MEDCHEM 562. Second Midterm. November 9, 2012

Transcription

1 Name MEDCHEM 562 Second Midterm November 9, 2012 Instructions: Exam packet totals 5 pages (counting this cover page). If you need additional space go to the back of that page and make a note that you did so. Write legibly and in complete sentences when indicated. Read the questions carefully and answer the questions you know first. 1

2 1. (20 points) Anthracyclines are very important anti-cancer agents. Name two anthracyclines: Name two types of cancer treated with anthracyclines. What are the two mechanisms of anti-cancer activity for anthracyclines? Name an extremely important toxicity of anthracyclines that is caused by one of these mechanisms. This important toxicity is caused by the formation of something reactive. What is this? What protective agent can be used to reduce this important toxicity? 2. (16 points) Cabazitaxel (Jevtana) is a new taxane that was approved in For what cancer indication was Cabazitaxel approved? What is the mechanism of action of all taxanes? (One sentence is sufficient.) Cabazitaxel and paclitaxel are mainly metabolized by which P450 enzyme(s)? (Hint: the enzymes are different.) If Cabazitaxel was formulated as Nab-cabazitaxel, briefly explain what the difference is and why might formulation be advantageous? (2-3 sentences are sufficient) Taxanes are most often administered every three weeks (q3w). Briefly explain why the dosing is typically q3w. (2 sentences are sufficient) 2

3 3. (14 points) The tyrosine kinase (TK) inhibitors are an important class of anti-cancer drugs and new TK agents are being approved every year. All TK inhibitors have the same mechanism of action. What is this mechanism? (One sentence is sufficient.) Are these agents cytostatic or cytotoxic? One group of TK inhibitors specifically targets the TK activity of EGFR-1. What type of cancer is targeted by these agents? Mutations in EGFR-1 tend to be activating and they are most common in female, Asian, nonsmokers. True or false? Many (most) TK inhibitors have a specific toxicity involving the heart. What is the mechanism or reason for this toxicity? Can this toxicity be fatal? Yes or No? Briefly describe how a strong P450 inhibitor could increase the heart toxicity of a TK agent (Two sentences are sufficient.) 4. (10 points) There are only two FDA approved topoisomerase I (Topo I) inhibitors for treating two types of cancer. Name these two agents: The metabolite of one of these agents is subject to polymorphic metabolism (PM) which can slow clearance of the agent. Name the parent drug, the metabolite and the enzyme involved in this PM. Is the parent drug a prodrug? Yes or no? This PM differs among the human races (African American, Asian, Caucasian). For which race is this PM issue the least? A serious toxicity (sepsis) can result from the combination of two specific side effects caused by the metabolite of this agent. These side effects can be impacted by the PM of this agent. Name these two side effects: 3

4 5. (10 points) Tamoxifen (Nolvadex) and Exemestane (Aromasin) are two hormonal agents that are approved for one type of cancer. For what type of cancer are these two agents approved? The mechanism(s) of action for the agents are related, but they differ in important ways. Briefly describe (1-2 sentences each) the general mechanism of action for: Tamoxifen: Exemestane: Tamoxifen is metabolized to an active metabolite. What is the name of this metabolite? What P450 enzymes are responsible for generating this metabolite? 6. (10 points) This antibody binds to an endogenous ligand of a receptor rather than the receptor itself. The antibody interferes with angiogenesis. What is the name of this antibody? What is the name of the ligand to which it binds? This antibody is used for the treatment of metastatic colorectal cancer (mcrc) commonly with either of two combination chemotherapy regimens. Name these two chemotherapy regimens: Name an important side effect of this antibody: 4

5 7. (8 points) A hypothetical new antibody called newmumab is being developed by a pharmaceutical company and it targets EGFR-2 (HER2). Also, like several new antibodies, this agent is conjugated to a cytotoxic drug. Is this antibody a mouse antibody, a chimeric antibody, or a humanized antibody? What type of cancer would this agent most likely target? Briefly explain why this agent might be more effective than the antibody itself. (1-2 sentences are sufficient). Unfortunately and surprisingly, this agent also causes severe depletion of B-cells. What serious side effect might be expected from this new agent? 8. (4 pts) These supportive agents are useful in a specific type of cytopenia, but they actually have been found to decrease lifespan and increase cancer recurrence. What specific kind of cytopenia are these agents used for? What is the name of one of these agents? 9. (4 pts) There are two approved vaccine agents for the prevention of cervical cancer. Provide the name one of these agents and the viruses it targets: 10. (4 points) This biological process in important in cancer therapy because it can cause a hormone dependent cancer to become hormone-independent. Furthermore, this process can allow a low-frequency mutation to become more important (common) in cancer cells. What is this process called? 5