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Cancer Y2 > Biological Basis of Cancer Therapy > Flashcards

Biological Basis of Cancer Therapy Flashcards

1
Q

5 most common cancers worldwide?

A

LUNG, BREAST, BOWEL, PROSTATE and STOMACH

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2
Q

MAIN ANTI-CANCER TREATMENT MODALITIES: (4)

A
  1. SURGERY
  2. RADIOTHERAPY
  3. CHEMOTHERAPY
  4. IMMUNOTHERAPY
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3
Q

What is cytotoxic therapy

A

Kills cancer cells by targeting their structures (mostly the DNA)

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4
Q

5 different types of cytotoxic therapy?

A
  1. Alkylating agents
  2. Antimetabolites
  3. Anthracyclines
  4. Vinca alkaloids and taxanes
  5. Topoisomerase inhibitors
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5
Q

2 types of targeted therapy?

A

There are 2 types:

  1. Small molecule inhibitors
  2. Monoclonal antibodies
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6
Q

2 types of systemic therapy?

A

cytotoxic and targeted therapy

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7
Q

how is cytotoxic chemotherapy administered (2+1)

A
  • Given intravenously or by mouth (occasionally into CSF)
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8
Q

Selectivity of chemotherapy

A

not targeted, affects of all rapidly dividing cells of the body

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9
Q

What is post op chemotherapy known as

A

Adjuvant

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10
Q

What is post op chemotherapy known as

A

neoadjuvant

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11
Q

MoA of alkylating agents in cytotoxic therapy?

A

Add alkyl (CNH2N+1) groups to GUANINE residues in DNA

  • Cross-link (intra, inter, DNA-protein) DNA strands and prevent DNA from uncoiling at replication
  • Trigger apoptosis (via checkpoint pathway)
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12
Q

Examples of alkylating agents? (4)

A

chlorambucil, cyclophosphamide, dacarbazine, temozolomide

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13
Q

Peak side effect of alkylating agents?

A
  • Can lead to secondary cancers because they encourage miss-pairing -> oncogenic
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14
Q

MoA pseudoalkylating agents?

A
  • Add platinum to guanine residues in DNA
    ross-link (intra, inter, DNA-protein) DNA strands and prevent DNA from uncoiling at replication
  • Trigger apoptosis (via checkpoint pathway)
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15
Q

Examples of pseudoalkylating agents (3)

A

carboplatin, cisplatin, oxaliplatin

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16
Q

chlorambucil is an example of…?

A

alkylating agent

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17
Q

cyclophosphamide is an example of…?

A

alkylating agent

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18
Q

dacarbazine is an example of…?

A

alkylating agent

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19
Q

temozolomide is an example of…?

A

alkylating agent

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20
Q

carboplatin is an example of…?

A

pseudoalkylating agent

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21
Q

cisplatin is an example of…?

A

pseudoalkylating agent

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22
Q

oxaliplatin is an example of…?

A

pseudoalkylating agent

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23
Q

Cisplatin MoA in detail starting with entry into cell via X channel:

A

1) Enters cells through copper channels CTR1/ATP7
2) Hydrolyses in a low chloride intracellular environment
3) Binds to guanine residues and cross-links DNA
4) DNA damage checkpoints detect damage
5) Cell tries to perform nucleotide excision repair
6) Mismatch repair pathway activated after many fruitless cycles of DNA repair attempts

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24
Q

Side effects of alkylating agents

A
  • Cause hair loss (not carboplatin)
  • Nephrotoxicity
  • Neurotoxicity
  • Ototoxicity (platinums)
  • Nausea
  • Vomiting
  • Diarrhoea
  • Immunosuppression -> Drop neutrophil count
  • Tiredness
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25
Q

Which cytotoxic drug doesn’t cause hair loss

A

Carboplatin

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26
Q

Why is carboplatin special

A

Doesn’t cause hair loss

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27
Q

What are antimetabolites structurally and MOA

A
  • Purine or pyrimidine analogues, or folate antagonists
  • Lead to blocking of DNA synthesis, replication and transcription, DNA double strand breaks and apoptosis
  • OR inhibit dihydrofolate reductase required to make folic acid, an important building block for all nucleic acids – especially thymine
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28
Q

Examples of antimetabolites

A

methotrexate (folate), 6-mercaptopurine, decarbazine and fludarabine (purine), 5-fluorouracil, capecitabine, gemcitabine (pyrimidine)

29
Q

Side effects of antimetabolites? (7)

A
  • Hair loss (alopecia) not 5FU or capecitabine
  • Bone marrow suppression causing anaemia, neutropenia and thrombocytopenia
  • Increased risk of neutropenic sepsis (and death) or bleeding
  • Nausea and vomiting (dehydration)
  • Mucositis and diarrhoea
  • Palmar-plantar erythrodysesthesia (PPE)
  • Fatigue
30
Q

Gemcitabine mechanism:

A

1) Comes into cell via the hENT transporters
2) Deaminated to form dFdU which is toxic
3) Phosphorylated
4) Inhibits DNA replication

31
Q

MoA of anthracyclines?

A
  • Inhibit transcription and replication by intercalating (i.e. inserting between) nucleotides within the DNA/RNA strand
  • Also block DNA repair mutagenic
  • They create DNA/cell membrane damaging free oxygen radicals
32
Q

Side effects of anthracyclins? (7)

A
  • Cardiac toxicity (arrhythmias, heart failure) – probably due to damage induced by free radicals Anyone going on an anthracycline should first have an ECG/other cardiac examinations to check suitability
  • Alopecia
  • Neutropenia
  • Nausea and Vomiting
  • Fatigue
  • Skin changes
  • Red urine (doxorubicin “the red devil”)
33
Q

MoA of vincalkaloids?

