pharmacology and physiology

Question 1

what is the difference between benign tumour and malignant tumour?

Answer 1

1- BN: encapsulated and held together in a capsule, easily differentiated, does not grow fast, does not take on phenotype, progress slow and most often harmless.
2- MT: not held in a capsule, grows faster, poorer prognosis and poorer outcomes, metastatic travels via vasculature, take on phenotype, not easily differentiated, adapts and grows in different environment in the body,

Question 2

give examples of benign tumour and malignant tumours:

Answer 2

BN: fibroma
TM: carcinoma 98%: arising from embryonic of endoderm or ectoderm epithelial cells such as colon, lungs, breast.
sarcoma: arising fro, the embryonic of mesoderm in the connective tissues, muscles, bones, fat.
lymphoma: in the lymph nodes and tissues of the immune system, can be solid mass or widespread.
leukaemia: in the white blood cells that grow in bone marrow and circulate around the body in the blood vessels, not solid mass

Question 3

what are the risk factors for cancer?

Answer 3

1- smoking: lung cancers
2- hormones: breast and testicular cancer
3- asbestos: mesotheliomas
4- UV: melanomas
5- infectious agents: viruses “HPV” cervical cancer, bacteria “H.pylori”: gastric ulcers cancer.
6-obesity,
7- chemotherapy
8- radiotherapy
9- pollution
10- genes
11- physical activity
12- diet

Question 4

what are the symptoms of lung cancer?

Answer 4

bleeding cough, chest pain, breathlessness, tiredness, sometimes pnuemonia and abnormalities in heart such as congestive heart failure.

Question 5

what are the symptoms of pancreatic cancer?

Answer 5

weight loss, chest or back pain, developing diabetes in more aggressive cancers.

Question 6

what are the symptoms of breast cancer?

Answer 6

lump or thickened breast, increase in size as the cancer progress, and discharge and bleeding from the breast associated with weight loss.

Question 7

describe how mutations might contribute to the metastatic potential in tumour cells:

Answer 7

mutagenic initiation: chemicals, radiation. increased genome instability, positively selected.
selected mutations: missense: swap a new nucleotide that leads to insertion of different amino acid and changes protein function, nonsense: introducing a STOP codon that results in shortened protein. silent mutation: alteration of target, this might me due a sequence thats been methylated.

chromosomal alteration: deletion, translocation.

epigenetic alteration: methylation, acetylation, histone modification

Question 8

explain the metastatic cascade:

Answer 8

cancer cells hijack vessels around them, they then diffuse to enter the circulation, there are blood-based cells that express selectins, vessel adhesion molecule to reduce interaction with cancer cells, these selectins are expressed by platelet, which recognise the carbohydrate moiety on the surface of cancer cells, forming a protective coat around them, and protect them through their travel from detection and shear force. once they reach their target, they arrest and then start crossing the vessel wall to move again to their next target where a second growth of tumour takes place.

Question 9

mention the problems associated with anti-cancer therapies:

Answer 9

1- lack of selectivity and specificity: anti-cancer drugs are not selective or specific to cancer cells targets, however they also target normal cells
2- off-target side effects
3- drug resistance: cancer cells can develop resistance to the drugs and pump the drug out of the cell.
4- hard to diagnose: because they share similar symptoms to many other diseases, which lead to misdiagnosing and progressing of cancer.
5- patient specific factors: drugs are general however, there are different factors between people that could effect how a drug acts and metabolise in the body, therefore, some patients may take drugs that do not work properly.

Question 10

which receptor is largely associated with tumour growth “angiogenesis”?

Answer 10

VEGF2

Question 11

which receptor is associated with breast cancer?

Answer 11

HER2

Question 12

why do patients who over-express HER2 have poorer outcomes?

Answer 12

because HER2 leads to more invasive phenotype, HER2 stimulates cell cycle, angiogenesis and invasion, also inhibits apoptotic pathways

Question 13

what is the use of Folfox combination?

Answer 13

bowel cancer: folinic acid, fluorouracil, oxaliplatin

Question 14

what is the use of folfiri ?

Answer 14

it is used in colorectal cancers: folinic acid, fluorouracil, irinotecan +/- cetuximab

Question 15

what classes of drugs target S phase?

Answer 15

alkylating-like agents, topoisomerase inhibitors, antimetabolites

Question 16

what class of drugs target M phase?

Answer 16

microtubule poisons.

Question 17

what cancers do alkylating-like agents treat?

Answer 17

breast, brain, cervix, bladder, testis, lung, ovary, endometrium, multiple myeloma etc..

Question 18

what are the adverse side effects of alkylating-like agents e.g. cisplatin?

