Biologic Antineoplastics - Fitz Flashcards
(100 cards)
1
Q
What are the three chemical types of Drugs that Interrupt Mitosis/Antimitotics/Spindle Poisons?
A
- Vinca alkaloids
- vincristine, etc.
- Taxanes
- paclitaxel, etc.
- Epilone
- ixabepilone
(All CCS: M-phase)
2
Q
What are the two groups of Plant Alkaloids?
A
- Vinca Alkaloids
- Taxanes
3
Q
What are the 3 Antimitotic Vinca Alkaloid drugs that we need to know?
A
- Vinblastine
- Vincristine
- Vinorelbine
4
Q
What are the 3 Antimitotic Taxane drugs that we need to know?
A
- Paclitaxel
- Capazitaxel
- Docataxel
5
Q
What is the only Antimitotic Epilone (antibotic) drug that we need to know?
A
Ixabepilone
6
Q
What is the MOA of Antimitotic Vinca Alkaloid antineoplastic drugs?
A
bind to tubulin at the forming end of microtubules and TERMINATE (disrupt) spindle assembly
7
Q
What are potential forms of resistance to Antimitotic Vinca Alkaloids?
A
- decreased accumulation via increased P-glycoprotein expression → MDR
- changes in target proteins
- mutations to tubulin that prevent binding
- cross reactivity among vinca alkaloids is not absolute
8
Q
What are the specific therapeutic uses of Antimitotic Vinca Alkaloids?
A
- routinely used in combination therapy because of distinct mechanisms of action and toxicities
- regimens:
- VINCRISTINE (Oncovin):
- MOPP for Hodgkin’s disease
- CHOP for non-Hodgkin’s lymphoma
- VINBLASTINE:
- ABVD for Hodgkin’s disease
- PVB for testicular cancer
- VINCRISTINE (Oncovin):
- regimens:
9
Q
As a drug class, the Antimitotic Vinca Alkaloids may cause what possible adverse side effects?
A
bone marrow suppression & neurotoxicity
10
Q
What specific adverse side effects may be caused by Vincristine?
A
- VINCRISTINE = CNS toxicity
- more lipid soluble → fatal if given intrathecally
-
neurotoxicity
- prominent because of the requirement for microtubules in axon transport
- common symptoms:
- motor: loss of reflexes
- autonomic: constipation, paralytic ileus, orthostatic hypotension
- sensory: paresthesias (“pins and needles”)
11
Q
What particular symptom is used as an indication of sufficient dose for Vincristine? What symptoms indicate the need to decrease the dose?
A
-
depression of deep tendon reflexes occurs within 2-3 weeks in 100% of patients
- used as an indication of sufficient dose
- this can be followed by severe paresthesias and mild-moderate sensory loss which is an indication to decrease the dose
12
Q
What specific adverse side effects may be caused by Vinblastine?
A
- Vinblastine = bone marrow suppression
- Nausea & vomiting
- Vesicant
- Alopecia
13
Q
What is the MOA of Antimitotic Taxanes (Paclitaxel, etc.)?
A
bind to tubulin and ENHANCE AND STABILIZE spindle assembly
14
Q
What is one potential form of resistance to Antimitotic Taxanes?
A
decreased accumulation via
increased P-glycoprotein expression → MDR
15
Q
What is important to know about the metabolism (pharmacokinetics) of Antimitotic Taxanes?
A
eliminated by extensive CYP 450 metabolism- hepatobiliary excretion
(i.e. liver function is critical)
16
Q
What are some possible toxic side effects of Antimitotic Taxanes?
A
- bone marrow suppression
- hypersensitivity/allergic reactions
- peripheral neuropathy
- nausea and vomiting
- hypotension, arrhythmias
17
Q
What is the MOA of the Antimitotic Epilone: Ixabepilone?
A
antibiotic that binds to tubulin and ENHANCES AND STABILIZES spindle assembly
(similar to paclitaxel)
18
Q
What is Ixabepilone used to treat?
A
IXABEPILONE does not produce MDR, and is therefore approved for use in breast cancer patients who have failed anthracycline antibiotic and taxane treatments.
- used in combination with CAPECITABINE for the treatment of metastatic breast cancer following treatment failure with an anthracycline antibiotic and PACLITAXEL
- (i.e., it is a 3rd line treatment)
19
Q
What are the potential toxic side effects of Ixabepilone?
A
- causes bone marrow suppression
- especially neutropenia
- peripheral neuropathy
- cardiac arrhythmias
- can also produce hypersensitivity reactions
20
Q
What are the 3 chemical classes of Immunosuppressives?
