do to HDACs
Overexpress/abherrently recruit HDAC-->causes silencing of tumor suppressor genes
79
Side effects of drugs that inhibit HDAC (romidepsin, vorinostat)
- -HEMATOLOGIC (Pulmonary embolism, deep vein thrombosis)
- -Drug-drug interations: severe thrombocytopenia and GI bleeding. PT and INR prolonged if given with Warfarin
- Nausea, vomiting, diarrhea
- Hyperglycemia
- Fatigue, chills
- Taste disorders
- Mutagenic
80
Differentiating agents
- Tretinoin (ATRA, retin-A)
- Arsenic trioxide
- Bexarotene
81
One hallmark of malignant transformation
Differentiation block
82
Drugs that treat Acute promyelocytic leukemia
Tretinoin, arsenic trioxide
83
Tretinoin (ATRA) mechanism
Promotes degradation of PML-RAR fusion protein, but doesn't kill cells. Given with arsenic trioxide or anthracycline antibiotic to cause cell death
84
Tretinoin (ATRA) toxicities
- CNS toxicity
- DIFFERENTIATION SYNDROME (fever, dyspnea, weight gain, pulmonary infiltrates)
- Birth defects
- Headache, dry skin, reversible hepatic enzyme abnormalities, bone tenderness, hyperlipidemia
85
Arsenic trioxide MOA
Promotes cell death through apoptosis and necrosis. Given in conjunction with tetinoin to cause death of differentiated granulocytes
86
Arsenic trioxide toxicities
Arrhythmias (prolonged QT). LEUKOCYTE MATURATION SYNDROME (similar to differentiation syndrome)
87
Bexarotene MOA
-Selectively activates retinoid X receptors involved in regulation of cell growth and differentiation.
88
Bexarotene use
Cutaneous T cell lymphoma
89
Bexarotene pharmacokinetics
metabolized by CYP3A4
90
Bexarotene side effects
GI symptoms, lipid abnormalities and pancreatitis
| TERATOGENIC
