Answer ALL questions. For each question, there is ONE correct answer. Use the answer grid provided for ALL your answers.

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1 UNIVERSITY OF EAST ANGLIA School of Pharmacy Main Series UG Examination CLINICAL THERAPEUTICS 8: ONCOLOGY PHA-MHCY Time allowed: 2 hours Part ONE Answer ALL questions. For each question, there is ONE correct answer. Use the answer grid provided for ALL your answers. Part TWO Answer TWO of the THREE questions. Use a SEPARATE answer book for EACH question in Part TWO. All questions have equal weighting. Answer ALL parts of each of the individual questions you select. The mark allocation for the paper is: Part ONE carries 50% of the total mark. Part TWO carries 50% of the total mark. This paper consists of 11 pages in total. The following is provided: Multiple choice answer grid. Dictionaries are not permitted in this examination. Notes are not permitted in this examination. Do not turn over until you are told to do so by the Invigilator. Do not take this question paper out of the examinations room. (PHA-MHCY) Module Contact: Prof Mark Searcey, PHA Copyright of the University of East Anglia Version 2

2 2 PART ONE SECTION A TYPE 1 MCQ Answer ALL questions. For each question there is ONE correct answer. Use the answer grid provided for ALL your answers. 1. According to Hanahan and Weinberg s seminal paper in 2000 entitled Hallmarks of Cancer, which ONE of the following was NOT listed as a hallmark of cancer cells at that time? Resisting cell death Enabling replicative immortality Activating invasion and metastasis Deregulating cellular energetics Inducing angiogenesis 2. According to Cancer Research UK statistics for 2010, which ONE of the following cancers is NOT in the top 10 most common causes of death in patients? Melanoma Bowel Lung Pancreatic Oesophageal 3. Which ONE of the following proteins is a GTPase commonly associated with activating mutations in cancer? MEK ERK EGF receptor Ras Raf 4. Which ONE of the following statements is CORRECT with regard to tumour suppressor genes? They are genes that are naturally cancerous They are genes whose activation leads to cancer They are genes that can only be mutated They are genes whose mutation only leads to activation They are genes that if inhibited can lead to cancer

3 3 5. Which ONE of the following cellular processes is NOT directly mediated by p53 signalling? Cell cycle arrest DNA repair Apoptosis Regulation of cellular energetics Blocking of immune cell destruction 6. In cancer biology the term TAM is an acronym of which ONE of the following? Tumour associated : Macrophage Monocyte Mast cell Mature B cell None of the above are correct 7. Which ONE of the following proteins would p53 increase the expression of? Cyclins Cyclin-dependent kinases Cyclin-dependent kinase inhibitors Growth factor receptors Actin 8. Which ONE of the following statements is FALSE? Classical antitumour agents target dividing cells Molecular therapeutics are aimed at individual cellular pathways The side effects associated with molecular therapeutics are due to indiscriminate targeting of dividing cells Testicular cancer is very responsive to chemotherapy A solid tumour contains a central core of necrotic cells 9. Which ONE of the following statements is FALSE? Doxorubicin is a substrate for the efflux pump P-glycoprotein Alkylating agent resistance can stem from enhanced DNA repair Mechlorethamine is a substrate for the efflux pump P-glycoprotein Alkylating agent resistance can stem from increased glutathione levels Topoisomerase inhibitors are generally substrates for the efflux pump P- glycoprotein TURN OVER

