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Cancer Pharmacology > Angiogenesis & tumour hypoxia > Flashcards

Angiogenesis & tumour hypoxia Flashcards

1
Q

What problems are associated with conventional cancer therapy?

A

Drug resistance,
Targeting of normal rapidly dividing cells:
- stomach lining(nausea/vomitting)
- hair follicles (hair loss)

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2
Q

What is angiogenesis?

A

The formation of new blood vessels from pre-exisiting vessels.

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3
Q

Name three normal physiological processes that require angiogenesis.

A

Embyro and tissue growth
Wound healing
Fertility

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4
Q

Name three pathological processes that require angiogenesis.

A

Cancer
Inflammation
Atherosclerosis

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5
Q

What are the steps in the progression of a mutation into an angiogenic tumour?

A
  1. Somatic mutation.
  2. Small avascular tumour
  3. Tumour secretion of angiogenic factors stimulates angiogenesis
  4. Rapid tumour growth and metastasis
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6
Q

What is hypoxia?

A

Reduction in the normal level of tissue oxygen tension which occurs during acute/chronic vascular disease, pulmonary disease and cancer.

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7
Q

When is cellular response classed as hypoxic?

A

when oxygen levels drop below 2-3%

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8
Q

What are 4 characteristics of hypoxic cancer cells?

A

Respond poorly to chemotherapy
Less efficiently killed by radiation
”Autoselect” for malignancy
Stimulate tumour vascularisation

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9
Q

What happens to HIF-1a during hypoxic conditions?

A
  1. HIF-1a is not hydroxy;ated and dimerises with HIF-1b in the nucleus.
  2. Stabilised HIF-1a translocates to the nucleus and complexes with other factors (p300/CBP).
  3. Complex binds to the hypoxia-responsive element.
  4. Transcription of target genes
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10
Q

What happens to HIF-1a during normoxic conditions?

A
  1. Oxygen-dependent propel-hydroxylases (PHD) modify proline residues 402 and 564 in HIF-1a.
  2. Binding of VHL to HIF-1a signals for HIF-1a degradation by ubiquitination.
  3. Proteosomal degradation of HIF-1a.
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11
Q

What are the HIF-1a target genes?

A

Glut1/Glut3 (glucose transporters)
Erythropoietin (more RBCs)
IGFs (survival signals)
VEGF-A (angiogenesis)

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12
Q

Describe some key differences seen in cancer blood vessels when compared to normal blood vessels.

A

Cancer blood vessels are highly irregular and twisting.
They are dependent on cell survival factors (VEGF) and are hyper-permeable.
They also result in abnormal microenvironment (hypoxia, low pH and interstitial hypertension.

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13
Q

How does VEGF stimulate angiogenesis?

A

VEGF-A ligand binds to a specific RTK (VEGFR-2/ KDR) present on vascular endothelial cells surface.
VEGFR-2 activation stimulates an intracellular signalling cascade leading to endothelial cell proliferation, survival and migration, ultimately resulting in angiogenesis.

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14
Q

Describe the structure of VEGFR-2?

A

consists of 4 domains:

  • signal sequence,
  • extracellular ligand binding domain,
  • transmembrane domain
  • intracellular domain
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15
Q

What components make up the VEGFR-2 intracellular domain?

A 
Kinase domain (split-kinase)
Kinase inert domain
C-terminal tail
Specific auto-phosphorylated Tyr residues
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16
Q

Describe the process of VEGF-2 activation?

A
  1. Ligand binding
  2. Dimerisation and auto-phosphorylation
  3. Recruitment of intracellular signalling proteins (through SH2 domain binding
  4. Activation of downstream signalling cascade
17
Q

What are the advantages of anti-angiogenic therapy over conventional chemotherapy?

A
  1. Easily targetable area for drug delivery
  2. Endothelial cells less likely to become drug-resistant (more genetically stable than tumour cells)
  3. Can be used in a range of cancers
  4. Reasonably large therapeutic window
18
Q

Why do renal cell cancers have such a high rate of angiogenesis?

A

VEGF over-expression found in 30-100% of tumours

Cause: mutations in the VHL proteins

19
Q

What is the rationale behind anti-angiogenic therapy?

A

Anti-angiogenesis aims to prevent blood vessel growth by either sequestering the VEGF-A ligand or blocking the activation of VEGFR-2 and other RTKs.

20
Q

What do direct angiogenesis inhibitors do?

A

Act directly on endothelial cells

Examples: angiostatin and endostatin

21
Q

What do indirect angiogenesis inhibitors do?

A

Inhibit tumour cell-derived growth factors which prevents angiogenesis stimulation

Example: Bevacizumab (VEGF ligand binding antibody) and Sorafenib (a small molecule RTK inhibitor)

22
Q

What does Bevacizumab recognise?

A

all isoforms of VEGF

23
Q

What are the anti-angiogenic effects of Bevacizumab?

A

Decreased tumor perfusion
Decreased microvascular density
Decreased interstitial fluid pressure
Decreased circulating endothelial and progenitor cells

24
Q

What are the side effects of Bevacizumab?

A 
Arterial thrombolytic events
Angina
Bowel perforation
Cardiovascular toxicity
Hypertension
Impaired wound healing 
Myocardial infarction

Cancer Pharmacology (5 decks)

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