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*Y2 MCD Cancer* > Biological Basis of Cancer Therapy > Flashcards

Biological Basis of Cancer Therapy Flashcards

1
Q

How is the incidence of cancer set to change in the future?

A

Incidence set to increase with a reduction in infection-based cancers and an increase in western cancers due to greater westernisation in developing countries

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2
Q

What are the four main modalities of anti-cancer therapy?

A

Surgery

Chemotherapy

Radiotherapy

Immunotherapy

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3
Q

What are the six types of genetic mutations that can cause cancer?

A

Chromosome Translocation

Gene Amplification (Copy Number Variation)

Point Mutations within promoter or enhancer regions of the genes

Deletions or insertions

Epigenetic alterations to gene expression

Can be inherited

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4
Q

What are the five main types of Cytotoxic Chemotherapy?

A

Alkylating agents

Antimetabolites

Anthracyclines

Vinca alkaloids and taxanes

Topoisomerase inhibitors

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5
Q

What is the principle of action behind Cytotoxic chemotherapy?

A

The drugs ‘select’ rapidly dividing cells by targeting their structures (mostly DNA)

(Non-targeted - they affect all rapidly dividing cells e.g. hair and intestinal epithelium)

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6
Q

What are the three different times at which Chemotherapy can be used?

A

Post-operatively - Adjuvant

Pre-operatively - Neoadjuvant

As a monotherapy or in combination

(with Curative or Palliative intent)

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7
Q

How do Alkylating agent work?

A

They add Alkyl groups to guanine residues in DNA

This cross-links DNA strands and prevents DNA from uncoiling at replication

This triggers apoptosis (via DNA checkpoint pathway)

It encourages mispairing

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8
Q

How do Pseudo-alkylating agents work?

A

These add platinum to guanine residues in DNA

Same mechanism of death as alkylating agents

(This cross-links DNA strands and prevents DNA from uncoiling at replication. This triggers apoptosis)

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9
Q

Name 4 Alkylating agents:

A

Chlorambucil

Cyclophosphamide

Dacarbazine

Temozolomide

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10
Q

Name three Pseudo-alkylating agents:

A

Carboplatin

Cisplatin

Oxaliplatin

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11
Q

Name 9 common side effects of Alkylating and Pseudo-Alkylating agents:

A

Hair loss (not carboplatin)

Nephrotoxicity

Neurotoxicity

Ototoxicity (platins) (ear)

Nausea

Vomiting

Diarrhoea

Immunosuppression

Tiredness

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12
Q

How do anti-metabolites work?

A

They masquerade as purine or pyrimidine residues

They lead to the inhibition of DNA synthesis, breaking of the double-strand and apoptosis

They block DNA replication and DNA transcription

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13
Q

What are the three main types of Anti-metabolites?

A

Purine Analogues

Pyrimidine Analogues

Folate Antagonists

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14
Q

What do folate antagonists do?

What type of chemotherapeutic are they?

A

Anti-metabolites

They inhibit dihydrofolate reductase which is required to make folic acid - an important building block for all nucleic acids (especially thymine)

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15
Q

Give 6 examples of anti-metabolites:

A

Methotrexate (Folate antagonist)

6-mercaptopurine

Fludarabine (purine)

5-fluorouracil

Capecitabine

Gemcitabine (pyrimidine)

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16
Q

What are common side effects of anti-metabolites?

A

Hair loss (not 5-flourouracil or capecitabine)

Bone marrow suppression causing anaemia, neutropenia and thrombocytopenia

Increased risk of neutropenic sepsis or bleeding

Nausea and vomiting

Mucositis and diarrhoea

Palmar-plantar erythrodysesthesia

Fatigue

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17
Q

How do Anthracyclines work?

(3 ways)

A

Inhibit transcription and replication by intercalating nucleotides within the DNA/RNA strand

They also block DNA repair (mutagenic)

They create DNA-damaging and cell membrane damaging oxygen free radicals

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18
Q

Give two examples of anthracyclines:

A

Doxorubicin

Epirubicin

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19
Q

Give eight common side effects of anthracyclines:

A

Cardiac toxicity (Arrhythmias, heart failure) (Probably due to damage by free radicals)

Alopecia

Neutropenia

Nausea

Vomiting

Fatigue

Skin changes

Red Urine

20
Q

How do Vinca Alkaloids and Taxanes work?

A

They inhibit the assembly (Vinca alkaloids) or disassembly (taxanes) of Mitotic microtubules causing dividing cells to undergo mitotic arrest

21
Q

What are common side effects of Vinca Alkaloids and Taxanes?

A

Nerve damage: peripheral neuropathy, autonomic neuropathy

Hair loss

Nausea

Vomiting

Bone marrow suppression (neutropenia, anaemia etc.)

Arthralgia (severe pain in a joint without swelling or other signs of arthritis)

Allergy

22
Q

How do Topoisomerases work?

A

Topoisomerases are responsible for the uncoiling of DNA

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

23
Q

How do Topoisomerase Inhibitors work?

