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Flashcards in Cancer pharmacology Deck (122)
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1
Q

Definition of apoptosis

A

Programmed cell death

2
Q

How is apoptosis and cell proliferation related?

A

Both occur continuously in the body

Billions of new cells are generated daily from proliferation, with equivalent numbers being removed by apoptosis

3
Q

Which processes is cell proliferation involved in?

A

Growth

Repair and healing after injury

Acute and chronic inflammation

Hypertrophy and hyperplasia

4
Q

Which processes is cell apoptosis involved in?

A

Embryogenesis

Development of self-tolerance in the immune system

Regression of mammary gland cells after lactation

Shedding of the intestinal lining

Pathophysiology of autoimmune, neurodegenerative and cardiovascular diseases

5
Q

What triggers the cell cycle?

A

Growth factor interaction

6
Q

What controls the cell cycle?

A

Kinases

7
Q

How do kinases control the cell cycle?

A

Act as transcription factors

Enable the transcription of positive and negative regulators of the cell cycle

8
Q

Example of positive regulators of the cell cycle

A

Cyclins

Cyclin-dependent kinases

9
Q

Examples of negative regulators of the cell cycle

A

p53 proteins

Rb proteins

Cdk inhibitors

10
Q

How do growth factors control the cell cycle?

A

Bind to receptor tyrosine kinases

Stimulate the production of kinases

Kinases then stimulate the production of positive and negative regulators of the cell cycle

11
Q

What is the role of integrins in the control of the cell cycle?

A

Integrins are transmembrane receptors

These bind to components of the extracellular matrix

Cooperate with GFs in the production of cell cycle transducers

12
Q

What, apart from the production of regulators of the cell cycle, can GFs stimulate the release of?

A

Can stimulate the cells to release MMPs

These degrade the local matrix

Make space for increasing cell numbers

13
Q

During which part of the cell cell cycle do growth factors act on?

A

G1 phase

14
Q

What are the 5 phases of the cell cycle?

A

G0

G1

S

G2

Mitosis

15
Q

What is the G0 phase?

A

Resting phase

16
Q

What is the G1 phase?

A

Gap between mitosis and S phase

Cell is preparing for DNA synthesis

17
Q

What is S phase?

A

Phase of DNA synthesis

During which the DNA is duplicated

18
Q

What is the G2 phase?

A

The gap between S phase and mitosis

Cell is duplicating its other constituents

19
Q

What is M?

A

Mitosis

Split into metaphase, anaphase and production of daugher phase

The daughter cells can then re-enter G1 or G0

20
Q

Where does checkpoint 1 target?

A

Between G1 and S

21
Q

Which proteins act on checkpoint 1?

A

The Rb protein acts as a break here, keeping the cell in G1 by inhibiting the genes necessary for entry into S phase

The p53 protein stops the cycle here if there has been DNA damage

22
Q

Where does checkpoint 2 target?

A

Between G2 and Mitosis

23
Q

What is the difference between apoptosis and necrosis?

A

Apoptosis is a programmed sequence of biochemical processes

Necrosis is disorganised disintegration of damaged cells, resulting in products that trigger the inflammatory response

24
Q

What is necessary for a cell to survive?

A

It must constantly be receiving continuous stimulation by survival factors

If this essential signalling by the anti-apoptotic pathway ceases, the cell’s self-destruct machinery is activated

= Death by neglect

25
Q

Pro-survival factors

A

Cytokines

Integrins

Hormones

Adhesion factors

26
Q

What are the two main apoptotic pathways?

A

Death receptor pathway

Mitochondrial pathway

27
Q

What is different about the death receptor pathway?

A

It involves binding of death receptor ligands

So it is a death by design mechanism

Not inhibited by the anti-apoptotic pathway

28
Q

Which apoptotic pathway is inhibited by the anti-apoptotic pathway?

A

The mitochondrial pathway

29
Q

Describe how binding of death receptor ligands triggers apoptosis

A
  1. Death receptor ligands bind to receptors
  2. The receptor dimerises, causing activation of adapter proteins
  3. Adapter proteins activate Caspase 8
  4. Caspase 8 activates caspase 3
30
Q

Example of a death receptor ligand

A

TNFa

31
Q

What does activation of caspase 3 result in?

A

Effector stage activation

  1. Cleavage and inactivation of enzymes and structural constituents
  2. Fragmentation of genomic DNA through DNAse activation
32
Q

Describe the mitochondrial apoptotic pathway

A
  1. DNA damage causes the mitochondria to stimulate caspase 9
  2. Caspase 9 activates caspase 3
33
Q

How does DNA damage cause the mitochondria to stimulate caspase-9?