4 4 10. With regard to the alkylating agents, which of the following statements is TRUE? Nitrogen mustards methylate the N7 of guanine Mechlorethamine is no longer used in the clinic due to its high toxicity Alkylating agents tend to exert their effects through the formation of intrastrand crosslinks on duplex DNA Aniline mustards are less reactive than mechlorethamine due to the overlap between the nitrogen lone pair and the aromatic ring Melphalan is an analogue of the amino acid phenylalanine 11. Which ONE of the following statements is FALSE? Intercalation increases the length of DNA Insertion of a chromophore between the bases of DNA always leads to an active antitumour agent Doxorubicin intercalates and sites its sugar sidechain in the minor groove of DNA Mitoxantrone is a synthetic topoisomerase II inhibitor Cardiotoxicity is a side effect of doxorubicin treatment 12. Which ONE of the following statements is FALSE? 6-Mercaptopurine inhibits purine synthesis Capecitibine is an inhibitor of thymidylate synthase Toxicity to purine antimetabolites includes bone marrow toxicity, nausea and vomiting Thymidine protects against 5-FU activity in tumour cells Resistance to methotrexate can be via gene amplification of the DHFR gene 13. Which ONE of the following statements is FALSE? Microtubules are involved in mitosis The assembly and disassembly of microtubules around the centrosome is a dynamic process Vinca alkaloids such as vincristine inhibit the formation of microtubules by binding to αβ-tubulin dimers The main resistance mechanism for the Vinca alkaloids is overexpression of glutathione-s-transferase Paclitaxel and docetaxel exert their effects by stabilising microtubules

5 5 14. Which ONE of the following statements is FALSE? Cisplatin binds to the N7 of guanine in the major groove of DNA In cells, low levels of chloride ions mean that the chloride ligands in cisplatin are displaced by water Cisplatin forms interstrand crosslinks as the main lethal event On treatment with cisplatin, the patient must be constantly hydrated in order to avoid kidney toxicity Cisplatin is used in the treatment of various cancers and is particularly effective in testicular cancer 15. Which ONE of the following statements is FALSE? Herceptin, used in the treatment of breast cancer, is an example of a molecular therapeutic drug Imatinib mesylate is only used in the treatment of chronic myelogenous leukaemia (CML) Imatinib targets the BCR-Abl kinase in CML The development of imatinib began with a library screen that identified 2- phenylaminopyrimidines as a class of kinase inhibitor Toxicities to imatinib are mild and include fluid retention, muscle cramps and diarrhoea TURN OVER

6 6 SECTION B TYPE 2 MCQ Answer ALL questions. For each question there is ONE correct answer. Use the answer grid provided for ALL your answers. Decide which of the responses to the following questions is/are correct, then choose: If (i), (ii) and (iii) are correct If (i) and (ii) only are correct If (ii) and (iii) only are correct If (i) only is correct If (iii) only is correct 16. Mrs ST is a 67 year old lady who is attending for her first cycle of chemotherapy as she has recently been diagnosed with breast cancer. She is being started on flurouracil, epirubicin and cyclophosphamide chemotherapy. Which of the following would be appropriate counselling points to cover with Mrs ST? (i) Epirubicin can discolour the urine red, though this is harmless (ii) Avoid contact with animal faeces e.g. cat litter trays (iii) Can cause drowsiness, if this happens avoid driving or using tools 17. Mr SP is a 70 year old man who has been diagnosed with colorectal cancer and started on oxaliptan and capecitabine chemotherapy. After the first cycle of chemotherapy he presents with sore red hands and feet with peeling skin. Which of the following would be appropriate course of action? (i) Advise Mr SP to have a hot bath each evening (ii) Advise Mr SP to regularly apply lanolin containing moisturisers (iii) Advise Mr SP to avoid tight fitting shoes 18. Which of the following statements are true, regarding classical chemotherapy? (i) (ii) Cytotoxic agents target dividing cells Molecular therapeutics target specific pathways to widen the therapeutic window (iii) Side effects of classical chemotherapy are largely associated with normal proliferating cells

7 Decide which of the responses to the following questions is/are correct, then choose: If (i), (ii) and (iii) are correct If (i) and (ii) only are correct If (ii) and (iii) only are correct If (i)

7 7 Decide which of the responses to the following questions is/are correct, then choose: If (i), (ii) and (iii) are correct If (i) and (ii) only are correct If (ii) and (iii) only are correct If (i) only is correct If (iii) only is correct 19. The molecule shown below is cisplatin. (i) Cisplatin intercalates into duplex DNA and inhibits topoisomerase II (ii) Cisplatin is useful in the treatment of testicular cancer (iii) Cisplatin was discovered when it was shown to inhibit the proliferation of bacteria in an electrochemical cell 20. The molecule shown below is imatinib. (i) Imatinib targets the Bcr-Abl kinase from the Philadelphia chromosone translocation (ii) Imatinib is totally selective for its target protein and has no effects on other kinases (iii) It was withdrawn from clinical use due to extensive side effects associated with off-target effects. TURN OVER

