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

Biological Basis of Cancer Therapy Flashcards

(53 cards)

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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?

Study These Flashcards
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?

Study These Flashcards
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

Study These Flashcards
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
Which drugs have anti-topoisomerase effects?
Anthracyclines | • through their action on DNA
26
Examples drugs of (5) of cytotoxic chemotherapy
Topotecan Irinotecan (topo1) Etoposide (topo2) Alter binding of complex to DNA AND induce PERMANENT DNA BREAKS
27
SEs of (5) of cytotoxic chemotherapy
Acute cholinergic type syndrome (Irinotecan) • diarrhoea, abdo cramps & diaphoresis (sweating) • SO given w. ATROPINE Alopecia Nausa/vomiting Fatigue Bone marrow suppression
28
Summary of the routes to apoptosis?
1. DNA double strand breaks • Apoptosis 2. DNA damage checkpoint • Apoptosis (using p53, bcl-2)
29
Resistance mechanisms that allow the cell to survive the damage by cytotoxic drugs?
• 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
What is the opposite no cytotoxic chemotherapy that can be used instead?
TARGETED (i.e. non-cytotoxic) therapy
31
How can targeted chemotherapy be used?
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
How can the problem with targeted chemotherapy for other cancers be tackled?
Dual kinase inhibitors • prevent the feedback loops BUT • increase toxicities (so new therapeutic strategies required)
33
The six hallmarks of cancer cells?
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
Another 4 hallmarks have been added to cancer cells - what are they?
DIE U D - dysregulated metabolism I - inflammation (tumour-promoting) E - evades immune systme U - unstable DNA
35
Relationship between GF and the cancer cell?
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
Outline common over-expression of receptors?
Her2 ; EGFR * Her2 - 25% of breast cancer * EGFR - breast & colorectal cancer * PDGFR - glioma (brain cancer) results in increase in kinase cascade & signal amplification
37
Outline common over-expression of ligands
VEGF • VEGF - prostate, kidney & breast cancer results in increase in kinase cascade & signal amplification
38
Outline common constitutive receptor activation
Constitutive (ligand independent) * EGFR - lung cancer * FGFR - head/neck cancer, myeloma results in increase in kinase cascade & signal amplification
39
Common suffix of (1) of targeted chemotherapy?
-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
Explain the MOA of (1) of targeted chemotherapy
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
What else can (1) of targeted chemotherapy activate?
Monoclonal Abs can also activate • Fcy-receptor-dependent phagocytosis • cytolysis induced complement-dependent cytotoxicity (CDC) • Ab-dependent cellular cytotoxicity (ADCC)
42
Examples drugs of (1) of targeted therapy?
Monoclonal Abs Bevacizumab • humanised • binds & neutralises VEGF (ligand) • improves survival in colorectal cancer Cetuximab • chimeric • targets EGFR • prevents receptor dimerization
43
Explain the general MOA of (2) of targeted chemotherapy
Small molecule inhibitors These bind to the KINASE DOMAIN and inhibit auto-phosphorylation and thus downstream signalling
44
Give an example drug of (2) of targeted chemotherapy
Glivec • first SMI • targets BCR-ABL fusion protein made in CML
45
Explain the function of the first (2) drug of targeted chemotherapy
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
(2) of targeted chemotherapy work on TK receptors but also on something else - what is this?
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
(2) drugs of targeted chemotherapy that work on TK receptors?
* Erlotibib - EGFR * Gefitinib - EGFR * Lapatinib - EGFR/HER2 * Sorafinib - VEGFR
48
(2) drugs of targeted chemotherapy that work on IC kinases?
* Sorafinib - Raf kinase * Dasatinib - Src kinase * Torcinibs - mTOR inhibitors
49
What is an advantage of targeted therapy?
By acting on receptors (IC/EC), targeted therapies BLOCK CANCER HALLMARKS • e.g. VEGF inhibitors alter blood flow to a tumour
50
Advantages and disadvantages of (1) and (2) of targeted chemotherapy?
ONENOTE!!
51
What is one of the largest disadvantages of targeted chemotherapy and explain how?
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
Explain anti-sense oligonucleotides
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
RNAi?
RNA Interference • single-stranded complementary RNA • has to be packaged to avoid degradation

Year 2 - MCD Cancer (14 decks)

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