A

DNA damage stimulates pro-apoptotic members of the Bcl-2 family to promote the release from the mitochondria of cytochrome c

Cytochrome c complexes with Apaf-1 (apoptotic protease-activating factor 1)

This complex activates caspase 9

34
Q

How does the action of caspase 3 lead to phagocytosis of the cell?

A

The cell is reduced to a cluster of membrane-bound bodies each containing a variety of organelles

These display eat-me signals which are recognised by macrophages

35
Q

Which proteins normally control the action of caspases?

A

Inhibitors of apoptosis proteins

36
Q

What does cancer refer to?

A

Malignant tumour

37
Q

What does cancer manifest as?

A

Uncontrolled proliferation

Invasiveness

Infiltration of normal tissue

Loss of function due to the lack of capacity to differentiate

38
Q

What are the two main alterations in DNA underlying cancerous change in a cell?

A

Inactivation of tumour suppressor genes (p53, APC)

Activation in proto-oncogenes (RAS, MYC)

39
Q

What type of process underlies the development of cancer?

A

Multistage process

More than one genetic change

Non-genetic factors increasing the likelihood that the mutation will result in cancer

40
Q

What are the drivers of the cell cycle?

A

CDK

Cyclins

41
Q

What happens if you have different amount of CDKs and cyclins than normal?

A

If too little - not enough cell replication

If too much - a lot of cell replication

42
Q

How do mutations in RAS (oncogene) lead to cancer?

A

RAS is a receptor-bound to GF receptors

When GFs bind to their receptors, the RAS protein becomes activated, it induces transcription of cyclins and CDK

Mutations to these RAS proteins leads to uncontrolled transcription CDK and cyclins

Causing uncontrolled cell growth

43
Q

What is the role of tumour suppressor genes?

A

Prevents abnormal cells from progressing in the cell cycle

44
Q

How does p53 suppress cell proliferation?

A

p53 is a transcription factor controlling the transcription of p21

p21 is tumour suppressing since it inhibits CDK and cyclins for carrying out their functions

45
Q

What process is required for cancer growth?

A

Angiogenesis

Allows cell infiltration to nearby tissues and metastasis

46
Q

What are most anticancer agents like?

A

Cytotoxic

Antiproliferative

47
Q

What, regarding cancer, are anticancer agents not able to target?

A

Invasiveness

Loss of differentiation

Tendency to metastasise

48
Q

What are the two types of chemotherapy used in disease?

A

Cancer chemotherapy

Antimicrobial chemotherapy

49
Q

What was the only option for cancer patients before chemotherapy?

A

Surgical methods to remove solid tumours

50
Q

Describe the history of chemotherapy development

A

Soldiers exposed to mustard gas developed neutropenia

This was interesting, since showed potential for treating WBC cancers

51
Q

Mehcanism of mustard gas

A

Alkylating agents

Form covalent bonds with bases in the DNA which induces apoptosis

52
Q

What was the problem with using mustard gas as a chemotherapy agent?

A

Toxic

53
Q

Experiment showing the efficacy of alkylating agents in cancer therapy

A

1943

Mouse model with lymphoma showed improved survival with nitrogen mustard

Goodman and Gilman then tested the gas on patients with lymphoma = increased survival

54
Q

How was Cyclophosphamide derived?

A

Mustard gas was modified through adding sulphate

55
Q

Mechanism of action of Cyclophosphamide

A

Pro-drug which actively transports into cells

Once inside cells they are enzymatically converted into active, toxic form = phosphoramide

Forms covalent bonds with bases of DNA, cross-linking the two strands together

This interferes with cell division and triggers apoptosis

56
Q

Side effects of Cyclophosphamide

A

Hair loss

GI disturbance

Nausea

Vomiting

57
Q

Specific side effect of Cyclophosphamide

A

Hemorrhagic cystitis

Due to urinary excretion of acrolein

58
Q

Active product of Cyclophosphamide

A

Phosphoramide mustard

59
Q

Toxic product of Cyclophosphamide metabolism leading to bladder cystitis

A

Acrolein

Causes production of free radicals

60
Q

How do you prevent bladder cystitis following Cyclophosphamide administration?

