THERAPEUTIC APPROACHES TO GASTROINTESTINAL DISEASES AND CANCER. Answer FOUR of the SIX questions. Use a SEPARATE answer book for EACH question.

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1 UIVERSITY F EAST AGLIA School of Pharmacy Main Series UG Examination THERAPEUTIC APPRACHES T GASTRITESTIAL DISEASES AD CACER PHAB6009Y Time allowed: 2 hours Answer FUR of the SIX questions. Use a SEPARATE answer book for EACH question. Each question has the same value. The marks distribution is shown as a percentage for each section of each question. Answer ALL parts of each of the individual questions you select. You are advised to spend an equal amount of time on each question. This paper consists of 6 pages in total. Do not take this question paper out of the examinations room. otes are not permitted in this examination. Do not turn over until you are told to do so by the Invigilator. (PHAB6009Y) Module Contact: Prof Maria Connell, PHA Copyright of the University of East Anglia Version 1

2 2 1. Answer ALL parts to (d). A patient diagnosed with breast cancer is started on a regimen of cyclophosphamide, vincristine and adriamycin (doxorubicin). After a period of remission lasting six months, the cancer returns and treatment with cisplatin and paclitaxel has no effect. Give reasons for the use of the three drugs in the first round of treatment. [10%] For TW of the three drugs from the FIRST round of treatment, describe the class of compound, mechanism of action and side effects associated with each drug. [50%] Briefly explain the main features of the care plan you would put in place for the first round of treatment. [20%] (d) Why was the second round of treatment unsuccessful? Focus on mechanisms associated with the two second line drugs to illustrate your answer. [20%]

3 3 2. Answer ALL parts to (e). Antibodies such as rituximab have been used as a single therapy for the treatment of chronic lymphocytic lymphoma. utline FUR mechanisms by which an antibody can promote cell death. [10%] Antibody-drug conjugates (ADCs) have also been developed for the treatment of cancer. Discuss, with the aid of diagrams, the difference between homogeneous and heterogeneous ADCs and the advantages of using homogeneous ADCs. [15%] Brentuximab vedotin is an ADC that contains a self-immolative spacer. With the aid of mechanistic diagrams, show how degradation of the linker results in the release of monomethyl auristatin E. [25%] H H H H H H H 5 Brentuximab vedotin H 2 S (d) Malnutrition is a common complication in patients with cancer. What are the main causes and consequences of malnutrition in this disease? [15%] (e) Describe the different nutritional options available for the management of cachexia, giving examples of each. [35%] TUR VER

4 4 3. Answer ALL parts to (d). Describe the role of the proteins BRCA1 and BRCA2 in the cell and outline their role in cancer. [20%] laparib is a PARP inhibitor. Describe the mode of action of PARP inhibitors and also the circumstances in which they may be viable as single agents for the treatment of breast cancer. [30%] RG7112 has just completed a Phase I clinical trial for the treatment of leukaemia. It is an inhibitor of the p53/mdm2 interaction. Describe the role of the p53/mdm2 interaction in normal cells and in cancer. [30%] (d) RG7112 is an analogue of the nutlins. Describe the development of the nutlins. [20%] 4. Answer ALL parts to. 62% of adults in the UK are overweight or obese according to the 2014 Health Survey for England. Discuss the main factors that contribute to energy intake and expenditure. [50%] Using chemical structures, describe the mechanism of action of orlistat on pancreatic lipase. Explain the beneficial physiological consequences and the side effects of lipase inhibition. [30%] In the UK, orlistat is only available in consultation with the pharmacist as part of a managed care plan. Discuss the potential benefits and issues of making orlistat freely available TC. [20%]

5 5 5. Answer ALL parts to. A patient who is experiencing epigastric pain after meals requests advice at a community pharmacy. They would like to purchase Zanprol (omeprazole), which a friend has told them will be very effective for their symptoms. Explain the appropriateness of the friend s recommendation with reference to the typical management of dyspepsia in the community pharmacy setting. [50%] Below is the structure of omeprazole and an analogue, which was synthesised during development. S H F F meprazole F F Fluoroprazole Describe how omeprazole works. [30%] Using your knowledge about the mechanism of action and SAR, evaluate whether fluoroprazole would show reduced or better activity compared to omeprazole. Explain your reasoning. [20%] TUR VER

6 6 6. Answer ALL parts to Mrs B, a 48 year old overweight woman, has recently been diagnosed with hypercholesterolemia and would like to include phytosterols in her diet. Describe the mechanism by which phytosterols act in the body and discuss the evidence for their use. [40%] List the main sources of phytosterols in the diet. [10%] She has also found a supplement in your pharmacy that is targeted for those at risk of heart disease. It contains RDA levels of vitamin E, omega 3 fatty acids and B vitamins (folic acid and vitamin B12). Discuss the reasons why these may have been included in this supplement and give your opinion on the evidence for their benefit. [50%] ED F PAPER