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ESA 5 - Pharmacology > Cancer Chemotherapy > Flashcards

Cancer Chemotherapy Flashcards

1
Q

How have new cancer drugs been discovered?

A
  • Random chance
  • Screening of compounds
  • Chemical engineering
  • Molecular targetting
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2
Q

Give an example of chemotherapy drug that was found by chance

A

Cisplatin

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3
Q

How was cisplatin discovered?

A

When conducted microbiological experiments in which electric currents were passed through E Coli, it was found that platinum electrodes stopped E Coli growth

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4
Q

Give an example of a chemotherapy drug that was found through screening of compounds

A

Trabectedin

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5
Q

How was trabectedin discovered?

A

The National Cancer Institute carried out screening of plant and marine organism material for anti-cancer activity, and found that the extract of a sea squirt had promising activity. It was then found that trabectedin was the active moiety

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6
Q

Give an example of a chemotherapy drug that was discovered using chemical engineering

A

Taxotere

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7
Q

How was taxotere developed?

A

It was found that paclitaxel could be used as a chemotherapy drug, however it could only be obtained from the Pacific Yew stem bark, meaning it was of limited consequences and very expensive, so taxotere was developed by copying the chemical structure

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8
Q

Give an example of a drug discovered using molecular targeting approaches

A

Imatinib

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9
Q

What is imatinib?

A

A Bcr-Abl tyrosine kinase inhibitor

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10
Q

What are the advantages of molecular targeted drugs?

A

They are tumour selective drugs, and so are more efficacious with fewer side effects

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11
Q

What change in the treatment and prognosis of cancer is being made from development of molecular targetted drugs such as imatinib

A

It is transforming cancer into a chronic disease that can be treated and maintained instead of a fatal disease

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12
Q

Describe the gross structure of DNA

A

It is a double helix of nucleotides

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13
Q

What does a nucleotide consist of?

A
  • Sugar
  • Phosphate
  • Base
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14
Q

What are the categories of bases?

A
  • Purines
  • Pyridimines
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15
Q

What are the purines?

A
  • Adenine
  • Guanine
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16
Q

What are the pyramidines?

A
  • Cytosine
  • Thymine
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17
Q

What factors determine the rate of tumour growth?

A
  • Growth fraction
  • Duration of cell cycle
  • Rate of cell loss
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18
Q

What is the range of number of cells at which cancer is detectable?

A

Between 10^9 and 10^12 (at which point the host dies)

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19
Q

How long does the cell cycle take in cancer cells?

A

Between 9 and 43 hours

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20
Q

How long does mitosis take?

A

<1hr

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21
Q

How long does DNA synthesis take?

A

6-8 hours

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22
Q

How long does G1 phase take?

A

0-30 hours

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23
Q

How long does G2 phase take?

A

2-4 hours

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24
Q

In what stage of the cell cycle can chemotherapy and radiotherapy not work?

A

G0 - the dormant phase

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25
Q

What can be given to combat the fact that chemotherapy and radiotherapy don’t work in G0?

A

Drugs to enhance the number of cells in the cell cycle

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26
Q

Why is chemotherapy given in pulses?

A

Chemotherapy kills both cells of the bone marrow, and tumour cells. Cells of the bone marrow are able to recover quicker and more effectively, and so if you give in pulses, the tumour cells are killed but the bone marrow survives.

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27
Q

Why is it important to get the timing of chemotherapy pulses right?

A
  • Too much delay means tumour cells can regrow
  • Too frequent and you get bone marrow depletion, potentially leading to neutropenic sepsis
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28
Q

Give 5 examples of cancers that are highly sensitive to chemotherapy

A
  • Lymphomas
  • Germ cell tumours
  • Small cell lung cancers
  • Neuroblastoma
  • Wilm’s tumour
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29
Q

Give 5 examples of tumours that are moderately sensitive to chemotherapy

A
  • Breast
  • Colorectal
  • Bladder
  • Ovary
  • Cervix
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30
Q

Give 4 examples of tumours that have low sensitivity to chemotherapy

A
  • Prostate
  • Renal cell tumours
  • Brain tumours
  • Endometrial tumours
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31
Q

What might tumours that have modest and low sensitivity to chemotherapy require?

A

Other treatments with chemotherapy used as an adjunct

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32
Q

What are the classes of cytotoxic agents

A
  • Antimetabolites
  • Alkylating agents
  • Spindle poisons
  • Intercalating agents
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33
Q

What is the mechanism of action of antimetabolites?

