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Year 2 - MCD Cancer > Biological Basis of Cancer Therapy > Flashcards

Biological Basis of Cancer Therapy Flashcards

1
Q

6 most common cancers worldwide?

A 
Lung
Breast
Bowel
Prostate
Stomach
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2
Q

What is included in ‘western cancers’?

A

Breast
Colorectal
Lung
Prostate

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3
Q

Main anti-cancer treatment modalities?

A
  • Immunotherapy
  • Chemotherapy
  • Radiotherapy
  • Surgery
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4
Q

What is cancer?

A

Disease of the genome

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5
Q

Types of genetic mutations causing cancer?

A

• Chromosome translocation

• Gene amplification
- copy no. variations

• Point mutations
- in promoter/enhancer regions of genes

  • Deletions/insertions
  • Epigenetic alterations
  • Heritable mutations
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6
Q

Broadly the 2 types of Systemic Therpay?

A
  • Cytotoxic chemotherapy

* Targeted therpaies

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7
Q

What is included in Cytotoxic chemotherapy

A

(1) Alkylating agents
(2) Antimetabolites
(3) Anthracyclines
(4) Vinca alkaloids & taxanes
(5) Topoisomerase inhibitors

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8
Q

What is included in Targeted therapies?

A

(2) Small molecule inhibitors

(1) Monoclonal antibodies

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9
Q

Generally, how do cytotoxic agents work?

A

Select rapidly DIVIDING CELLS by targeting their structures
• i.e. their DNA
• target ALL rapidly dividing cells

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10
Q

Generally, how can cytotoxic agents be given?

A

Given via.
• IV
or
• Orally

Functions SYSTEMICALLY

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11
Q

How are cytotoxic agents administered?

A

Post-operatively
• adjuvant

Pre-operatively
• neoadjuvant

Monotherapy/combinantion

With curative or pallative intent

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12
Q

Explain the MOA of the (1) of cytotoxic chemotherapy

A

Alkylating agents

  • add alkyl (CnH2n+1) groups to G residues
  • cross-link DNA strands (intra, inter, DNA-protein) = prevents it from uncoiling @ replication
  • triggers APOPTOSIS (via. checkpoint pathway)
  • encourages miss-pairing (oncogenic)

Pseudoalkylating agents
• add PLATINUM to G residues
• SAME other effects as above

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13
Q

Example agents of (1) of cytotoxic chemotherapy

A 
Alkylating agents
 • Chlorambucil
 • Cyclophosphamide
 • Dacarbazine
 • Temozolomide

Pseudoalkylating agents
• Carboplatin
• Cisplatin
• Oxaliplatin

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14
Q

Side effects associated with (1) of cytotoxic chemotherapy

A

Hair loss
• NOT carboplatin

Nephrotoxicity
Neurotoxicity
Ototoxicity (ear)
Nausea
Vomiting
Diarrhoea
Immunosuppresion
Tiredness
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15
Q

Explain the MOA of (2) of the cytotoxic chemotherapy?

A

ANTI-METABOLITES

Analogues of 
 • PURINE
or
 • PYRIMIDINE
residues

BLOCK DNA replication & transcription
• inhibit DNA synthesis, double strand breaks = APOPTOSIS

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16
Q

Examples of potential metabolites (2) can be for cytotoxic chemotherapy

A

Can be:

  • Purine (A, G)
  • Pyrimidine (C, T/U)

• Folate antagonists
- inhibit DIHYDROFOLATE REDUCTASE needed to make folic acid = needed to make nucleic acids

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17
Q

Drug examples of (2) for cytotoxic chemotherapy

A

Folate
• Methotrexate

Purine
• 6-mercaptopurine
• Decarbazine
• Fludarabine

Pyrimidine
• 5-flurouracil
• Capecitabine
• Gemcitabine

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18
Q

SEs associated with (2) of cytotoxic chemotherapy?