A

Conjugation of the dangerous metablite Acrolein with Mesna

Mesna is a sulfhydryl donor

Acts as an antioxidant and neutralises the damaging effect of Acrolein

61
Q

Name another newer alkylating agent

A

Cisplatin

62
Q

Describe how Cisplatin was discovered

A

Barnett Rosemberg wanted to check whether electrical stimulation could kill cancer cells

He observed that an electrical field caused bacteria to grow 300 times the length

This was because corrosion of the platinum electrodes formed a compound (Cisplatin) that inhibited DNA replication

63
Q

Why did Cisplatin cause prokaryotic cells to grow?

A

There is no apoptotic mechanism in prokaryotic cells

Therefore, Cisplatin cause the bacteria to grow due to its inhibition of cell division

In eukaryotic cells, Cisplatin causes apoptosis due to its effect on DNA replication

64
Q

What are antimetabolites?

A

Interfere with DNA synthesis

65
Q

Describe the history behind antimetabolites

A

Studying vitamin deficiencies

Folate is important in cell replication

Folate deficiency = megaloblastic (very large cells) anaemia and increases the rate of spina bifida

66
Q

Why is folate important in cell replication?

A

Without folate there is a build-up of uracil and little thymidine

Inhibiting this cycle through mimicking the mechanisms in spina bifida could help the replication of cells in cancer

67
Q

How can nucleotide synthesis be targeted in cancer therapy?

A

Folate antagonists

Purine analogues

68
Q

How do we make thymidine from uracil?

A

Methylation

Using Thymidylate synthase

69
Q

Describe how folate is used in the production of thymidine

A

Folate is converted into dihydrofolate

Dihydrofolate reductase converts DHF into tetrahydrofolate

Tetrahydrofolate forms methyl-THF

Methyl-THF and Thymidylate synthase work together to convert uracil into thymidine

70
Q

How do purine analogues interfere with cancer replication?

A

Cause destruction of the enzymes of the elongating chain of DNA due to the explosive nature of the elements attached to the nucleotides

71
Q

Example of pyramidine/purine analogues used in cancer therapy

A

5-fluorouracil

Cytarabine

Fludarabine

72
Q

Example of a folate antagonist

A

Methotrexate

73
Q

Mechanims of action of Methotrexate

A

Blocks Dihydrofolate reductase

74
Q

Why do antimetabolites have fewer side effects?

A

More selective to cancer cells, since these are replicating more often and therefore use more nucleotides

75
Q

Where in nature have new cytotoxic agents been found?

A

Bacterial cytotoxic agents (-icin)

Plant derived cytotoxic agents

76
Q

Examples of antibacterial cytotoxic agents

A

Doxorubicin

Bleomycin

77
Q

Mechanism of action of Doxorubicin

A

Inhibits progression of topoisomerase II

78
Q

What is the function of topoisomerase II?

A

Essential in the separation of entangles daughter strands during replication

Twisting tension builds up and at some point you can not separate two chains and a supercoil is formed

Topoisomerase relaxes these supercoils

79
Q

What is the specific side effect of Doxorubicin?

A

Cardiomyopathy

80
Q

What is the speicific side effect of Bleomycin?

A

Cardiomyopathy

81
Q

Mechanism of action of Belomycin

A

Cause DNA fragmentation

82
Q

Example of plant derived cytotoxic agents

A

Paclitaxel - Yews plant

Vincristine - Rose periwinkle

83
Q

Mechanism of action of plant derived cytotoxic agents

A

Suppress microtubule formation

Suppress cell stabilisation

This induces apoptosis

84
Q

Other pharmacoloical treatments for neoplastic disorders

A

Radioactive iodine

Hormone sensitive tumours

Monoclonal antibodies

85
Q

Mechanism of action of radioactive iodine

A

Thyroid cells have unique abilities to take up iodine

I-131 is taken up and kills surrounding thyroid cells

86
Q

Example of therapies given to hormone sensitive tumours

A

Prostate cancer - androgen antagonists

Estrogen positive breast cancer - oestrogen antagonists

Lymphoid cancer - glucocorticoids

87
Q

Why are glucocorticoids effective treatments for lymphoid cancers?

A

Glucocorticoids inhibit lymphoid cell proliferation

88
Q

Mechanism of action behind hormone antagonists

A

Hormone induces proliferation and survival of cancer cells

Antagonists blocks this survival signal

Leads to cell death

89
Q

Example of an anti-oestrogen drug

A

Tamoxifen

90
Q

Example of monoclonal antibodies used in cancer therapy

A

Her2+ in breast cancer

Anti-EGFR

91
Q

Example of anti-EGFR monoclonal antibody therapies

A

Herceptin

Trastuzumab

92
Q

Examples of antineoplastic resistance

A

Altered membrane transport

Enhanced enzymatic deactivation

Apoptotic pathway defects

Enhanced DNA repair mechanisms

93
Q

What is a way to reduce resistance in cancer cells?

