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Cancer > Biological Basis of Cancer Therapy > Flashcards

Biological Basis of Cancer Therapy Flashcards

1
Q

What are the five most common cancers worldwide? What are the four main anti-cancer modalities?

A 
Lung 
Breast 
Bowel 
Prostate 
Stomach

Radiotherapy
Chemotherapy
Surgery
Immunotherapy

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2
Q

List the 6 types of cytotoxic chemotherapy.

A 
Alkylating agents 
Pseudoalkylating agents 
Antimetabolites 
Anthracyclines 
Vinca alkaloids and taxanes 
Topoisomerase inhibitor
  • Apart from vinca alkaloids and taxanes, the rest target rapidly dividing cells targeting their DNA
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3
Q

What are the main types of targeted therapy for cancer?

A

Monoclonal antibodies

Small molecule inhibitors

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4
Q

Describe the administration and general mode of action

A
  • Given intravenously or by mouth (occasionally) as a monotherapy or in combination
  • Works systemically, with curative or palliative intent
  • Non “targeted” so affects all rapidly dividing cells in the body
  • If given post-operatively = called an adjuvant
  • If given pre-operatively = called a neoadjuvant
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5
Q

How do alkylating agents work?

A
  • They add an alkyl group to the guanine residues in DNA
  • This causes cross-linking of the DNA strands (intra, inter, DNA-protein) and prevents DNA from uncoiling at replication
  • This then triggers apoptosis (via a DNA checkpoint pathway)
  • It encourages mis-pairing
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6
Q

Name four alkylating agents.

A

Chlorambucil
Cyclophosphamide
Dacarbazine
Temozolomide

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7
Q

How do pseudoalkylating agents work?

A

They have the same mechanism as alkylating agents but use platinum instead of alkyl groups

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8
Q

Name three pseudoalkylating agents.

A

Carboplatin
Cisplatin
Oxaliplatin

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9
Q

What are some side effects of alkylating and pseudoalkylating agents?

A 
Nephrotoxicity 
Alopecia (except carboplatin) 
Neurotoxicity 
Ototoxicity (platins) 
Nausea, Vomiting, Diarrhoea, Immunosuppression, Tiredness
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10
Q

How do anti-metabolites work?

A
  • They masquerade as purine or pyrimidines
  • They can also be folate antagonists, folic acid being an important building block for all nucleic acids (dihydrofolate reductase inhibitors)

=> This leads to inhibition of DNA replication and transcription

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11
Q

Give six examples of anti-metabolites.

A 
Methotrexate (folate)
Capecitabine 
Gemcitabine (pyrimidine)
Fludarabine (purine)
5-fluorouracil 
6-mercaptopurine
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12
Q

State some side effects of anti-metabolites.

A
  • Alopecia (not 5-fluorouracil or capecitabine)
  • Bone marrow suppression, anaemia, neutropenia and thrombocytopenia
  • Increased risk of neutropenic sepsis
  • Nausea, Vomiting, Fatigue
  • Mucositis and Diarrhoea
  • Palmar-plantar erythrodysesthesia (PPE)
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13
Q

How do anthracyclines work?

A
  • Inhibit transcription and replication by intercalating (i.e. inserting between) nucleotides within the DNA/RNA strand.
  • Block DNA repair - mutagenic
  • They create DNA and cell membrane damaging free oxygen radicals
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14
Q

Give two examples of anthracyclines.

A

Doxorubicin

Epirubicin

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15
Q

State some side effects of anthracyclines.

A
  • Cardiac toxicity (probably due to the free radicals)
  • Alopecia
  • Neutropenia
  • Nausea, Vomiting, Fatigue
  • Red urine (doxorubicin – ‘the red devil’)
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16
Q

How do vinca alkaloids and taxanes work?

A

Vinca alkaloids inhibit assembly and taxanes inhibit disassembly of mitotic microtubules causing dividing cells to undergo mitotic arrest

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17
Q

List the side effects of microtubule targeting drugs (vinca alkaloids and taxanes)

A
  • Peripheral neuropathy, autonomic neuropathy
  • Alopecia
  • Nausea, Vomiting
  • Bone marrow suppression (neutropenia, anaemia etc)
  • Arthralgia
  • Allergy
18
Q

Why is topoisomerase important? Hence, explaining how topoisomerase inhibitors work?

A
  • Topoisomerases are required to prevent DNA torsional strain during DNA replication and transcription
  • They induce temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA
  • They protect the free ends of DNA from aberrant recombination events

=> Topoisomerase inhibitors alter binding to DNA and allow permanent DNA breaks.

19
Q

Give three examples of topoisomerase inhibitors.

A

Topotecan (topo1)
Irinotecan (topo1)
Etoposide (topo2)

20
Q

State some side effects of topoisomerase inhibitors.

A

Irinotecan = acute cholinergic type syndrome (diarrhoea, abdominal cramps, diaphoresis; so they are given atropine)

  • Hair loss
  • Nausea, Vomiting, Fatigue
  • Bone marrow suppression
21
Q

What are the six hallmarks of cancer?

