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MCD Cancer > Biological basis of cancer therapy > Flashcards

Biological basis of cancer therapy Flashcards

1
Q

What are the 5 most common cancers worldwide?

A 
Lung
Breast
Bowel
Prostate
Stomach
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2
Q

What is expected to happen to the incidence of cancer?

A

It is expected to increase- 27 million cases in 2030

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3
Q

What is expected to happen to distribution in terms of infection-based and western cancers?

A

Greater westernisation in developing countries will reduce infection based cancers (cervical, stomach etc) and increase western cancers such as breast, colorectal, lung and prostate

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4
Q

What are the 4 main anti-cancer modalities?

A

Surgery
Radiotherapy
Chemotherapy
Immunotherapy

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5
Q

What types of genetic mutation are there that cause cancer?

A

Chromosome translocation
Gene amplification
Point mutations within promoter or enhancer regions of genes
Deletions or insertions
Epigenetic alterations to gene expression
Inherited

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6
Q

What types of cytotoxic chemotherapy are there?

A 
Alkylating agents
Antimetabolite
Anthracyclines
Vinca alkaloids and taxanes
Topoisomerase inhibitors
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7
Q

What targeted therapies are there?

A

Small molecule inhibitors

Monoclonal antiboides

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8
Q

How is cytotoxic chemotherapy normally given?

A

IV or occasionally orally

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9
Q

What cells does cytotoxic chemotherapy target?

A

It is non-targeted - it targets all rapidly dividing cells in the body e.g. hair and intestinal epitherlium

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10
Q

What does adjuvant chemotherapy mean?

A

Given post op

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11
Q

How do alkylating agents work?

A

These add alkyl groups to guanine residues in DNA which cross-links DNA strands and prevents DNA from uncoiling at replication and then triggers apoptosis

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12
Q

How do pseudo-alkylating agents work?

A

These add platinum to guanine residues in DNA which triggers the same mechanism of death as alkylating agents

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13
Q

Give some examples of alkylating agents?

A

Chlorambucil
Cyclophosphamide
Dacarbazine
Temozolomide

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14
Q

Give some examples of pseudo-alkylating agents?

A

Carboplatin
Cisplatin
Oxaliplatin

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15
Q

What are the side effects of alkylating and pseudo-alkylating agents?

A 
Hair loss
Nephrotoxicity
Neurotoxicity
Ototoxicity
Nausea
Vomiting
Diarrhoea
Immunosuppression
Tiredness
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16
Q

How do anti-metabolites work?

A

These masquerade as purine or pyrimidine residues leading to inhibition of DNA synthesis, breaking the double strand of DNA and apoptosis- they block DNA replication and transcription

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17
Q

What can anti-metabolites be?

A

Purine analogues
Pyrimidine analogues
Folate antagonists- directly inhibit folate reductase which is required to make folic acid- important building block for all nucleic acids especially thymine

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18
Q

Give some examples of anti-metabolites?

A 
Methotrexate
6-mercaptopurine
Fludarabine
5-fluorouracil
Capecitabine
Gemcitabine
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19
Q

What are the side effects of anti-metabolites?

A 
Hair loss
Bone marrow suppression
Increased risk of neutropenic sepsis or bleeding
Nausea and vomiting
Mucositis and diarrhoea
Palmar-plantar erythrodysesthesia
Fatigue
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20
Q

For which anti-metabolites is hair loss not a side effect?

A

5-fluorouracil or capecitabine

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21
Q

What does bone marrow suppression cause?

A

Anaemia, neutropenia and thrombocytopenia

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22
Q

What do anthracyclines do?

A

Inhibit transcription and replication by intercalating nucleotides within the DNA/RNA strand and block DNA repair- they create DNA damaging and cell membrane damaging oxygen free radicals

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23
Q

Give some examples of anthracyclines?

A

Doxorubin

Epirubicin

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24
Q

What are the side effects of anthracyclines?

A 
Cardiac toxicity
Alopecia
Neutropenia
Nausea
Vomiting
Fatigue
Skin changes
Red urine (doxorubicin- red devil)
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25
Q

What do vinca alkaloids and taxanes do?

A

Inhibit the assembly (vinca alkaloids) or disassembly (taxanes) of mitotic microtubules causing dividing cells to undergo mitotic arrest

26
Q

What are the side effects of microtubule targeting drugs (VAs and Texans)?

A 
Nerve damage- peripheral neuropathy and autonomic neuropathy
Hair loss
Nausea
Vomiting 
Bone marrow suppression
Arthralgia
Allergy
27
Q

What are topoisomerase responsible for?

A

Uncoiling of DNA- prevent DNA torsional strain during DNA replication and transcription

28
Q

How do topoisomerase work?

A

They induce temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA and protect the free ends of DNA from aberrant recombination events

29
Q

How do topoisomerase inhibitors work?

A

Some alter the binding of the DNA to the complex and allow permanent DNA breaks

30
Q

Give some examples of topoisomerase inhibitors?

A

Topotecan (topo 1)
Irinotecan (topo 1)
Etoposide (topo 2)

31
Q

What are the side effects of topoisomerase inhibitors?