A
- Glucocorticoids
- Antibiotics
- Antibodies and fusion proteins
21
Q
What is the MOA of Glucocorticoids?
A
- interfere with the concentration, distribution and function of leukocytes
- increases the concentration of neutrophils; decreases T & B lymphocytes, monocytes, eosinophils and basophils
- end result is decrease in cytokine release, including decreases in IL-2 and TNF α
22
Q
What is the naturally occurring compound associated with Glucocorticoids?
A
Cortisol
23
Q
How are Glucocorticoids administered in chemotherapy treatments compared to their use in treating inflammatory diseases (asthma, arthritis, lupus, etc.)?
A
- Chemotherapy:
- given in higher doses, using a “pulse” regimen
- Conventional Immunosuppression:
- low dose, continuous
24
Q
What are the four Immunosuppressive Antibiotics that we need to know?
A
- Cyclosporine
- Everolimus
- Tacrolimus
- Temsirolimus
25
What are Immunosuppressive Antibiotics used for?
* prevent rejection following bone marrow transplants
* Cyclosporine, Tacrolimus
* angiogenesis inhibitors
* Everolimus, Temsirolimus
26
What are the two pathways that Imunosuppressive Antibiotics are involved in?
1. NFAT-mediated regulation of interleukin synthesis
2. mTOR regulation of cell growth and angiogenesis
27
What effect does Cyclosporine and Tacrolimus have on calcineurin in Antirejection? What is the ultimate result?
* bind to cytoplasmic proteins and **inhibit calcineurin**
* CYCLOSPORINE binds to cyclophilin
* TACROLIMUS binds to FK-binding protein
* calcineurin is necessary for activation of NFAT
* a T cell-specific transcription factor that is involved in the synthesis of interleukins by activated T cells → **decreased release of IL-2** → decreased activation of IL-2 receptor → decreased cell proliferation
28
What signalling molecule do tyrosine kinases increase expression of but Everolimus and Temsirolimus inhibit in order to prevent angiogenesis/proliferation?
* receptor tyrosine kinases can also increase expression of **mTOR**
* intracellular signaling molecule that:
* increases cell division
* increases bioenergetics
* facilitates angiogenesis in many cell types
* therefore, EVEROLIMUS and TEMSIROLIMUS function as **mTOR inhibitors**
29
Antibodies have been designed to target what CD molecules?
* **CD20** in Non-Hodgkin's Lymphoma
* Rituximab
* Ibritumomab
* Tositumomab
* **CD52** in B-Cell Chronic Lymphoblastic Leukemia
* Alemtuzumab
30
Antibodies have been designed to target what cell surface proteins that are overexpressed in specific cancers?
HER2, VEGF, EGFR
31
What is the MOA of the fusion protein, DENILEUKIN DIFTITUX, that has diphtheria toxin coupled to IL-2?
* diphtheria toxin catalyzes the ADP-ribosylation of elongation factor-2 →
* inhibits protein translation by inactivating EF2
* goal is to kill cells expressing IL-2 receptors (activated T-lymphocytes, B lymphocytes and macrophages)
32
What is a potential form of resistance to immunosuppressive antibodies?
changes in target protein that prevent the antibody from recognizing its antigen
33
How are immunosuppressive antibodies administered? Half life?
* IV administration
* long half-lives - detectable at least 3-6 months after completion of treatment
34
What are the possible toxic effects of immunosuppressive antibodies and fusion proteins?
* **infusion reactions** (77% of patients on rituximab)
* **hypersensitivity reactions**: fever, muscle aches, headaches, rashes, anaphylaxis
* mouse (MO) \>\> chimeric (XI) \> humanized (ZU) for HAMA reaction
* **infections**
* esp reactivation of tuberculosis
* unknown effects on immunization, carcinogenesis, mutagenesis, impairment of fertility, pregnancy, nursing infants (human IgG is secreted in milk)
35
What are possible specific toxicities of immunosuppressive anti-CD antibodies?
* cardiac arrhythmias
* tumour lysis syndrome
36
What are possible unique toxic side effects of Alemtuzumab?
* cough
* tightness in chest
37
What are the two types of Immune System Stimulants?
* Cytokines
* (biological response modifiers)
* Hematopoietic Growth Factors
* (supporting agents)
38
What are the three Cytokines (that we need to know) that are used as Immune System Stimulants?
1. Interferon alpha
2. Interleukin 2
3. Tumor Necrosis Factor Alpha
39
What are 3 common characteristics that all cytokines used for cancer chemotherapy have in common?
