Cancer agents - Problem set #3
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1 Cancer agents - Problem set #3 1. Define the term angiogenesis (use complete sentences). In your answer explain whether solid or liquid tumors should be more sensitive to altering angiogenesis. (Two short sentences can answer this question). 2. The agent below is a topoisomerase (topo) inhibitor. Is it a topo I or topo II inhibitor? Explain the different mechanisms of topo I and topo II agents. Name one use of this agent. Is it a prodrug? Name this agent if you can. 1
2 3. Below is a recently approved anti-androgen agent. Name this agent. What type of cancer is it used for? Describe its mechanism of action. Is it a prodrug? It is generally well tolerated, but does have a unique and unusual toxicity. What is this toxicity? Taking the drug with food can make this toxicity worse. Explain how this can happen. 4. Tamoxifen, shown below, is an old but still useful anti-estrogen agent. It can be metabolized to an important metabolite that is active. What is the name of this metabolite? What two CYP enzymes are important to its formation? With arrows, show the two sites of metabolism. 2
3 5. The tyrosine kinase (TK) inhibitor shown below was very recently approved (in 2012) for Ph+ leukemias. This agent lacks an important toxicity common to TK inhibitors. Name this toxicity. Name this agent. This agent is not useful for cancers that have an additional mutation. What is this mutation called? 6. This antibody targets the HER-2/neu (EGFR-2) receptor. Name this antibody. Name an important use of the agent. Do patients need to be HER-2 positive or negative for this drug to work? 7. The vaccine/immunostimulatory agent Provenge (Sipuleucel-T) was recently (on 2010) for prostate cancer. Explain how this drug is prepared and administered to patients. 3
4 Solutions to Problem Set #3: 1. Define the term angiogenesis (use complete sentences). In your answer explain whether solid or liquid tumors should be more sensitive to altering angiogenesis. (Two short sentences can answer this question). Angiogenesis is the formation of new blood vessels (vasculature) in tumors to meet the increasing demand for nutrients and oxygen for the growing tumor mass. This process is more important for solid tumors than liquid tumors because liquid tumors have ready access to nutrients and oxygen in the blood, whereas solid tumors have cells that reside deep within the tumor mass. These cells can be hypoxic and nutrient starved. 2. The agent below is a topoisomerase (topo) inhibitor. Is it a topo I or topo II inhibitor? Explain the different mechanisms of topo I and topo II agents. Name one use of this agent. Is it a prodrug? Name this agent if you can. This agent is a topo I inhibitor. Topo I inhibitors specifically inhibit the topo I enzyme by forming a ternary complex involving the inhibitor, DNA, and the topo I enzyme. Topo II agents inhibit the topo II enzyme by binding to minor grooves in DNA and prevent the action of topo II enzymes. It is not a prodrug. It is useful for small cell lung cancer and ovarian cancer. This agent is called topotecan. 4
5 3. Below is a recently approved anti-androgen agent. Name this agent. What type of cancer is it used for? Describe its mechanism of action. Is it a prodrug? It is generally well tolerated, but does have a unique and unusual toxicity. What is this toxicity? Taking the drug with food can make this toxicity worse. Explain how this can happen. This agent is abiraterone (or abiraterone acetate; or Zytiga). It is used for prostate cancer (or metastatic prostate cancer). It specifically inhibits the enzyme (the C17,20-lyase enzyme) that forms androgens (e.g. testosterone). Yes, it is a prodrug. It can cause hypertension. Intake of food with the drug can cause an increase in the systemic Cmax and AUC of the drug and this can increase hypertension. 4. Tamoxifen, shown below, is an old but still useful anti-estrogen agent. It can be metabolized to an important metabolite that is active. What is the name of this metabolite? What two CYP enzymes are important to its formation? With arrows, show the two sites of metabolism. The name o f the active metabolite is endoxifen. The two important enzymes are CYP2D6 and CYP3A4. 5
6 5. The tyrosine kinase (TK) inhibitor shown below was very recently approved (in 2012) for Ph+ leukemias. This agent lacks an important toxicity common to TK inhibitors. Name this toxicity. Name this agent. This agent is not useful for cancers that have an additional mutation. What is this mutation called? The important toxicity is QT prolongation. The agent is bosutinib (Bosulif). This additional mutation is the T315-I mutation. 6. This antibody targets the HER-2/neu (EGFR-2) receptor. Name this antibody. Name an important use of the agent. Do patients need to be HER-2 positive or negative for this drug to work? The antibody is trastuzumab (Herceptin). It is used in breast cancer. Patients must be HER-2 positive in order to use this drug. 7. The vaccine/immunostimulatory agent Provenge (Sipuleucel-T) was recently approved (in 2010) for a major cancer type. What type of cancer? Explain how this drug is prepared and administered to patients. The major cancer type is prostate cancer, specifically hormone refractory prostate cancer. Other names for this cancer are androgen independent prostate cancer (AIPC), and castrate resistant prostate cancer (CRPC). The drug is prepared by first harvesting a patient s own blood and then isolating specific white blood cells (dendritic cells). These cells are sent to a special facility where the dendritic cells are stimulated by exposure to the prostate antigen, prostatic acid phosphatase (PAP), which is present on almost all prostate cancer cells. Then the cells are then exposed to GM-CSF to stimulate the dendritic cells to maturity. Finally, the cells are shipped back to the patient s clinic and re-infused into the patient. 6
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