8 8 SECTION C TYPE 3 MCQ Answer ALL questions. For each question there is ONE correct answer. Use the answer grid provided for ALL your answers. The questions consist of a statement in the left-hand column followed by a second statement in the right-hand column. Decide whether the first statement is TRUE or FALSE. Decide whether the second statement is TRUE or FALSE. Then choose: A B C D E If both statements are TRUE and the second statement is a correct explanation of the first statement. If both statements are TRUE but the second statement is NOT a correct explanation of the first statement. If the first statement is TRUE but the second statement is FALSE. If the first statement is FALSE but the second statement is TRUE. If both statements are FALSE. Directions Summarised A B C D E First Statement Second Statement 2 nd statement is a correct explanation of the first. 2 nd statement is NOT a correct explanation of the first. 21. FIRST STATEMENT SECOND STATEMENT Granulocyte colony stimulating factor (GCSF) is indicated in neutropenic sepsis. 22. FIRST STATEMENT Melphalan is a nitrogen mustard used in the clinic as part of the treatment for multiple myeloma. GCSF stimulates the production of neutrophils. SECOND STATEMENT Melphalan exerts its effects through forming intrastrand crosslinks on DNA.

9 9 Directions Summarised A B C D E First Statement Second Statement 2 nd statement is a correct explanation of the first. 2 nd statement is NOT a correct explanation of the first. 23. FIRST STATEMENT SECOND STATEMENT p53 is mutated in around 50% of all tumours. 24. FIRST STATEMENT Methotrexate was originally developed for the treatment of children with acute lymphoblastic leukaemia (ALL). 25. FIRST STATEMENT Most chemotherapeutic regimens involve 2-4 drugs given in combination. p53 is an oncogene that undergoes transformation to a form that promotes the proliferation of cells. SECOND STATEMENT Methotrexate is an anti-folate drug. SECOND STATEMENT Combination therapy is given in order to maximise the benefits of aseptic preparation of cytotoxics together prior to administration. END OF PART ONE TURN OVER

10 10 PART TWO Answer TWO of the THREE questions. Use a SEPARATE answer book for EACH question. 26. Answer ALL parts (a) to (e). Patient A is a 42 year old woman with a family history of breast cancer based upon the BRCA1 mutation. She has a 17 year old daughter. After a diagnosis of cancer, she undergoes a mastectomy, targeted radiotherapy and begins on adjuvant chemotherapy of epirubicin (an analogue of doxorubicin), cyclophosphamide and 5-fluorouracil. (a) Why does the chemotherapy regimen include three drugs? [10%] (b) For two of these drugs, give a detailed description of their mode of action. [30%] (c) Give a detailed mechanistic account of the contribution of a BRCA1 mutation on the development of a breast tumour. [30%] (d) What advice would you give to the daughter of Patient A. [10%] (e) Briefly describe some of the main considerations of patient A s pharmaceutical care in relation to her chemotherapy. [20%] 27. Give a detailed explanation of the two categories of genes and proteins known as oncogenes and tumour suppressor genes, using examples of both categories of genes, including their mechanism of action and their potential as drug targets. [100%]

11 Answer ALL parts (a) to (c). Patient B undergoes surgery, radiotherapy and chemotherapy (including cisplatin and paclitaxel) for ovarian cancer and is in remission when the tumour returns with metastases to several distant sites. A new course of chemotherapy, involving liposomal doxorubicin, topotecan and paclitaxel is ineffective. (a) Describe the structure of a solid tumour, including in your answer the definition of the term growth fraction. Explain the relevance of this term to cancer chemotherapy. [30%] (b) Why was the second course of chemotherapy ineffective? [15%] (c) Briefly explain why liposomal doxorubicin was used as opposed to doxorubicin alone. [15%] (d) Describe the mechanisms by which chemotherapy involving any TWO of the five drugs above may become ineffective. [40%] END OF PAPER

Principles of chemotherapy

Principles of chemotherapy Chemotherapy first coined by Paul Ehrlich Aim to selectively destroy cancer cells whilst relatively sparing tumours cells Growth characteristics of cancer cells allows for selective