* Short half-lives
* Not cytotoxic themselves
* Recruit immune cells to do the actual cell killing
* means the immune system has to recognize the tumor cells as foreign
40
What immune system response does Interleukin 2 induce?
induces and expands a **T-cell** response cytolytic for tumor cells
41
How is Interleukin 2 given as a chemotherapy?
* used either alone or with IL-2-stimulated autologous lymphocytes ("lymphokine-activated-killer" or LAK cells; cytokine induced killer or CIK cells)
* short half-life (t1/2 = 13 minutes) → either continously infused or given as multiple intermittent daily doses
42
What are potential toxic side effects of high doses of Interleukin 2?
* activation and expansion of lytic lymphocytes causes inflammation, vascular leak and secondary release of other cytokines (such as TNF, interferon α) = **cytokine storm**
* can produce mild/moderate symptoms such as fever/chills, diarrhea and weight gain or hand-foot syndrome (palmar-plantar erythrodysesthesia)
* serious toxicities such as thrombocytopenia, shock, respiratory distress, coma and **fatal hypotension**
43
What are the three mechanisms of anti-tumor activity of Interferon-alpha?
* decreases the production of fibroblast growth factor (FGF)
* anti-FGF actions may be responsible for actions against leukemic stem cells in chronic myeloid leukemia
* FGF is angiogenic
* inhibition of cell division of both normal and tumor cells
* increases class I MHC expression on tumor cells
* actually restores normal MHC expression levels → increased activity of cytotoxic T lymphocytes
44
What are four main potential toxic side effects of Interferon-alpha?
* flu-like symptoms: fever, arthralgias, headache, fatigue
* hypotension
* myelosuppression
* depression
45
What are the 3 immune responses that Tumor Necrosis Factor alpha produces?
* causes fibroblast proliferation
* chemokine induction (IL-6, IL-8)
* T and B cell activation
46
How is Tumor Necrosis Factor alpha administered? Why?
intra-arterial administration due to extremely short half-life and toxicity
47
What is the severe dose-limiting toxicity of Tumor Necrosis Factor alpha?
malaise and flu-like symptoms - can cause hemorrhagic necrosis
48
What progenitor cells does Filgrastim activate?
G-CSF → neutrophils
49
What progenitor cells does Sagramostim activate?
GM-CSF → granulocytes, eosinophils, basophils, and monocytes
50
What cells does Interleukin 11 and Thrombopoietin activate?
Platelets
51
What are tyrosine kinases important targets in cancer treatment?
because they are regulators of intracellular signal transduction pathways, where they are involved in development and multicellular communication
52
What two things have been designed to interfere with the actions of specific tyrosine kinases?
* signal transduction inhibitors
* antibodies
53
What do signal transduction inhibitors bind to?
bind to the **ATP-binding site** of tyrosine kinases (NOT the substrate binding site)
54
Why do Signal Transduction Inhibitors generally have fewer side effects than conventional chemotherapies?
they are targeted toward the specific defect of a particular cancer (bcr-abl, EGFR, etc.)
55
What are the four inhibitors of Bcr-abl?
1. Bosutinib
2. Imatinib
3. Nilotinib
4. Dasatanib
56
What is the MOA of the three STI's that target Bcr-abl (DASATANIB, IMATINIB (Gleevec), NILOTINIB)?
* competitive antagonists of the ATP-binding site of:
* **bcr-abl**, the non-receptor tyrosine kinase whose activity is deregulated by the translocation of its gene from chromosome 9 to chromosome 22 in most patients with CML
* also target **c-kit**, the tyrosine kinase altered in gastrointestinal stromal tumours (GIST), and are weak antagonists of the platelet-derived growth factor (PDGF) receptor
57
What cancer type is the tyrosine kinase Bcr-abl associated with?
Chronic Myeloid Leukemia (CML)
58
How are the STI's that target Bcr-abl (DASATINIB, IMATINIB, NILOTINIB) metabolized?
metabolized in the liver (**CYP 3A4**), and excreted in the feces (hepatobiliary excretion)
59
What are potential forms of resistance to STI's that target Bcr-abl?
* **change in target proteins**
* mutation of ATP-binding site that prevents drug binding in the cancer cells, often due to further mutations of bcr-abl gene (heterogeneity of tumour) - secondary resistance
* sometimes see **overexpression of bcr/abl** or expression of other kinases (form of primary resistance)
* DASATINIB and NILOTINIB were developed to target cells that have become resistant to IMATINIB
60
What are the therapeutic uses of STI's targeting Bcr-abl (DASATINIB, IMATINIB, NILOTINIB)?
