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Semester 2 Pharmacology > Cancer Chemotherapy > Flashcards

Cancer Chemotherapy Flashcards

1
Q

What is neoplasia?

A

A new growth- uncontrolled proliferation of abnormal forms of the body’s own cells

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2
Q

What are the 3 characteristics of cancer cells?

A

1) Uncontrolled proliferation
2) Invasiveness
3) Metastasis

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3
Q

What are the 2 causes of cancer?

A

1) Mutations in the DNA causing the cell’s proliferation mechanism to change
2) Changes to the DNA caused by covalent modification:
• Spontaneous or genetic predisposition
• Ionising radiation or UV radiation
• Chemical carcinogens

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4
Q

What are the 3 categories of treatments?

A

1) Surgical excision
2) Radiotherapy
3) Chemotherapy

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5
Q

Why is it hard to treat cancer?

A
  • The body’s own immune response against the cancer cells is poor
  • The body defences are poor
  • The tumour cells are recognised as ‘self’
  • The biochemistry of the tumour cells and the cancer cells are the same so it is hard to get drugs that act on just the cancer itself
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6
Q

What are the 4 traditional types of Chemotherapy agents ?

A

1) Alkylating agents
2) Antimetabolites
3) Cytotoxic antibodies
4) Plant derivatives

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7
Q

Which is the most common chemotherapy agent?

A

Alkylating agents

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8
Q

Broadly speaking, how do alkylating agents work?

A
  • Forms covalent bonds with the DNA
  • Causes the intrastrand cross linking of DNA which causes a conformational change in the DNA helix and the cell either has to fix this or it will die by apoptosis
  • Guanine usually exists as a keto tautomer which can pair with cytosine
  • Alkylation of N7 on the guanine becomes alkylated making it more acidic and it forms a enol tautomer which can pair with thymine
  • This destabilises the imidazole ring which can be opened resulting in deprivation (excision of guanine)
  • This resulting damage triggers cell death by apoptosis
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9
Q

What are the major groups of alkylating agents?

A
  • Nitrogen mustards
  • Alkyl sulphonates
  • Nitrosoureas
  • Platinum based compounds
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10
Q

Give an example of a nitrogen mustard alkylating agent and explain its mechanism of action and what category it is classed in

A

Cyclophosphamide
• Activated in the liver by p450 mixed function oxidases to become Aldophosphamide
• Aldophosphamide is transported to other tissues and then becomes phosphoramide which is cytotoxic and kills cancer cells
• It is a type of alkylating agent

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11
Q

Which drug is used to minimise negative side effects of Cyclophosphamide?

A

Mensa

• Counteracts the effects of acrolein a cytotoxic by product

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12
Q

Give an example of a alkylsulphonate and describe how it works and what it is used to treat and what category it is classed in

A

Busulphan
• Has a selective effect on the bone marrow
• Little to no effect on the GI tract or the lymphatics
• Used to treat chronic granulocytic leukaemia
• It is an alkylating agent

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13
Q

Give two examples of Nitrosoureas and describe how it works and what it is used to treat and What category is it classed in

A

Lomustine, Carmustine
• Lipid soluble so can cross the blood brain barrier
• Treatment of brain and meninges
• It is a type of alkylating agent

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14
Q

Give an example of a Platinum based compound and describe how it works and what category it is classed in

A
  • Cisplatin
  • Platinium atom core surrounded by two Chlorine and 2 ammonia
  • One chlorine dissociates when it enters into the cell, leaving a reactive complex that reacts with water then it interacts with DNA
  • Causes intrastrand cross linking of the DNA chain between N7 and O6 of the adjacent guanine molecules resulting in the local denaturation of the DNA chain
  • It is a type of alkylating agent
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15
Q

What are the 3 major groups of Antimetabolites?

A

1) Antifolates
2) Antipyrimidines
3) Antipurines

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16
Q

Give and example of an antifolate and describe how it works and what cateogory it is classed in

A

Methotrexate
• Folate analogue
• Low lipid solubility- doesn’t cross the blood brain barrier
• Polyglutamated so it is retained within the cells for weeks
• The target is DHFR (which is involved with one carbon metabolism)
• it is an antimetabolite

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17
Q

Give two examples of antipyrimidines and describe how they work and what category they are classed in

A

Fluorouracil (5-Fu)
• Interferes with the enzyme Thymidylate synthesise which converts DUMP to DTMP
• Converted into a fraudulent nucleotide FDUMP which cannot be converted into DTMP

Cytarabine
• Analogue of cytosine which has an arabinose instead of a ribose
• Undergoes phosphorylation to become cytosine arabinose triphosphate
• Inhibits DNA polymerase

They are both a type of antimetabolite

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18
Q

Give three examples of antipurines and describe how two of them work and what category it is classed in

A

Mercaptopurine
• Converted to 6-mercaptopurine-ribose phosphate called lethal synthesis
• Inhibits enzymes involved in the de novo synthesis of purines - fraudulent nucleotide

Fludarabine
• Inhibits DNA polymerase in its triphosphate form

Thioguanine

They are all a type of antimetabolite

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19
Q

What are cytotoxic antibiotics and what are the 4 main categories?

A

Antitumour antibiotics which have a direct action on DNA

1) Anthracyclines
2) Dactomycin
3) Bleomycin
4) Mitomycin

20
Q

What is an example of an Anthracyclines and how does it work? What category is it classed in?

