Targets Drugs for Cancer Flashcards
What are some types of monoclonal antibodies used in cancer treatment?
1) Naked monoclonal antibodies
2) Conjugated monoclonal antibodies
3) Bispecific antibodies
What is the basis of naked monoclonal antibodies?
Most attach to cancer cell antigens to block proliferation, others work by boosting the patient’s immune response against the cancer
What is the basis of conjugated monoclonal antibodies?
antibodies conjugated to another compound to deliver it to a tumor for cytotoxic effect usually
What is Rituximab used to treat?
CLL, NHL
How does Rituximab work?
The binding of naked antibody drugs to the target cell can elicit one of a number of effects leading to the death of the cell. Overall clinical activity is derived from a combination of the following mechanisms.
“1) CD20 has an associated intracellular signal transduction mechanism following external receptor stimulation. It has been found that binding of Rituximab to CD20 induces the B lymphocyte to enter the apoptotic pathway.
2) Rituximab is an IgG class antibody that has an Fc portion. After binding to CD20 on B lymphocytes, the Fc portion is able to be bound by complement C1 protein. Binding of C1 activates the classical complement cascade which leads to the formation of the membrane attack complex and cell lysis.”
“3. After binding of Rituximab to CD20 on B lymphocytes, complement C1 protein binds to the Fc portion and activates the classical complement cascade. The classical complement cascade generates complement C3b proteins from soluble complement C3 proteins. C3b covalently attaches to the surface of cells and opsonises them. C3b opsonised cells are detectable by complement receptors on phagocytes such as neutrophils, dendritic cells and macrophages.
- Binding of Rituximab to CD20 on B lymphocyte opsonises them with IgG. The Fc portion of the IgG is detectable by Fc receptors on phagocytes. Recognition of IgG opsonised cells by phagocytes induces phagocytosis and destruction of the cell.
- Binding of Rituximab to CD20 on B lymphocytes can also initiate ADCC since it is an IgG antibody.
What is Trastuzumab used to treat?
Breast Cancer
How does Trastuzumab work? Side-effect?
With trastuzumab, binding leads to immediate inhibition of a stimulatory signal and, in consequence, the HER-2 receptor is downregulated, p27 accumulates, and cell cycle arrest occurs.
big unintended side effect is cardiotoxicity
A monoclonal drug called Pertuzumab also to treat breast cancer. How does it work?
In the case of HER2 signaling, a functional and physical association with a second related receptor, HER-3, is often important. HER-2 kinase phosphorylates
the HER-3 cytoplasmic domain, activating it as a scaffold to promote the PI3-kinase cascade. Pertuzumab’s likely mechanism of action is to block heterodimerization of HER-2 and HER-3.
Which anticancer drugs bind and block the EGFR pathway?
Cetuximab and Panitumumab
Cetuximab and Panitumumab are used primarily to treat what?
colorectal cancer
Adverse effects with Cetuximab and Panitumumab?
skin rash with sun
Which monoclonal drugs works by binding to free VEGF and preventing its association with its cell surface receptor, thus blocking angiogenesis in tumors?
Bevacizumab (used to treat colon cancer)
How are Mabs given?
IV, SC, or IM only. Size limitations require multiple injections
they tend distribute via lymphatics
Why are Mabs mostly IgGs?
because this offers the best characteristics in terms of duration or persistence in the body following administration.
How are Mabs eliminated?
Rather than being modified structurally to yield water soluble and thus more readily eliminated metabolites (like small molecule drugs), Mabs are degraded in lysosomal or cytosolic processes.
these are often conjugated to polyethylglycol to prevent GF and renal excretion
Are drug-drug interactions with Mabs common?
Drug-drug interactions, at least in the conventional sense, have not been reported. However, indirect effects may impact CYPs