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27 Cards in this Set
- Front
- Back
Cancer therapy is divided into these 4 main subgroups
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Cytotoxic Chemotherapy
Immune Therapy Hormone Therapy Biological Target Therapy |
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Biological Target Therapy is...
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A type of treatment that uses drugs or other substances to identify or attack specific cells through biological recognition
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How does biological targeted therapy work?
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The agent targets a tumor-specific antigen that is expressed at high levels in the tumor and low levels in normal tissue.
The pathologist analyzes the tumor for specific antigens. For example, breast cancer can be analyzed for the Herceptin (HER) - 2 marker which occurs in 25% of patients. Those with the marker are eligible for therapy. |
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How is this therapy normal used?
What is a benefit of this therapy? |
With chemo or radiation therapy
It has a better toxicity profile than cytotoxic chemotherapy |
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Describe the different types of targeted therapy.
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Targeted Therapy -->
Antibody - Unconjugated antibody and Conjugated antibody radioactive Small Molecular Inhibitor- TKI (ATP mimetics) and 26S proteosome inhibitor |
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On an antibody, what is the function of the tip of the Fab portion?
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To recognize the antigen
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Describe the different antibody types from mouse to human and the differences between them.
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Mouse = 100% mouse
Chimeric = 70% human Humanized = 90% human Human = 100% human As the antibody gets more "human", there is a decreased chance of immunological reaction and a greater risk in the loss of specificity |
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Explain how these monoclonal antibodies are named.
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Mouse = O
Chimeric = xi Humanized = zu Human = u Chimeric-humanized = xizu |
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Cetuximab is therefore what type of antibody?
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Human Chimeric monoclonal antibody
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What are the 4 main modes of action of therapeutic antibody?
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Signaling Blockade
Antibody dependent cell mediated cytotoxicity Complement dependent cytotoxicity Delivery of payload |
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Describe how Signaling Inhibition works.
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Normally, a ligand will bind to a receptor and dimerize leading to activation and downstream signaling.
In signaling inhibition, a Mab will bind directly to the receptor or to the ligand binding domain or cause internalization of the receptor. |
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Describe how Antibody - dependent cell-mediated cytotoxicity works.
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The target cell is coated with antibodies and lysed or phagocytosed by macrophages or Natural Killer cells.
l |
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Which portion of the antibody binds to the antigen? Effector cell?
Which antibody type holds the greatest effector cell function? |
Fab portion of antibody - recognizes antigen
Fc portion - recognizes immune system effector cell IgG1 |
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How does Complement-dependent cytotoxicity work?
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Antibody-Antigen binding initiates the complement cascade. Chemotactic factors are released from effector cells that result in the formation of a membrane attack complex and the creation of large pores in the cell.
This is thought to have minimal effect in terms of biological targeted therapy. |
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Describe how Delivery of Payload works.
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In this scenario, antibodies aren't expected to elicit any biological effect other than to "carry" (be conjugated to) a radioactive or therapeutic molecule. The conjugated molecule then carries out therapeutic action.
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Any type of tumor component can be a target for Mab therapy! The Mab is injected. It can bind to the surface of endothelial cells, secreted proteins, circulatory cells (blood cells), epithelial cells and tumor stroma inside the tumor parenchyma.
Which are these are currently clinically available? |
Mab's that bind to secreted proteins, circulatory cells and epithelial cells
However endothelial and stroma cell therapy is showing good efficacy in clinical trials. |
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One of the major advantages of Mab's are that they have less cytotoxicity than chemotherapy. What are some of the drawbacks? (3)
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Hypersensitivity reaction (minimized by human antibody)
Limited route of injection -- IV Long half life |
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Name the two types of small molecular inhibitor.
These are much smaller than Mab's and therefore can enter and target many parts of a cell. |
Tyrosine Kinase Inhibitors - small molecules bind to the ATP binding pocket at the activation loop of target kinases inhibiting their kinase activity (ATP Mimetics)
26S Proteosome Inhibitor - Inhibition of 26S Proteosome activity. |
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So the size of small molecular inhibitors vs Mab's is a big difference, as well as the site of action. Where do Mab's work in comparison to small molecular inhibitors?
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Mab's - surface antigens, secreted proteins
Small Molecular inhibitors work intracellularly at a number of potential sites. |
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What are the mechanism's of action of both Mab's and Small Molecular Inhibitors?
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Mab's - ADCC, CDC, Signaling Blockade
Small Molecular Inhibitors - Inhibition of ATP binding Inhibition of proteosome activity |
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What are the differences between Mab's and SMIs in terms of route of administration and access to the BBB?
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Mab's are limited to IV Injection and cannot cross the BBB
SMI's can be given IV or PO and may or may not be able to cross the BBB. |
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What is the difference in half life and dose rate?
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Mab's have a half life of weeks and are administered once/week
SMI's have a half life of days and are administered once/day |
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What is the difference in specificity and cross reactivity?
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Mab's are more specific and less cross reactive
Mab's also have had a greater success rate in terms of FDA approval |
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What type of agent is Bortezomib?
How does it work? |
A Small Molecular Inhibitor
Inhibits the 26S Proteosome leading to inhibtion of degradation of ubiquitinated tumor suppressor proteins and activates the NFkB pathway Proteosome function is crucial to the degradation of ubiquitinated proteins and without this function cell death occurs quickly. |
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What is Bortezomib indicated for?
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Advanced Multiple Myeloma and Relapsed Mantle cell Myeloma
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What are the side effects of Bortezomib?
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Thrombocytopenia, Neutropenia, Anemia
It is highly metabolized in the liver and has a half life of 50-100 hours. |
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Describe the significance of NFkB in Bortezimab.
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Bortezimab inhibits the degradation of IkB, which keeps the NFkB pathway activated. When the NFkB pathway is activated, there is a decrease in the number of anti-apoptotic factors released. This is bad for a cancer cell.
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