* can induce a complete hematological and cytological response in 85-95% of patients in the **chronic phase of CML**
* can delay death in 25% of patients in blast crisis (75% of these patients initially respond)
* also effective in **gastrointestinal stromal tumours** expressing **c-kit**
61
What are the three severe potential toxic side effects of STI's in general?
* can cause **congestive heart failure** and/or **myocardial infarction**
* incidence and severity vary widely within STIs
* more common and more severe with DASATINIB, IMATINIB and NILOTINIB, because Abl tyrosine kinases are necessary for maintenance of normal heart function
* **teratogenic**
62
What are the four drugs that target EGFR?
1. Cetuximab
2. Erlotinib
3. Gefitinib
4. Panitumumab
63
What is the MOA of Cetuximab and Panitumumab?
monoclonal antibodies directed against EGFR
64
What is the MOA of Erlotinib and Gefitinib?
competitive antagonists of the ATP-binding site of EGFR
65
What type of cancer is Cetuximab & Panitumumab used primarily for?
Metastatic Colon Cancer
66
What are the potential toxic side effects of Cetuximab & Panitumumab?
* **infusion/hypersensitivity reactions**: fever, muscle aches, headaches, rashes, anaphylaxis, infusion reactions
* mouse (MO) \>\> chimeric (XI) \> humanized (ZU) for HAMA reaction
* **infections**
* unknown effects on immunization, carcinogenesis, mutagenesis, impairment of fertility, pregnancy, nursing infants (human IgG is secreted in milk)
* unique toxicities include **skin** (rash, photosensitivity, necrotizing fascitis) and lung (interstitial lung disease)
67
What are the potential toxic side effects of Erlotinib & Gefitinib?
* as with other STIs, relatively minor side effects (esp. compared to conventional therapies that work by preventing rapid cell growth): nausea, vomiting, fatigue, myalgia, diarrhea, skin rashes and acne, drug interactions
* can cause **congestive heart failure** and **myocardial infarction** (less likely than with STIs that inhibit Bcr-Abl)
* **teratogenic**
* interstitial pneumonia (which can be fatal)
68
What type of cancer is Erlotinib & Gefitinib used for?
approved for use in metastatic non-small cell lung cancer (NSCLC) after failure of standard chemotherapies
69
What is HER2?
Human epithelial growth factor receptor 2
(HER2) = Neu = ErbB2 = CD340
70
What type of cancer is HER2 overexpressed?
Aggressive breast cancers
71
What are the three drugs approved to targed HER2?
1. Trastuzumab
2. Pertuzumab
3. Ado-Trastuzumab Emtansine
72
What is the MOA of Trastuzumab in targeting HER2?
binding of the antibody interferes with HER2 signaling, and identifies the HER2-overexpressing cells as foreign, so that they can be destroyed by the immune system
73
What is the MOA of Pertuzumab in targeting HER2?
it prevents HER2 from dimerizing with other HER receptors
```
first antineoplastic DIMERIZATION INHIBITOR
(a new class of drugs)
```
74
What is the MOA of Ado-Trastuzumab Ematansine?
* internalized and undergoes lysosomal degradation to form 2 components
* TRASTUZUMAB
* DM1, a small molecule inhibitor that _disrupts microtubule_ networks by binding to **tubulin**
75
What is the one potential form of resistance to drugs targeting HER2?
altering HER2 so that the antibody doesn't recognize its target
76
What three unique toxic side effects have been caused by treatment with Trastuzumab?
* Birth defects/fetal loss
* Ventricular dysfunction
* Congestive heart failure
77
How is asparagine used in normal cells?
the asparagine used for protein synthesis is generated from aspartate by asparagine synthase;
asparagine outside the cell is converted to aspartate by L-ASPARAGINASE before being pumped into the cell and converted back to asparagine
78
What does administration of L-Asparaginase cause?
selective toxicity because some tumour cells lack asparagine synthase (i.e., they require an exogenous sources of L-asparagine for protein synthesis), therefore decreasing the asparagine concentration by giving L-ASPARAGINASE deprives tumour cells of asparagine
79
What type of cancer is treated with L-Asparaginase?
childhood acute lymphocytic leukemia
80
What is the main side effect of chemotherapy treatment with L-Asparaginase? Why?