A 
Irinotecan- acute cholinergic type syndrome- diarrhoea, abdominal cramps and diaphoresis (sweating)- given atropine
Hair loss
Nausea
Vomiting
Fatigue
Bone marrow suppression
32
Q

How can cells survive despite chemotherapy?

A

There are resistance mechanisms:
DNA repair mechanisms unregulated
DNA adducts replaced by base excision repair
Drug effluxed from cell by ATP-binding cassette transporters

33
Q

What to targeted/non-cytotoxic therapies mainly involve?

A

Monoclonal antibodies and small molecule inhibitors

34
Q

What are the 6 hallmarks of cancer?

A 
SPINAP:
Self sufficient
Pro-invasive and metastatic
Insensitive to anti-growth signals
Non-senescent
Anti-apoptotic 
Pro-angiogenic
35
Q

What are the 4 hallmarks that have been added to the previous 6?

A 
DIE U
Dysregulated metabolism
Inflammation
Evades the immune system
Unstable DNA
36
Q

In terms of growth signals what is the difference between normal cells and cancer cells?

A

Normal cells require growth signals to move from quiescent state to an active proliferating state which are transmitted via growth factors by signalling pathways
Cancer cells are self sufficient in growth signals (tyrosine kinase receptor is associated with >50% of malignancies)

37
Q

Which receptors are overexpressed in certain types cancer?

A

HER2- amplified and over expressed in 25% of breast cancers
EGFR- over expressed in breast and colorectal cancer
PDGFR- Glioma (brain cancer
All growth factor receptors so lead to up regulation of kinase cascade and signal amplification

38
Q

What ligand is over expressed in prostate, kidney and breast cancer?

A

VEGF- leads to up regulation of kinase cascade and signal amplification

39
Q

What receptors is there constitutive (ligand independent) receptor activation of?

A

EGFR- lung cancer

FGFR- head and neck cancers, myeloma

40
Q

If a monoclonal antibody ends in momab, where is it derived from?

A

Mouse antibodies

41
Q

If a monoclonal antibody ends in ximab, where is it from?

A

Chimeric

42
Q

If a monoclonal antibody ends in mumab, where is it from?

A

Fully human

43
Q

What part of the receptor do monoclonal antibodies target?

A

Extracellular component

44
Q

What do monoclonal antibodies do?

A

Neutralise the ligand
Prevent receptor dimerisation
Cause internalisation of the receptor
Activate Fcy receptor dependent phagocytosis or cytolysis induced complement-dependent cytotoxicity or antibody dependent cellular cytotoxicity

45
Q

Give some examples of monoclonal antibodies in oncology and what they do?

A

Bevacizumab binds and neutralises VEGF- improves survival in colorectal cancer
Cetuximab targets EGFR

46
Q

What do small molecule inhibitors do?

A

Bind to the kinase domain within the cytoplasm and block autophosphorylation and downstream signalling

47
Q

What was the first targeted therapy?

A

Glivec- small molecule inhibitor that targets ATP binding region within kinase domain- inhibits the kinase activity of ABL1

48
Q

What do small molecule inhibitors act on?

A

Receptor protein tyrosine kinases and intracellular kinases- therefore affect cell signalling pathways

49
Q

Give some small molecule inhibitors that inhibit receptors

A

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

50
Q

Give some small molecule inhibitors that inhibit intracellular kinases

A

Sorafenib (Raf kinase)
Dasatinib (Src kinase)
Torcinib (mTOR inhibitors)

51
Q

What are the advantages of monoclonal antibodies?

A 
High target specificity
Cause ADCC, complement mediated cytotoxicity and apoptosis induction
Can be radio labelled
Cause target receptor internalisation
Long half life
Good for haematological malignancies
52
Q

What are the disadvantages of monoclonal antibodies?

A 
Large and complex structure 
Less useful against bulky tumours
Only useful against targets with extracellular domains
Not useful for constitutively activated receptors
Cause immunogenicity
Parenteral administration
Risky!
Expensive
53
Q

What are the advantages of small molecules?

A 
Can target TKs without an extracellular domain or which are constitutively activated
Pleiotropic targets
Oral administration
Good tissue penetration
Cheap
54
Q

What are the disadvantages of small molecules?

A

Shorter half life- more frequent administration

Pleiotropic targets

55
Q

What is the big problem with targeted therapies?

A

Resistance

56
Q

What resistance mechanisms to targeted therapies are there?

A

Mutations in ATP-binding domain
Intrinsic resistance
Intragenic mutations
Upregulation of downstream or parallel pathways

57
Q

What are anti-sense oligonucleotides?

A

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

58
Q

What do anti-sense oligonucleotides do?

A

Hybridise to the complementary gene and hinders translation of specific mRNA- it recruits RNaseH to cleave target mRNA

59
Q

What is RNA interference?

A

Single stranded complementary RNA- lagged behind anti-sense technology

60
Q

What is another major obstacle to the targeted approach?

A

Tumour heterogeneity

61
Q

What are the new therapeutic avenues for cancer treatment?

A

Nanotherapies- delivering cytotoxic more effectively
Virtual screening technologies to identify undruggable targets
Immunotherapies using antigen presenting cells to present artificial antigens
Targeting cancer metabolism

MCD Cancer (15 decks)

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