A

Doxorubicin
• Binds to DNA and inhibits both DNA and RNA synthesis
• Has an effect on topoisomerase II which is increased in proliferating cells
• During replication, reversible swivelling needs to take place to prevent tangling
• The topoisomerase II nicks both of the DNA strands and then reseals the breaks
• Doxorubicin intercalates in the DNAand stabilises the DNA topoisomerase II complex, causing the process to seize up

It is a type of cytotoxic antibiotics

21
Q

How does Dactomycin work and what category is it classed in?

A

• Intercalates in the minor groove of DNA between adjacent Guanosine- Cytosine pairs, interfering with the movement of RNA polymerase, preventing transcription

It is a type of cytotoxic antibiotics

22
Q

How does Bleomycin work and what category is it in?

A

• Degrades preformed DNA
• Oxidises the iron and generates superoxide hydroxyl radicals
• Most effective in the g2 phase of the cell cycle but it is also active against non-dividing cells
It is a type of cytotoxic antibiotic

23
Q

How does Mytomycin work and what category is it in?

A

• Acts as a bifunctional alkylating agent, alkylating at o^ of guanine
• Cross links DNA and may also degrade the DNA through the generation of free radicals
It is a type of cytotoxic antibiotic

24
Q

What are the five plant derivatives that are used in Chemotherapy?

A

1) Spindle poisons
2) Vinca alkaloids
3) Taxanes
4) Camptothecins
5) Etoposide

25
Q

How do spindle poisons work?

A

Affect microtubule function and prevent mitotic spindle formation

26
Q

How do Vinca alkaloids work and what are 2 examples?

A

Paclitaxcel (taxol) and Docetaxel

Stablises (freeze) microtubules

27
Q

How do Camptothecins work and what is an example?

A

Irinotecan

Binds to and inhibits topoisomerase I

28
Q

How does Etoposide work?

A

Inhibits mitochondrial function, nucleoside transport and topoisomerase II

29
Q

What are the other treatments for cancer?

A
  • Hormones
  • Monoclonal antibodies
  • Protein kinase inhibitors
  • Miscellaneous agents
30
Q

What are the main drawbacks to chemotherapy?

A
  • Most target cell proliferation, not the more lethal effects of metastasis and invasiveness
  • Non specific cell killers
  • Cancers can develop resistance
  • Leaves some remaining cells (could mean relapse)
  • Some cells have high proliferation rates so are especially effected: bone marrow, hair, GI mucosa and skin
  • Patient compliance may be low due to the side effects - don’t complete full treatment regimen
31
Q

Describe Tumour Lysis Syndrome and how it is managed

A
  • Occurs due to rapid lysis (death) and large amount of metabolites present in the blood
  • Can lead to accute renal failure, cardiac arrest and death
  • Patient is risk assessed before chemotherapy
  • Monitor and respond to deranged urea and electrolytes/fluid balance: dialysis may be required
32
Q

What are the characteristics of Tumour Lysis Syndrome?

A
  • Hyperuricaemia: excess of uric acid in blood
  • Hyperphosphataemia: excess of phosphate in the blood
  • Hyperkalaemia: High potassium level in blood
  • Hypocalcaemia: Low calcium level in the blood
33
Q

What is the effect of chemotherapy on bone marrow?

A
  • Myelosuppression: reduced production of cells which provide immunity, oxygen transport and clotting- common with many chemotherapy agents(except Vincristine and Bleomycin)
  • Only the actively dividing cells are affected i.e. stem cells
  • Monitor full blood count prior to and during treatment cycles
  • Cells with a shorter life span are more affected
34
Q

How can the effect on the bone marrow by chemotherapy be reduced?

A

Occasional use of recombinant granulocyte colony stimulating factors

35
Q

Which chemotherapy drugs do not cause myelosuppression?

A
  • Bleomycin

* vincristine

36
Q

What are the Gastrointestinal effects?

A
  • Nausea and vomiting
  • Loss of appetite
  • Constipation
  • Diarrhoea
37
Q

Which chemotherapy drug is highly emetogenic?

A

Cisplatin

38
Q

Which chemotherapy drug is moderately emetogenic?

A

Doxorubicin

39
Q

Which chemotherapy drug is middle emetogenic?

A

Etoposide

40
Q

How is the side effect of nausea and vomiting managed?

A
  • Pretreatment with low does benzodiazepines (lorazepam)
  • Use of steroids (e.g. dexamethasone)
  • Use of anti-emetics e.g. 5HT3 receptor antagonists
41
Q

What causes the side effect of constipation and how is it managed?

A
  • Due to reduced motility, reduced fluid intake, reduced activity and side effects of concurrent anti-emetics
  • Manage by taking laxatives
42
Q

How is the side effect of Diarrhoea managed?

A
  • Stop oral chemotherapy
  • Give IV fluids if required
  • Consider adding anti-diarrhoeal e.g.loperamide
43
Q

What is mucositis?

A

Ulceration, dry mouth, pain, taste alterations

44
Q

How is mucositis managed?

A
  • Prevention: assess oral cavity regularly
  • Encourage good oral hygiene and regular dental visits
  • Anti bacterials and antivirals
45
Q

What are the other possible side effects commonly seen in chemotherapy (not GI, mucositis, tumour lysis syndrome or effect on bone marrow)

A
  • Fatigue
  • Body image: hair loss, weight loss/gain, appearance of intervention wounds
  • Peripheral neuropathy: consider analgesia for nerve pain
  • Altered renal function: consider drug choice, dose and frequency
  • Delayed effects: infertility, secondary malignancy

Semester 2 Pharmacology (11 decks)

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