**hypersensitivity reactions** (fever, chills, nausea/vomiting, skin rash and urticaria) because L-ASPARAGINASE is isolated from bacteria
81
Why is L-Asparaginase usually used with other antineoplastic agents?
sequence of drug administration is critical, for example:
* if METHOTREXATE is given first, you have **synergistic cytotoxicity** (due to synchrony)
* if L-ASPARAGINASE is given first, the METHOTREXATE cytotoxicity is reduced as METHOTREXATE cell kill is dependent upon synthesis of the enzymes necessary for DNA synthesis (DHFR and thymidylate synthase, specifically)
82
What two drugs are inhibitors of the 26S proteosome?
1. Bortezomib
2. Carfilzomib
83
What does the 26S proteosome normally do? What happens when it is inhibited?
* the ubiquitin-26S proteasome pathway regulates the intracellular concentration of proteins, thereby maintaining cellular homeostasis
* inhibition of the 26S proteasome affects multiple signalling cascades, triggering **apoptosis** and leading to cell death
84
Which drug is reversible/irreversible between Bortezomib and Carfilzomib?
* **Bortezomib = reversible**
* Carfilzomib = irreversible
85
What are three potential toxic side effects of Bortezomib and Carfilzomib?
* Thrombocytopenia, neutropenia, and/or anemia
* Peripheral neuropathy
86
What type of cancer is Bortezomib/Carfilzomib used to treat?
Multiple Myeloma
87
What do histone deacetylases (HDACs) do in normal cells?
* histone deacetylases (HDACs) work in conjunction with histone acetyltransferases to regulate gene expression
* acetylation is associated with euchromatin ("open for transcription")
* deacetylation is associated with heterochromatin("closed")
88
What do histone deacetylases (HDACs) do in cancer cells?
* some cancer cells overexpress or aberrently recruit HDACs, leading to hypoacetylation of histones, condensed chromatin structure and decreased transcription
* causes silencing of tumor suppressor genes (esp. **p53**)
89
What is the MOA of HDAC inhibitors like ROMIDEPSIN, VORINOSTAT?
HDAC inhibitors increase transcription, and lead to cell cycle arrest and apoptosis
90
What cancer type is Vorinostat used for?
approved for use in cutaneous T-cell lymphoma, and is under investigation in glioblastoma multiforme and HIV
91
What are the potential toxic side effects of HDAC inhibitors like Romidepsin and Vorinostat?
* Hematologic:
* pulmonary edema
* deep vein thrombosis
* Drug/Drug interations:
* severe thrombocytopenia and GI bleeding result from coadministration with valproic acid
* PT and INR are prolonged if given with WARFARIN
92
What are the three Differentiating Agents that we need to know?
1. Tretinoin (ATRA, RETIN-A)
2. Arsenic Trioxide (ATO)
3. Bexarotene
93
What is the MOA of Tretinoin?
in acute promyelocytic leukemia (APL), activates the differentiation program (converting promyelocytes into granulocytes) and promotes degradation of the PML-RAR fusion protein
94
Why does treating cancer with Tretinoin require the addition of a cytotoxic agent?
doesn't kill cells itself!
requires cytotoxic agent like ARSENIC TRIOXIDE or anthracycline antibiotic
95
What are potential toxic side effects of Tretinoin?
* headache, dry skin, reversible hepatic enzyme abnormalities, bone tenderness, hyperlipidemia
* **CNS toxicity**: dizziness, anxiety, depression, confusion, agitation
* **DIFFERENTIATION SYNDROME** (formerly called retinonic acid syndrome): fever, dyspnea, weight gain, pulmonary infiltrates
* with or without pleural or pericardial effusions
* with or without leucocytosis
* can be fatal
* **birth defects** (teratogenic)
96
What is the MOA of Arsenic Trioxide (ATO)?
* heavy metal toxin that promotes cell death through both apoptosis and necrosis
* given in conjunction with TRETINOIN to cause death of differentiated granulocytes
97
What are two potential toxic side effects of Arsenic Trioxide (ATO)?
* **arrhythmias** (prolongation of QT interval)
* **leukocyte maturation syndrome** similar to differentiation syndrome
98
What is the MOA of Bexarotene?
rexinoid that selectively activates retinoid X receptors, which are involved in the regulation of cell growth and differentiation
99
What type of cancer is treated with Bexarotene?
approved for use in patients with cutaneous **T-cell lymphoma** that is refractory to skin-directed treatment
100
What are the potential toxic side effects of Bexarotene?
* metabolized by **CYP3A4** (potential for many drug interactions)
* side effects include: GI symptoms, **lipid abnormalities and pancreatitis** (must monitor blood lipid levels)
* **TERATOGENIC**