A

They inhibit DNA synthesis

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34
Q

What is the mechanism of action of alkylating agents?

A

Disrupt DNA directly

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35
Q

What is the mechanism of action of intercalating agents?

A

Disrupt DNA transcription and DNA duplication

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36
Q

What is the mechanism of action of spindle poisons?

A

They inhibit mitosis

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37
Q

How do alkylating agents disrupt DNA?

A

They bind DNA strands together, so they cannot be separated during DNA replication and so replication is impaired

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38
Q

How do platinum compounds act as cytotoxic drugs?

A

They cause formation of platinated inter- and intrastrand adducts, leading to inhibition synthesis

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39
Q

How do DACH platinum adducts compare to platinum adducts?

A

They are bulky, and thought to be more effective in inhibiting DNA synthesis than platinum adduct

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40
Q

What happens if DNA cannot replicate?

A

Causes a single strand break, then a double strand break, causing apoptotic death

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41
Q

What is the problem with the DNA disruption of tumour killing?

A

It doesn’t always work, because the cell has repair mechanisms that fix DNA

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42
Q

Give two examples of antimetabolite chemotherapy drugs

A
  • 5-fluorouracil
  • Methotrexate
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43
Q

How does 5-flurouracil work?

A

It interferes with thymidylate synthase, which is a crucial enzyme for incorporating pyramidine and therefore essential for DNA synthesis

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44
Q

How does methotrexate work?

A

It inhibits dehydrofolate reductase, stopping the synthesis of purines

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45
Q

How are spindles involved in mitosis?

A

Once chromosomes are aligned at metaphase plates, spindle microtubules depolymerise, moving sister chromatids towards opposite poles

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46
Q

How do microtubule-binding agents affect microtubule dynamics?

A
  • Inhibit polymerisation
  • Stimulate polymerisation and prevent depolymerisation
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47
Q

Give an example of a class of drugs that promote spindle assembly and prevent disassembly

A

Taxoids

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48
Q

Give a class of drugs that prevent spindle formation

A

Vinca alkaloids

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49
Q

Where do chemotherapy drugs have to get to in order to have an effect?

A

The nucleus

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50
Q

What are the mechanisms of chemotherapy resistance?

A
  • Decreased entry, or increased exit of agent
  • Inactivation of agent in cell
  • Enhanced repair of DNA lesions produced by alkylations
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51
Q

How might there be increased exit of chemotherapy agents?

A

Cell might express pumps to remove the drug

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52
Q

How might there be inactivation of the chemotherapy agent in the cell?

A

Proteins might bind with the agent to nullify its action

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53
Q

What are the indications for chemotherapy?

A
  • -Cancer
  • Rheumatoid arthritis
  • Other conditions
54
Q

What is predicted response in the same cancer dependant on?

A
  • Performance score
  • Clinical stage
  • Prognostic factors or score
  • Molecular or cytogenetic markers
55
Q

What is the range of performance scores?

A

1 - 5, with 1 being fine and 5 being dead

56
Q

At what performance scores will chemotherapy be given?

A

1-2, maybe 3 if have very sensitive tumour

57
Q

What needs to be considered when prescribing chemotherapy?

A

Side effects vs anticipated best outcome

58
Q

When are less side effects acceptable?

A

In palliative care

59
Q

When are more side effects acceptable?

A

In paediatric leukaemia, which has 95% cure rate

60
Q

What will the chemotherapy regimen consist of for many types of cancer?

A

A number of different drugs

61
Q

What are the different routes of administration for chemotherapy?

A
  • IV
  • PO (oral)
  • SC (subcutaneous)
  • Into a body cavity -
  • ntralesional
  • Intrathecal
  • Topical
  • IM
62
Q

What is the most common route of administration for chemotherapy?

A

IV

63
Q

How can chemotherapy be delivered IV?

A
  • Bolus
  • Infusional bag
  • Continuous pump infusion
64
Q

What is the advantage of PO administration of chemotherapy?

A

Convenient

65
Q

What is PO administration of chemotherapy dependant on?

A

Oral bioavailability

66
Q

What is the advantage of SC administration of chemotherapy?

A

Convenient in a community setting

67
Q

Give two examples of body cavities that chemotherapy could be administered into?