A

Alopecia (hair loss)
• NOT 5FU or Capectiabine

Bone marrow suppression
• causes anaemia, neutropenia & thrombocytopenia

Sepsis
Nausea/vomiting (dehydration)
Mucositis/diarrohea
Palmar-plantar erythrodysethesia (PPE)
Fatigue
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19
Q

MOA of (3) of cytotoxic chemotherapy

A

ANTHRACYCLINES

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

Block DNA repair (mutagenic) & create free radicals
• DNA/membrane damaging

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20
Q

Example drugs of (3) of cytotoxic chemotherapy

A

Docorubicin

Epirubicin

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21
Q

SEs of (3) of cytotoxic chemotherapy

A

Alopecia (HAIR LOSS)

Cardiac problems
• due to free radicals

Neutropenia
Nausea/vomiting
Fatigue
Skin changes
Red urine
 • Doxorubicin
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22
Q

MOA of (4) of cytotoxic chemotherapy?

A

VINCA ALKALOIDS & TAXANES

Inhibit either
• Assembly - VA
OR
• Disassembly -T

of mitotic microtubules CAUSING mitotic arrest

23
Q

SEs of (4) of cytotoxic chemotherapy?

A

Nerve damage
• peripheral neuropathy

Alopecia
Nausea/vomiting

Bone marrow suppression
• neutropenia/anaemia

Arthralgia (joint pain)
Allergy

24
Q

MOA of (5) of cytotoxic chemotherapy

A

TOPOISOMERASE INHIBITORS

Topoisomerases:
• are required to PREVENT DNA torsional strain during DNA replication & transcription
- SO inhibitors allow for this

• induce temporary single (topo1) OR double (topo2) strand breaks in the DNA backbone

  • allowing for uncoiling
  • induce apoptosis in checkpoints

• protect the free ends from aberrant recombination

25
Q

Which drugs have anti-topoisomerase effects?

A

Anthracyclines

• through their action on DNA

26
Q

Examples drugs of (5) of cytotoxic chemotherapy

A

Topotecan

Irinotecan (topo1)

Etoposide (topo2)

Alter binding of complex to DNA
AND
induce PERMANENT DNA BREAKS

27
Q

SEs of (5) of cytotoxic chemotherapy

A

Acute cholinergic type syndrome (Irinotecan)
• diarrhoea, abdo cramps & diaphoresis (sweating)
• SO given w. ATROPINE

Alopecia
Nausa/vomiting
Fatigue
Bone marrow suppression

28
Q

Summary of the routes to apoptosis?

A
  1. DNA double strand breaks
    • Apoptosis
  2. DNA damage checkpoint
    • Apoptosis (using p53, bcl-2)
29
Q

Resistance mechanisms that allow the cell to survive the damage by cytotoxic drugs?

A

• DNA repair mechanisms upregulated
- so DNA does NOT break

• DNA adducts replaced by Base Excision repair
- using PARP

• Drug efflux from cell
- via. ATP-binding cassettes (ABC) transporters

ALL may lead to lower chance of relapse/cure

30
Q

What is the opposite no cytotoxic chemotherapy that can be used instead?

A

TARGETED (i.e. non-cytotoxic) therapy

31
Q

How can targeted chemotherapy be used?

A

Cancer cells have INTERNAL PATHWAYS which can be targeted in treatment

• in monogenic cancers, this is useful
BUT
• in other cancers, parallel pathways OR feedback cascades are often activated

32
Q

How can the problem with targeted chemotherapy for other cancers be tackled?

A

Dual kinase inhibitors
• prevent the feedback loops

BUT

• increase toxicities (so new therapeutic strategies required)

33
Q

The six hallmarks of cancer cells?

A

SPINAP

S - self-sufficient
P - pro-invasive and metastatic
I - insensitive to anti-growth signals
N - non-senescent
A - anti-apoptotic
P - pro-angiogenic
34
Q

Another 4 hallmarks have been added to cancer cells - what are they?

A

DIE U

D - dysregulated metabolism
I - inflammation (tumour-promoting)
E - evades immune systme
U - unstable DNA

35
Q

Relationship between GF and the cancer cell?

A

Normal cells need GROWTH SIGNALS to move from
quiescent –> active

These signals are trasmitted by the GF receptor pathway (another lecture!!)

• e.g. Receptor TYROSINE KINASE

  • responsible for >50% of human malignancies
  • results in increase in kinase cascade & signal amplification
36
Q

Outline common over-expression of receptors?