A

Specific Topoisomerase inhibitors alter the binding of the complex to DNA and allow permanent DNA breaks

Drugs, such as anthracyclines, have anti-topoisomerase effects through their action on DNA

24
Q

Give some examples of Topoisomerase Inhibitors:

A

Topotecan (topo 1)

Irinotecan (topo 1)

Etoposide (topo 2)

25
Q

What are the common side effects of Topoisomerase inhibitors?

What does this mean they are frequently coadministered with?

A

Irinotecan = acute cholinergic type syndrome (diarrhoea, abdominal cramps, diaphoresis (sweating) - they are therefore given atropine)

Hair loss

Nausea

Vomiting

Fatigue

Bone marrow suppression

26
Q

What are the three common Resistance mechanisms to chemothrapy?

A

DNA repair mechanisms upregulated and DNA damage is repaired

DNA adducts replaced by Base Excision repair

Drug effluxed from cell by ATP-binding cassette transporters

27
Q

How has supportive care for chemotherapeutics been improved?

A

GCSF (Granulocyte-colony stimulating factor)

Bone marrow transplants

Anti-emetics

All reduce impact of side-effects

28
Q

How do Small Molecule Inhibitors and Monoclonal antibodies tend to work, and what is the problem with them?

How are we combatting this?

A

Tend to ‘cut’ cell signals which can be effective in monogenic cancers but in more complex cancers parallel pathways and feedback cascades are activated

We have started to use Dual Kinase Inhibitors which prevent feedback loops but increase toxicities

29
Q

What is the Acronym for the six hallmarks of cancer?

What does it stand for?

A

SPINAP

Self-sufficient

Pro-invasive and metastatic

Insensitive to anti-growth signals

Non-senescent

Anti-apoptotic

Pro-angiogenic

30
Q

What are the four new, additional hallmarks of cancer?

What is their acronym?

A

DIE U

Dysregulated metabolism

Inflammation

Evades the immune system

Unstable DNA

31
Q

What are three causes of the rapid growth of cancer cells?

A

Over-expression of Growth Factor receptors

e.g. HER2, EGFR

Over-expression of Ligand

e.g. VEGF

Constitutive Receptor activation

e.g. EGFR, FGFR

Which all lead to downstream kinase cascade amplification

32
Q

Where are -zumab Monoclonal antibodies derived from?

Example?

A

Humanised

e.g. Bevacizumab

33
Q

Where are -momab Monoclonal antibodies derived from?

A

Derrived from mouse antibodies

34
Q

Where are -mumab Monoclonal antibodies derived from?

Example?

A

Fully Human

e.g. Panitumumab

35
Q

Where are -ximab Monoclonal antibodies derived from?

Example?

A

Chimeric

e.g. Cetuximab

36
Q

How do Monoclonal antibodies work?

A

Bind to Extracellular component of the growth factor receptor and:

Neutralise the ligand

Prevent receptor dimerisation

Cause internalisation of the receptor

Activate Fcγ-receptor-dependent phagocytosis or cytolysis induced complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC)

37
Q

How does Bevacizumab work?

A

Binds and neutralises VEGF

  • shown to increase survival in colorectal cancer
38
Q

How does Cetuximab work?

A

Targets EGFR

39
Q

How do Small Molecule Inhibitors work?

A

Bind to the kinase domain (inside cell) on the growth factor receptor and block autophosphorylation and downstream signalling

40
Q

What is Glivec and how does it work?

A

First targeted therapy:

‘73 a Chromosome translocation in patients with chronic myeloid Leukemia was discovered that created a unique fusion protein called Bcr-abl - enzyme which drove over-production of white cells

Glivec targets ATP binding region within Kinase domain which inhibits the activity of ABL1

41
Q

Apart from receptor protein tyrosine kinases, where else can small molecule inhibitors work?

A

Intracellular kinases - therefore they can affect cell signalling pathways to block cancer hallmarks without the toxicity of cytotoxics

42
Q

What is the main problem with Targeted Therapies?

A

Resistance

43
Q

What are the four main resistance mechanisms in Targeted therapies?

A
  • Mutations in ATP-binding domain (e.g. BCR-Abl fusion gene and ALK gene, targeted by Glivec and crizotinib respectively)
  • Intrinsic resistance (Herceptin is effective in 85% of HER2+ breast cancers, suggesting other driving pathways)
  • Intragenic mutations
  • Upregulation of downstream of parallel pathways (that lead to cell proliferation)
44
Q

How do Anti-sense Oligonucleotides work as a targeted therapy?

A

Single-stranded, chemically modified DNA-like molecule 17-22 nucleotides in length

This complementary nucleic acid hybridisation to the target gene hinders translation of specific mRNA

It recruits RNase H to cleave target mRNA

This is good for ‘undruggable’ targets

45
Q

What is the major obstacle to Targeted Therapy of cancer?

A

Tumour Heterogeneity

*Y2 MCD Cancer* (3 decks)

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