A

Combination therapy

94
Q

Why does combination therapy reduce chances of developing resistance?

A

The possibility for cell to be resistant for one treatment = 1 in 1 000 000

The possibility for cell to be resistant to 3 treatments = 1 in 1 000 000 ^ 3

95
Q

What is important in cancer therapy administration?

A

The way it is administered is specific to allow for the best effect on patients

96
Q

Features of chemotherapy administration

A

Given in cycles

Given as a combination

Targeted therapy is only given after chemotherapy

97
Q

Why is chemotherapy given in cycles rather than one administration?

A

Reduce toxicity

Target all the cancer cells

98
Q

How does giving chemotherapy in cycles reduce the drugs’ toxicity?

A

Chemotherapy kills cells other than the cancer that are also dividing rapidly

Cycles means that the chemotherapy is given with days in between to allow for the normal cells to get back to their normal levels

Since chemotherapy affects cancer cells more than normal cells, loss of cancer cells is cumulative, whereas normal cell count goes back to normal

99
Q

How does giving chemotherapy in cycles allow all cells to be targeted?

A

Chemotherapy targets dividing cells

Not all cells are dividing at one time

Giving the chemotherapy in cycles increases the possibility for targeting dividing cells

100
Q

Are all cells killed by chemotherapy?

A

No

Maintaining the immune system healthy will make them deal with the cancer cells

101
Q

What does giving chemotherapy in combination mean?

A

Less chance for resistance

Allows the dose of each individual drug to be lower

102
Q

Why is giving smaller concentrations of each chemotherapeutic agent beneficial?

A

Less fewer side-effects

Doxorubicin - myopathy
Cyclophosphamide - bladder cystitis

103
Q

Why must the targeted therapy only be given after the chemotherapy?

A

Chemotherapy targets specifically replicating cells.

Targeted treatments target specific cells and make them dormant.

Therefore, if you were to give the targeted treatment with chemotherapy, you would increase the number of dormant cells and therefore decrease the effect of the chemotherapy on the cancer cells.

104
Q

Side effects of EGFR antagonists

A

Mental disturbances

Increased cholesterol

Problems with fertility

105
Q

Why is there interest in targeting EGFR upstream?

A

Lots of side-effects in EGFR antagonists

106
Q

What are alternatives to EGFR antagonists?

A

Drugs that target oestrogen before it is produced

Androgens become aromatised to produce oestrogen

Aromatase inhibitors prevent this and so are effective oestrogen receptors

107
Q

Non-specific side-effects of chemotherapy

A

Hair loss

Nausea

GI problems

Anaemia

108
Q

GI problems induced by chemotherapy agents

A

Ulcers

109
Q

What causes vomiting upon chemotherapy administration?

A

Gastric damage

Chemoreceptor trigger zone

110
Q

How does gastric damage cause vomiting?

A

Epithelial cells of the gastric lining become targeted by chemotherapy agents

Neurons innervating the GI sense the damage and release substance P

Substane P activates afferent neurons which send signals to the vomiting center

111
Q

Where is the vomiting center found?

A

In the brainstem

112
Q

Where is the chemoreceptor trigger zone found?

A

Outside the BBB

On the area postrema

113
Q

What does the Area Postrema control?

A

Controls blood osmolarity

114
Q

What does the CTZ get activated by?

A

Poisons

115
Q

What happens when the CTZ becomes activated?

A

Serotonin and dopamine is released

116
Q

What are the targets of anti-emetics?

A

Substance P

5HT3 - causing serotonin release

Dopamine

117
Q

When does anaemia develop?

A

2 months after chemotherapy

Due to the lifespan of RBCs

118
Q

Ways to treat ulcers

A

H2 antagonists

Proton pump inhibitors

Carbonate tablets

119
Q

Ways to treat neutropenia

A

Injection of cytokines involved in bone marrow cell proliferation

CM-CSF

120
Q

Why is IL-10 not a good target to treat neutropenia?

A

Causes sickness behaviour

121
Q

When are cytokines given to treat neutropenia?

A

After chemotherapy

Giving them before will increase cell proliferation

As chemotherapy agents target rapidly dividing cells, this will worsen the neutropenia

122
Q

How do EGFR antagonists increase cholesterol levels?

A

EGFR is important in controlling HDL levels

Blocking these reduces the concentration of HDL in the blood