A
  1. Self-sufficient
  2. Pro-invasive and metastatic
  3. Insensitive to anti-growth signals
  4. Non-senescent
  5. Anti-apoptotic
  6. Pro-angiogenic
22
Q

What are the four hallmarks of cancer that have recently been added?

A

Dysregulated metabolism
Inflammation promoting
Evades the immune system
Unstable DNA

23
Q

Give three examples of receptors that are over-expressed in cancer. State the cancer types

A

EGFR – over-expressed in many breast and colorectal cancers
HER2 – breast
PDGFR – glioma (brain)

=> increased kinase cascade and signal amplification

24
Q

Give an example of a ligand that is over-expressed in some cancers.

A

Vascular Endothelial growth factor (VEGF) – prostate, kidney and breast cancer

25
Q

Give two examples of constitutive (ligand independent) receptor activation in cancer.

A

EGFR – lung cancer

FGFR – head and neck cancers, myeloma

26
Q

What do each of the following suffixes mean in relation to monoclonal antibodies:

a. -momab
b. -ximab
c. -zumab
d. -mumab

A 
momab = Derived from mouse antibodies 
ximab = Chimeric antibody 
zumab = Humanised antibody 
mumab = Fully human antibody
27
Q

Describe the structure of humanised monoclonal antibodies.

A

Murine regions are interspersed within the with the light and heavy chains of the Fab portion

28
Q

Describe the structure of chimeric monoclonal antibodies.

A

The murine component of the variable region of the Fab section is maintained integrally

29
Q

What effect can monoclonal antibodies have on receptors and their activation?

A
  • They target the extracellular component of receptors and can prevent receptor dimerization, neutralise the ligand and cause internalisation of the receptor
  • They also activate Fc-receptor-dependent phagocytosis or cytolysis induced complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity (ADCC)
30
Q

Give two examples of monoclonal antibodies used in oncology.

A

Bevacizumab – binds and neutralises VEGF

Cetuximab – targets EGFR

31
Q

How do small molecule inhibitors work?

A

They bind to the kinase domain of tyrosine kinase receptors within the cytoplasm and block autophosphorylation and downstream signalling

32
Q

What was the first targeted treatment for cancer and how did it work?

A

Glivec (imatinib) – it is a small molecule inhibitor that targets the ATP binding region within the kinase domain of BCR-ABL1
This inhibits the kinase activity of ABL1

33
Q

Give four examples of small molecule inhibitors that inhibit receptors.

A

Erlotinib (EGFR)
Gefitinib (EGFR)
Lapatinib (EGFR/HER2)
Sorafenib (VEGFR)

34
Q

Give three examples of small molecule inhibitors that inhibit intracellular kinases.

A
  1. Sorafenib (Raf kinase) – this is in addition to its anti-VEGFR effects
  2. Dasatinib (Src kinase)
  3. Torcinibs (mTOR inhibitors)
35
Q

State some advantages and disadvantages of monoclonal antibodies.

A

Advantages:

  • High target specificity
  • Cause ADCC, complement-mediated cytotoxicity and apoptosis induction
  • Can be radiolabelled
  • Long half-life
  • Good for haematological malignancies

Disadvantages:

  • Large and complex structure
  • Less useful against bulky tumours
  • Only useful against targets with extracellular domains
  • Not useful for constitutively activated tumours
  • Cause immunogenicity and allergy
  • IV administration
  • Expensive
36
Q

State some advantages and disadvantages of small molecule inhibitors.

A

Advantages:

  • Can target tyrosine kinases without an extracellular domain or which are constitutively activated
  • Pleiotropic targets (useful in heterogenic tumours)
  • Oral administration
  • Good tissue penetration
  • Cheap

Disadvantages:

  • Shorter half-life, more frequent administration
  • Pleiotropic targets (more unexpected toxicity)
37
Q

State some resistance mechanisms to targeted therapies.

A
  • Mutations in ATP binding domain
  • Intrinsic resistance
  • Intragenic mutations
  • Upregulation of downstream signalling pathways
38
Q

Explain how anti-sense oligonucleotides work.

A

These are short single-stranded DNA-like molecules
They bind to the complementary sequence on mRNA and hinder its translation
It then recruits RNase H to cleave the target mRNA

39
Q

Name a successful B-Raf inhibitor.

A

Vemurafenib

NOTE: side effects include arthralgia, skin rash and photosensitivity

40
Q

Explain how the PD-1 receptor-PDL1 ligand system works.

A

PD-1 receptor is on the cell membrane
When the ligand (PDL-1) binds to the PD-1 receptor, the body’s T cells can no longer recognise tumours as foreign
So blocking the PD-1 receptor will stimulate the immune system

41
Q

Name a drug that inhibiting PD-1.

A

Nivolumab (anti-PD1 antibody)

Cancer (15 decks)

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