A
  • Work by inhibiting assembly of mitotic microtubules causing dividing cells to undergo mitotic arrest Can’t replicate
34
Q

MoA of taxanes?

A
  • Work by inhibiting disassembly of mitotic microtubules causing dividing cells to undergo mitotic arrest Can’t replicate
35
Q

Side effects of vinca alkaloids and taxanes?

A
  • Nerve damage: peripheral neuropathy (tingling in hands and feet), autonomic neuropathy
  • Hair loss
  • Nausea
  • Vomiting
  • Bone marrow suppression (neutropenia, anaemia etc.)
  • Arthralgia joint pain
  • Allergy
36
Q

What is the purpose of topoisomerase

A

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

37
Q

What drugs have an indirect anti-topoisomerase effect

A

Anthracyclins

38
Q

What is topotecan an example of

A

anti-topoisomerase

39
Q

What is irinotecan an example of

A

anti-topoisomerase

40
Q

How do anti-topoisomerases work

A
  • Specific topoisomerase inhibitors include Topotecan and irinotecan (topo1) and etoposide (topo2) alter binding of the complex to DNA and allow permanent DNA breaks
41
Q

Side effects of topoisomerase (5)

A
  • Irinotecan causes acute cholinergic type syndrome diarrhoea, abdominal cramps and diaphoresis (sweating) therefore given with (anti-cholinergic) atropine
  • Hair loss
  • Nausea, vomiting
  • Fatigue
  • Bone marrow suppression
42
Q

MECHANISMS OF RESISTANCE TO CYTOTOXIC THERAPIES:

A
  1. DNA repair mechanisms upregulated and DNA damage is repaired This would cause resistance to DNA double strand breaks
  2. DNA adducts replaced by Base Excision repair (using PARP)
  3. Drug effluxed from the cell by ATP-binding cassette (ABC) transporters
43
Q

Problem with dual kinase inhibitors?

A

Increased toxicity

44
Q

10 hallmarks of a cancer cell?

A
  1. Self-sufficient
  2. Insensitive to anti-growth signals
  3. Anti-apoptotic
  4. Pro-invasive and metastatic
  5. Pro-angiogenic
  6. Non-senescent
  7. Dysregulated metabolism
  8. Evades the immune system
  9. Unstable DNA
  10. Inflammation
45
Q

Examples of cancers with over expressed RPTK

A
  • HER2 – amplified and over-expressed in 25% breast cancer
  • EGFR – over-expressed in breast and colorectal cancer
  • PDGFR- glioma (brain cancer)
46
Q

Examples of cancers with over expressed ligands

A
  • VEGF – prostate cancer, kidney cancer, breast cancer
47
Q

Examples of cancers with constitutive ligand independent receptor activation

A
  • EGFR (lung cancer)

- FGFR (head and neck cancers, myeloma)

48
Q

Three ways cancers can cause an increase in the kinase cascade?

A
  • Constitutive ligand independent receptor activation
  • Over expressed ligands
  • Over expressed RPTK
49
Q

What’re - -momab antibodies

A

derived from mouse

50
Q

What’re - -mumab antibodies

A

(fully human

51
Q

What’re - -ximab antibodies

A

chimeric

52
Q

What’re - -zumab antibodies

A

humanised

53
Q

What suffix is a chimeric Ab

A

-ximab

54
Q

What suffix is a (fully human Ab

A

-mumab

55
Q

What suffix is a humanised Ab

A

-zuman

56
Q

What suffix is a derived from mouse Ab

A

-momab

57
Q

What do monoclonal antibodies do to the ligand and receptors in cancer therapy (3)

A
  • Neutralise the ligand
  • Prevent receptor dimerization
  • Cause internalisation of receptor
58
Q

What do small molecule inhibitors do in cancer therapy

A
  • Bind to the kinase domain of the tyrosine kinase within the cytoplasm
  • Block autophosphorylation and downstream signalling
59
Q

IMATINIB is an e.g. of?

A

Small molecule inhibitor

60
Q

Do targeted therapies have toxicity and why

A

by acting on receptors, targeted therapies don’t have cytotoxicity

61
Q

Resistance to targeted therapies? (4)

A
  1. Mutations in ATP-binding domain (e.g BCR-Abl fusion gene and ALK gene, targeted by Glivec and crizotinib respectively)
  2. Intrinsic resistance (herceptin effective in 85% HER2+ breast cancers, suggesting other driving pathways)
  3. Intragenic mutations
  4. Upregulation of downstream or parallel pathways
62
Q

What are anti-sense oligonucleotides

A
  • Single stranded, chemically modified DNA-like molecule 17-22 nucleotides in length
  • Complementary nucleic acid hybridisation to target gene hindering translation of specific mRNA
  • Recruits RNase H to cleave target mRNA
  • Good for “undruggable” targets
63
Q

2 cancer treatments still in development?

A

Anti-sense oligonucleotides

RNA interference

64
Q

Advantages of monoclonal Antibodies? (3)

A

High target specificity
Long half life so lower dosing frequency
Cause target receptor internalisation

65
Q

Advantages of small molecule inhibitors? (4)

A

Oral admin
Cheap
Good tissue penetration
Can target TK without an extracellular domain

66
Q

Disadvantages of monoclonal Antibodies? (3)

A

Expensive
Less useful against bulky tumours
Only works on targets with EC domains

67
Q

Disadvantages of small molecule inhibitors? (3)

A

Short half life so have admin more frequently

Pleiotropic targets so more unexpected toxicity

68
Q

The future for cancer therapies? (2)

A
  1. SEQUENCING TUMOURS PRIOR TO STARTING THERAPY:

2. NEW THERAPEUTIC AVENUES:

Cancer Y2 (15 decks)

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