A
  • Bladder
  • Pleural effusion
68
Q

What is meant by intralesional administration of chemotherapy?

A

Directly into the cancerous area

69
Q

What should be considered with intralesional administration of chemotherapy?

A

pH

70
Q

What is meant by intrathecal administration of chemotherapy?

A

Into the CSF

71
Q

How is intrathecal administration of chemotherapy conducted?

A
  • Lumbar puncture
  • Omaya reservoir (directly into the ventricles)
72
Q

Give two types of IV pumps

A
  • PICC line
  • Hickman line
73
Q

Where does the Hickman line go into?

A

The subclavian vein

74
Q

Why is the Hickman line tunelled under the skin?

A

To reduce the risk of infection, as there is immune action here

75
Q

What is the advantage of IV pumps?

A

May have IV drug administered over several hours, so allows person to be mobile during this time

76
Q

What are the side effects of chemotherapy?

A
  • Mucositis
  • Alopecia
  • Pulmonary fibrosis
  • Cardiotoxicity
  • Local reaction
  • Renal failure
  • Myelosuppression
  • Phlebitis
  • Neuropathy
  • Myalgia
  • Sterility
  • Cystitis
  • Diarrhoea
  • Nausea/vomiting
77
Q

What chemotherapy adverse effects can occur due to the effect of treatment on the tumour

A
  • Acute renal failure
  • GI perforation at site of tumour
  • Disseminated intravascular coagulopathy
78
Q

How does treatment of the tumour cause acute renal failure?

A

Hyperuricaemia caused by rapid tumour lysis, leading to precipitation of urate crystals in the renal tubules

79
Q

What kind of tumours may cause acute renal failure on treatment?

A

Very sensitive tumours

80
Q

Why shouldn’t acute renal failure due to tumour treatment happen in modern medicine?

A

Because preventative drugs are given first

81
Q

In what cancer is GI perforation at the site of the tumour reported?

A

Lymphoma

82
Q

What is done to reduce the risk of GI perforation due to treatment of tumours?

A

It is recognised as a potenital problem, and the patient is given nil by mouth, so if there is a perforation there is less of a risk of peritonitis

83
Q

When might disseminated intravascular coagulopathy occur?

A

Within a few hours of starting treatment for acute myeloid leukaemia

84
Q

What causes vomiting in chemotherapy?

A

Multifactorial, but includes direct action of chemotherapy drugs on the central chemoreceptor trigger zone

85
Q

What are the different patterns of emesis in chemotherapy?

A
  • Acute phase, 4-12 hours after administration
  • Delayed onset, 2-5 days later
  • Chronic phase, may persist up to 14 days
  • Anticipatory nausea, due to association
86
Q

When does alopecia due to chemotherapy occur?

A

After 2-3 weeks

87
Q

What drugs cause marked alopecia?

A
  • Doxorubicin
  • Vinca alkaloids
  • Cyclophosphamide
88
Q

What drugs minimise alopecia?

A

Platinum

89
Q

What can be done to reduce alopecia caused by chemotherapy?

A

Scalp cooling

90
Q

What happens in scalp cooling?

A

The scalp is cooled to <4 degrees before, during, and after chemotherapy

91
Q

What local skin toxicities might chemotherapy cause?

A
  • Irritation and thrombophlebitis of veins
  • Extravasation
92
Q

How can local skin toxicities be avoided?

A

Administer chemotherapy drug directly into the vein

93
Q

What chemotherapy drug might cause general skin toxicities?

A

Bleomycin

94
Q

What skin toxicities might be caused by bleomycin?

A
  • Hyperketatosis
  • Hyperpigmentation
  • Ulcerated pressure sores
95
Q

What chemotherapy drugs might cause hyperpigmentation?

A
  • Busulphan
  • Doxorubicin
  • Cyclophosphamide
  • Actinomycin D
96
Q

Why might giving chemotherapy as a tablet lead to skin toxicity?

A

May lead to overcompliance as so convenient and doesn’t have constant monitoring, so patient might ignore skin problems

97
Q

What is mucositis?

A

Gastrointestinal tract epithelial damage, which may be profound and involve the whole tract

98
Q

Where is mucositis caused by chemotherapy most commonly worse?

A

In the oropharynx

99
Q

How does mucositis present?

A
  • Sore mouth/throat
  • Diarrhoea
  • GI bleed
100
Q

What can the diarrhoea in mucositis lead to?