Answer 18

nephrotoxicity: because renal excretion is the primarily way for cisplatin to be removed from the body, and the kidney can accumulate large amount of it than other organs, and this result is due to the uptake of proximal tubule cells of nephron
hepatotoxicity: caused by oxidative stress, as cisplatin increases the levels of cytochrome P450 that is associated with liver injury. treated with high doses of selenium and Vitamin E.
gastrointestinal toxicities: increased nausea ad vomiting, and it gets worse when combined with antineoplastic agents.

Question 19

what are the antimetabolite agents?

Answer 19

methotrexate, 5-fluorouracil

Question 20

what cancers are treated with antimetabolite agents?

Answer 20

lymphoma, leukaemia, breast, head and neck, oesophagus, lung and bladder.

Question 21

what are the side effects associated with antimetabolites?

Answer 21

1- nephrotoxicity: cytotoxic to the cells of nephron, methotrexate and its metabolites cause crystal nephropathy by precipitating in renal tubules.
2- hepatotoxicity: causes fibrosis and cirrhosis, more common in the long term use of methotrexate.
3- pulmonary: less common, but present dry cough, chest pain, fever.
4- mucositis: require use of opioids-causes a delay in the treatment due to increased risk of infection. result from damaging of mucosal barrier.
5- neurotoxicity: chronic demyelinating encephalopathy “ADEM” with dementia, motor paralysis. seizure, stroke-like symptoms.

Question 22

what cancers are treated with topoisomerase I inhibitors? and give an example of the inhibitors

Answer 22

1- topotecan, treats small cell lung cancers, metastasis ovarian cancer, cervical carcinoma.

Question 23

what cancers are treated with topoisomerase II inhibitors? give an example of the inhibitor

Answer 23

1- doxorubicin, leukaemia, lymphoma, breast, head and neck, lung, ovarian, oesophagus, bladder, gastric cancers.

Question 24

what are the side effects associated with topoisomerase inhibitors?

Answer 24

topoisomerase I inhibitor: myelosupression, nausea, vomiting anaemia.
topoisomerase II inhibitor: cardiotoxicity: dilative cardiomyopathy and congestive heart failure CHF, suggested to be due to the disruption of sarcomere structure, with mayofilament disorganisation within cardiomyocyte.
and genotoxic stress, mitochondrial dysfunction and oxidation of cellular components lead to activation of protein degradation and suppression of sarcomeric synthesis.

Question 25

anti-neoplastic examples and describe its mechanism of action

Answer 25

vincristine, it binds to the tubulin structure and prevents polymerisation into microtubules, it stops cell mitosis.

Question 26

what cancers are treated with anti-neoplastic?

Answer 26

acute lymphoblastic leukaemia in children especially when combined with prednisone. as well as haematologic malignancies including hodgkin’s lymphomas and multiple myeloma.

Question 27

what side effects associated with anti-neoplastic agents?

Answer 27

1- cardiovascular: orthostatic hypotension (due to neurotoxicity, autonomic dysfunction)
2- peripheral neuropathy: parasthesias, neuropathic pain, motor nerve damage in the long term use.
3- gastrointestinal: constipation, abdominal cramps, nausea and vomiting.

Question 28

what is bevacizumab?

Answer 28

monoclonal antibody that bind to VEGF and prevents it from binding to VEGFR2.

Question 29

what is sorafinib?

Answer 29

small molecules that enters the cytoplasm of the cell, binds to the internal domains of VEGFR2 “ATP binding pocket”, and prevent phosphorylation.

Question 30

what are the pathways used to inhibit VEGFR?

Answer 30

1- binding to the VEGF and preventing it from binding to the receptor e.g. bevacizumab, VEGF-trap
2- binding to the internal domains of VEGFR2 and prevent phosphorylation. sorafinib, sunitinib
3- binds directly to the VEGFR2 receptor and inhibit its activation. ramucirumab

Question 31

name two monoclonal antibodies inhibitors

Answer 31

bevacizumab, avastin

Question 32

what cancers are treated with bevacuzimab?

Answer 32

it is not used alone and it is used to treat advanced stage cancers e.g. metastatic colorectal, non-small-cell lung and ovarian cancers, recurrent glioblastoma and breast cancer.

Question 33

VEGFR2 inhibitors sorafinib and axinitib

Answer 33

1- used in mutli-targeted RTKi, used in advanced renal cell carcinoma RCC, hepatocellular carcinoma HCC, and thyroid cancer

2- second line for RCC, and not responding to multi-targeted RTKIs, more VEGFR2 selective.

Question 34

what are the consequences of anti-VEGF therapies? and how do they occur?