A

Her2 ; EGFR

  • Her2 - 25% of breast cancer
  • EGFR - breast & colorectal cancer
  • PDGFR - glioma (brain cancer)

results in increase in kinase cascade & signal amplification

37
Q

Outline common over-expression of ligands

A

VEGF

• VEGF - prostate, kidney & breast cancer

results in increase in kinase cascade & signal amplification

38
Q

Outline common constitutive receptor activation

A

Constitutive (ligand independent)

  • EGFR - lung cancer
  • FGFR - head/neck cancer, myeloma

results in increase in kinase cascade & signal amplification

39
Q

Common suffix of (1) of targeted chemotherapy?

A

-momab
• derived from mouse Abs

-ximab
• chimeric
• fusing the antigen binding region (variable domains of the heavy and light chains, VH and VL ) from one species with the constant domain (effector region) from another species

-zumab
• humanised
• a type of Ab made by combining a human antibody + a small part of a mouse/rat monoclonal antibody

-mumab
• fully human

40
Q

Explain the MOA of (1) of targeted chemotherapy

A

Monoclonal Abs

Target the EC component of the receptor
• the Ab can bind to one of the two receptors and PREVENT receptor dimerization
• this causes internalisation of the receptor
• and this NEUTRALISES the ligand

41
Q

What else can (1) of targeted chemotherapy activate?

A

Monoclonal Abs can also activate
• Fcy-receptor-dependent phagocytosis
• cytolysis induced complement-dependent cytotoxicity (CDC)
• Ab-dependent cellular cytotoxicity (ADCC)

42
Q

Examples drugs of (1) of targeted therapy?

A

Monoclonal Abs

Bevacizumab
• humanised
• binds & neutralises VEGF (ligand)
• improves survival in colorectal cancer

Cetuximab
• chimeric
• targets EGFR
• prevents receptor dimerization

43
Q

Explain the general MOA of (2) of targeted chemotherapy

A

Small molecule inhibitors

These bind to the KINASE DOMAIN and inhibit auto-phosphorylation and thus downstream signalling

44
Q

Give an example drug of (2) of targeted chemotherapy

A

Glivec
• first SMI
• targets BCR-ABL fusion protein made in CML

45
Q

Explain the function of the first (2) drug of targeted chemotherapy

A

BCR-Abl translocation in CML was discovered
• created its own fusion protein - BCR-Abl
• it drove the over-production of WBCs

Gilvec (SMI) was made
• targeted the ATP-binding region within the kinase domain
• inhibited the kinase activity of ABL1

46
Q

(2) of targeted chemotherapy work on TK receptors but also on something else - what is this?

A

Also on IC kinases
• SO can affect cell signalling pathways (e.g. kinase cascade)

i.e. they bind not just to TK but also to Raf, MEK, Akt etc. proteins

47
Q

(2) drugs of targeted chemotherapy that work on TK receptors?

A
  • Erlotibib - EGFR
  • Gefitinib - EGFR
  • Lapatinib - EGFR/HER2
  • Sorafinib - VEGFR
48
Q

(2) drugs of targeted chemotherapy that work on IC kinases?

A
  • Sorafinib - Raf kinase
  • Dasatinib - Src kinase
  • Torcinibs - mTOR inhibitors
49
Q

What is an advantage of targeted therapy?

A

By acting on receptors (IC/EC), targeted therapies BLOCK CANCER HALLMARKS

• e.g. VEGF inhibitors alter blood flow to a tumour

50
Q

Advantages and disadvantages of (1) and (2) of targeted chemotherapy?

A

ONENOTE!!

51
Q

What is one of the largest disadvantages of targeted chemotherapy and explain how?

A

RESISTANCE!!

The mechanisms are
• Mutation in ATP-binding domain (e.g. BCR-Abl fusion gene)

  • Intrinsic resistance
  • Intragenic mutations
  • Upregulation of downregulation or parallel pathways
52
Q

Explain anti-sense oligonucleotides

A

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

The complementary nucleic acid hybridisation to target genes HINDERS translation of specific mRNA

It recruits RNase H
• to cleave target mRNA
• good choice for un-druggable targets

BUT £££

53
Q

RNAi?

A

RNA Interference
• single-stranded complementary RNA
• has to be packaged to avoid degradation

Year 2 - MCD Cancer (14 decks)

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