A

Dehydration and renal failure, can be life threatening

101
Q

What cardiac problems can result from chemotherapy use?

A
  • Cardio-myopathy
  • Arrythmias
102
Q

What chemotherapy drugs can cause cardio-myopathy?

A
  • Doxorubicin (>550mg/m2)
  • High dose cyclophosphamide
103
Q

What chemotherapy drugs can cause arrythmias?

A
  • Cyclophosphamide
  • Etoposide
104
Q

What chemotherapy drug can cause pulmonary fibrosis?

A

Bleomycin

105
Q

Why must patients who have been treated with bleomycin carry a warning card?

A

Because if they present to A&E with shortness of breath, without this information they will be given oxygen, which worsens fibrosis

106
Q

What is the most frequent dose limiting toxicity in chemotherapy?

A

Haemotological toxicity

107
Q

What does RBC depletion lead to?

A

Anaemia

108
Q

What does white cell depletion lead to?

A

Sepsis

109
Q

What does platelet depletion lead to?

A

Bruising and bleeding

110
Q

Why do cytotoxic chemotherapy drugs need a specialist to prescribe?

A
  • Narrow therapeutic window
  • Significant side effect profile
  • Need for dose alterations
  • Treatment phasing needs to be determined
111
Q

What does the chemotherapy dose need to be altered based on?

A
  • Patients surface area and/or body mass index
  • Drug handling ability
  • General wellbeing
112
Q

What is considered in the drug handling ability of a patient?

A
  • Liver function
  • Renal function
113
Q

What is considered in the general wellbeing of the patient?

A
  • Performance status
  • Comorbidities
114
Q

What does treatment phase need to take into account?

A

The balance between;

  • Growth fraction
  • The ‘cell kill’ of each cycle of the chemotherapy regimen
  • Marrow and GI tract recovery before the next cycle
  • How tolerable the regimen is
115
Q

What is considered in how tolerable a chemotherapy regime is?

A
  • Short term organ toxicity
  • Physical side effects
  • Long term damage causing late effects
116
Q

What causes variability in the pharmacokinetics of chemotherapy?

A
  • Abnormalities in absorption
  • Abnormalities in distribution
  • Abnormalities in elimination
  • Abnormalities in protein binding
117
Q

What can cause abnormalities in absorption?

A
  • Nausea and vomiting
  • Compliance
  • Gut problems
118
Q

What causes abnormalities in distribution?

A
  • Weight loss
  • Reduced body fat
  • Ascites
119
Q

What is the problem with abnormalities in distribution due to ascites?

A

Chemotherapy agents sit in the ascites and don’t get metabolised, which can lead to lots of side effects

120
Q

How can problems with distribution due to ascites be combatted?

A

Draining ascites prior to treatment

121
Q

What causes abnormalities in elimination?

A
  • Liver and renal dysfunction
  • Other medications
122
Q

What can cause abnormalities in protein binding?

A
  • Low albumin
  • Other drugs
123
Q

What drug interacts with vincristine?

A

Itraconazole (a commonly used antifungal)

124
Q

What drug interacts with capecitabine?

A

Warfarin

125
Q

What drugs interact with methotrexate?

A
  • Penicillin
  • NSAIDs
126
Q

What drugs interact with capecitabine?

A

St Johns Wort

127
Q

What monitoring needs to be done during chemotherapy treatment?

A
  • Response of the cancer
  • Drug levels
  • Checks for organ damage
128
Q

How is the response of the cancer to chemotherapy monitored?

A
  • Radiological imaging
  • Tumour marker blood tests
  • Bone marrow/cytogenetics
129
Q

Give an example of drug level monitoring in chemotherapy

A

Methotrexate drug assays taken on serial days to ensure clearance from the blood after folinic acid rescue

130
Q

How is organ damaged checked for in chemotherapy?

A
  • Creatinine clearance
  • Echocardiogram
131
Q

What classes of chemotherapy drugs are beginning to be introduced?

A
  • Hormones
  • Targeted drug therapy
132
Q

Give 7 examples of targeted drug chemotherapies

A
  • Monoclonal antibodies
  • Drugs inhibiting angiogenesis
  • Drugs targeting gene expression
  • Signal transduction inhibitors
  • Drugs interfering with apoptotic pathways
  • Drugs interfering with cell cycle control
  • Cytokines

ESA 5 - Pharmacology (28 decks)

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