Answer 34

1- VEGF are responsible for the release of nitric oxide, which plays a role in vasodilation, when VEGF are inhibited, this lead to vasoconstriction, therefore hypertension.
2- arterial thromboembolic events: which is mediated by platelets, VEGF helps maintaining the lining of vessels, when it is inhibited, the lining cells become sticky and likely to adhere, leading to the formation of clots-> increased risk of cardiac or cerebral ischaemic.
3- haemorrhage: especially in lung and GIST tumour.
4- ventricular dysfunction and congestive heart failure: VEGF maintains cardiomyocyte survival, and inhibiting VEGF lead to the death of these cells and therefore heart failure.
5- renal adverse events: when inhibiting VEGF, this will lead to deletion of VEGF in podocytes that is crucial in protecting endothelial lining, therefore, this will lead to leaky, damaged vessels.
6- wound complications

Question 35

what are the advantages of combining bevacizumab to chemotherapy?

Answer 35

1- bevacizumab inhibits VEGFA which act as a protector to the vessels and this helps chemotherapy to penetrate into the tumour
2- it also lead to smaller tumour due to the inhibition of VEGF that plays a role in angiogenesis.
3- addition of anti-VEGF will result in pruning of immature cells, therefore, inhibits metastasis because mature cells are less leaky and permeable.

Question 36

how do tumours become anti-VEGF resistant?

Answer 36

1- by the production of other angiogenic factors e.g. hypoxia can switch on growth factors.
2- bone marrow derived cells, macrophages can rescue tumour vascularisation.
3- vasculogenesis, intussusception, co-option may lead to less sensitive to VEGF blockade.
4- as the vessels mature, they become covered with pericytes, lead to less sensitive to VEGF blockade.

Question 37

give examples of tyrosine kinase receptors

Answer 37

VEGFR: vascular endothelial growth factor receptor.
HER2: human epidermal growth factor receptor 2.

Question 38

what is HER2?

Answer 38

a transmembrane tyrosine kinase receptor that helps promote tumour growth and development.

Question 39

why is over-expressing HER2 lead to more invasive and aggressive tumours?

Answer 39

because when it is activated, this stimulates RAS and PI3 kinase that is followed by downstream signalling : RAS: RAF, MEK, ERK. PI3K: AKT/PKB, mTOR which lead to loss of cell control and apoptosis, induction of growth, angiogenesis and invasion.

Question 40

what is the treatment for HER2 breast cancer?

Answer 40

Herceptin, trastuzumab: an monoclonal antibody that is given to patient who undertook genetic test and showed an over-expressed HER2, it is given in combination with other chemotherapy for better outcomes. however, in the long term use, people showed resistance to the medicine and adverse side effects.

Question 41

what are the limitation and side effects for Herceptin-trastuzumab?

Answer 41

1- pain, gastrointestinal disturbance, pulmonary symptoms, as well as cardiac toxicity, and the risk factors for cardiac toxicity are: hypertension, pre-existing diabetes and congestive heart failure, as well as exposure to other treatments such as anthracycline.

Question 42

what are the side effects associated with tamoxifine?

Answer 42

nausea/vomiting, hot flushes, fatigue, sweating, mood swings, weight gain due to water retention, vaginal bleeding, dryness and changes in menstruation. and long term use may lead to a secondary endometrial cancer.

Question 43

what is CAR-T therapy?

Answer 43

it is an immunotherapy that uses patient’s own immune cells that are reprogrammed to treat their condition, it’s shown a success in terms of haematological cancers e.g. non-hodgkin lymphoma and acute lymphoblastic leukaemia ALL. CAR-T stand for chimeric antigen receptor T.

Question 44

what are the therapeutic agents of CAR-T?

Answer 44

1- cytokines, 2- vaccines, 3- checkpoint inhibitor, 4- adoptive T cells.

Question 45

what are the formulations of CAR-T?

Answer 45

1- hydrogels, 2- nano-carriers, 3- micro-particles, 4- cellular vehicles

Question 46

what are the route of administration for CAR-T?

Answer 46

1- transdermal patch, 2- injection, 3- sprayable gel.

Question 47

explain the mechanism of action of immunotherapy

Answer 47

1- the patient undergoes immunisation for the specific antigen, 2- maximising monoclonal antibody production, 3- injecting it to the patient where the monoclonal antibody bind to cancer cells, 4- the immune system recognises these antibody and initiate an attack, 5- cancer cells death.

Question 48

how to treat cervical cancer caused by HPV virus?

Answer 48

it is been shown that pre-sexual age girls are offered HPV vaccine such as gardasil and cervavix to prevent cervical cancers caused by HPV.

Question 49

what are the side effects associated with gardasil and cervavix vaccines?

Answer 49

headache, sore muscle, nausea and vomiting, diarrhoea, pain, slightly raised temperature, stomach pain, itching and skin rash

Question 50

what are the limitations for gardasil and cervavix?

Answer 50

1- it does not prevent incidence of cervical cancer in women who are already infected with HPV
2- it does not inhibit all types of HPV
3- the duration of immunity is not known
4- need for longer-term community surveillance.