Novel Targets in Cancer Therapy and Cancer Therapy Resistance Flashcards
(38 cards)
What are the major side effects of cancer therapies that target rapidly growing cells?
1) Gut lining-mucositis
2) Bone marrow-myelosuppression
3) Hair follicles-alopecia
Define oncogene.
A gene that normally directs cell growth.
- If altered, an oncogene can promote or allow the uncontrolled growth of cancer
What is a tumor suppressor gene?
Tumor suppressor genes are normal genes which are lost or altered and cause malignancy (recessive mutations)
- Tumor suppressor genes cooperate with oncogenes in carcinogenesis.
What is imatinib mesylate (Gleevec)?
[2nd generation drugs nilotinib and dasatinib]
Gleevec is a tyrosine kinase inhibitor of Bcr-Abl fusion protein in CML (chronic myelogenous leukemia)
- Blocks phosphorylation of downstream protein targets.
- Also inhibits platelet-derived growth factor receptor (PDGFR), stem cell factor, and c-kit (in gastrointestinal stromal tumors).
Describe the kinetics of Gleevec/ imatinib mesylate.
Orally well absorbed with hepatic (CYP3A4) metabolism.
What is the major adverse drug reaction of imatinib mesylate?
Cardiac toxicity.
What interactions should be considered in patients taking imatinib mesylate?
Cyp inhibitors CYP3A4
What is Trastuzumab (Herceptin)?
Trastuzumab is an antibody that has single agent activity in advanced estrogen resistant breast cancers
- when combined with chemotherapy enhanced clinical responses are observed.
What is the mechanism of action of trastuzumab?
Trastuzumab recognizes the Her2/neu receptor and blocks it so growth factor cannot bind.
- Her-2/neu receptor is over-expressed in a subset of poor prognosis breast cancers.
Describe the kinetics of trastuzumab.
Median half-life of 5.8 days after a 4mg/kg of body weight loading dosage. (given IV)
What major adverse drug reactions is associated with trastuzumab?
Cardiac toxicity and dyspnea.
What major interaction should be considered in patients on trastuzumab?
Possible allergic reaction
What is the importance of the EGFR pathway in lung cancer?
In lung cancers a subset of patients have an activating mutation of the EGFR which sensitizes them to EGFR inhibitors
- EGFR pathway can be blocked by receptor specific antibodies (e.g. Cetuximab and Panitumumab) or by small molecule tyrosine kinase inhibitors (Erlotinib and Gefitinib)
To what drug class does Erlotinib belong?
Small molecule epidermal growth factor receptor (EGFR) inhibitor.
- Active against lung and pancreatic cancers.
What is the mechanism of action of Eroltinib?
Inhibits kinase activity of this receptor and is active against lung cancers having kinase domain activating mutations.
Describe the kinetics of Eroltinib.
- Well absorbed orally and half-life is about 36 hours.
- Hepatic (Cyp3A4) and biliary metabolism.
What major adverse drug reactions are associated with Eroltinib?
Rash, diarrhea, and dyspnea.
What interactions should be considered in patients on Erlotinib?
Smoking and Cyp3A4 inhibitors
What are the advantages of anti-angiogenic factors?
1) Resistance is infrequent (normal vascular cells are targeted)
2) Activity does not depend on tumor cell targeting
3) Chronic therapy could prevent vascularization of tumors
What is Bevacizumab (Avastin) and what is it used for?
- Bevacizumab recognizes vascular endothelial growth factor (VEGF) and blocks its angiogenic activity.
- Used to treat colon and lung cancers and has shown some use for macular degeneration and retinal diseases
To what class does Bevacizumab (Avastin) belong?
Anti-vascular endothelial growth factor antibody (VEGF, humanized monoclonal).
What is the action of bevacizumab?
Blocks the angiogenic actions of VEGF in colon and lung cancers.
What are the adverse side effects of bevacizumab?
Bleeding, allergic reactions, wound healing, and GI perforation.
What are the major drug interactions with bevacizumab?
Possible allergic reactions
