Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Year 2 - Cancer > Biological basis of cancer treatment > Flashcards

Biological basis of cancer treatment Flashcards

1
Q

What are the leading cause of cancer death in males in the UK

A

LUNG > PROSTATE > COLORECTAL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the leading cause of cancer in males and females in the UK?

A

Lung cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Cancer incidence in 2030

How will westernisation affect cancer incidence?

A

22 million cases in 2030

There is greater westernisation of developing countries

This will reduce infection-based cancers (cervical, stomach etc.)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the main anti-cancer modalities?

A

Surgery, chemotherapy, radiotherapy and immunotherapy (some cancers like breast may use endocrine therapy)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are the 2 branches of systemic therapies and give examples of each?

A

Cytotoxic chemotherapy (this kills the cells)

  • Alkylating agents
  • Antimetabolites
  • Anthracyclines
  • Vinca alkaloids and taxanes
  • Topoisomerase inhibitors

Targeted therapies

  • Small molecule inhibitors
  • Monoclonal antibodies
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Cytotoxic therapies - what do they target? How can they be administered?

A
  • They select rapidly dividing cells by targeting their DNA
  • Cytotoxic chemotherapy agents are not that specific
  • Cytotoxic chemotherapy is given intravenously or by mouth (occasionally), and works systemically
  • Any other normal tissues with high turnover will suffer consequences of cytotoxic chemotherapy
  • E.G. effects on the gut mucosa – mucositis (which can -> mouth ulceration and severe diarrhoea
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

….

A
  • Cytotoxic chemotherapy is given post-operatively to deliver adjuvant chemotherapy
  • Chemotherapy can also be given pre-operatively to deliver neoadjuvant chemotherapy
  • Cytotoxic chemotherapy can be given as a singly agent (monotherapy) or in combination
  • It can be given with CURATIVE or PALLIATIVE intent
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are alkylayting agents? How do they work?

A
  • These agents add alkyl (CNH2N+1) groups to guanine residues in DNA
  • This causes cross-linking (intra, inter, DNA-protein) of DNA strands
  • This prevents DNA from uncoiling at replication
  • This triggers apoptosis (via checkpoint pathway)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is a risk of alkylating agents?

A

Occasionally alkylating agents can lead to secondary cancers (they encourage miss-pairing – oncogenic)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Give examples of alkylating agents

A

Chlorambucil, cyclophosphamide, dacarbazine, temozolomide

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are pseudo-alkylating agents?

A
  • Instead of an alkyl group, these agents add platinum to guanine residues in DNA
  • They follow the same mechanism of cell death as alkylating agent
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Give examples of pseudo-alkylating agents

A

carboplatin, cisplatin, oxaliplatin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What are the side effects of alkylating agents?

A

cause hair loss (not carboplatin), nephrotoxicity, neurotoxicity, ototoxicity (platinums), nausea, vomiting, diarrhoea, immunosuppression, tiredness

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are anti-metabolites? How do they work?

A
  • These agents masquerade as purine or pyrimidine residues
  • They incorporate into the DNA -> inhibition of DNA synthesis, DNA double strand breaks and apoptosis
  • Block DNA replication (DNA-DNA) and transcription (DNA –RNA)
  • Can be purine (adenine and guanine), pyrimidine (thymine/uracil and cytosine) or folate antagonists
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are folate antagonists?

A
  • Folate antagonists inhibit dihydrofolate reductase required to make folic acid
  • Folic acid is an important building block for all nucleic acids – especially thymine
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Give examples of anti-metabolites

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What are the side effects of anti-metabolites?

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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

How do anthracyclines work?

A
  • Inhibit transcription and replication by intercalating nucleotides within the DNA/RNA strand
  • They also block DNA repair, so can be mutagenic
  • They create DNA and cell membrane damaging free oxygen radicals
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Give examples of anthracyclines

A

Doxorubicin, epirubicin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What are the side effects of anthracyclines?

A
  • Cardiac toxicity (arrythmias, heart failure) – probably due to damage induced by free radicals
  • Alopecia
  • Neutropenia
  • Nausea and vomiting
  • Fatigue
  • Skin changes
  • Red urine (doxorubicin “the red devil”)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

How do vinca alkaloids and taxanes work?

A
  • Originally derived from natural sources
  • They work by inhibiting assembly (vinca alkaloids) or disassembly (taxanes) of mitotic microtubules
  • This causes dividing cells to undergo mitotic arrest
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What are the side effects of vinca alkaloids/taxanes?

A
  • Nerve damage: peripheral neuropathy, autonomic neuropathy
  • Hair loss
  • Nausea
  • Vomiting
  • Bone marrow suppression (neutropenia, anaemia etc.)
  • Arthralgia
  • a Allergy
23
Q

How do topoisomerase inhibitors work?

A
  • Topoisomerases are 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
  • Topoisomerase inhibitors alter binding of the complex to DNA and allow permanent DNA breaks
  • This causes apoptosis at DNA check points
24
Q

Give examples of topoisomerase inhibitors and are they type 1 or 2?

A

Topotecan and irinotecan (topo I) and etoposide (topo II)

25
Q

What are the side effects of topoisomerase inhibitors?

A
  • Acute cholinergic type syndrome (Irinotecan):
  • Diarrhoea, abdominal cramps and diaphoresis (sweating) -> therefore given with atropine
  • Hair loss
  • Nausea, vomiting
  • Fatigue
  • Bone marrow suppression
26
Q

look at table in notes

A

ON DRUGS

27
Q

How may cancer cells develop resistance to cytotoxic agents?

A
  • Resistance may be multifactorial
  • DNA repair mechanisms may be up-regulated to repair damage caused by chemotherapeutic agents
  • This means that the DNA double strands won’t break -> cell survival
  • Alternatively, DNA adducts may be replaced by base excision repair (using PARP)
  • The drugs may be effluxed from the cell by ATP-binding cassette (ABC) transporters
28
Q

………

A
  • Modern, targeted (i.e. non-cytotoxic) therapies seek to manipulate what we know about cancer cells
  • Mainly using monoclonal antibodies and small molecule inhibitors
  • Cancer cells have ‘wiring’ that may be cut in monogenic cancers
  • For other cancers, parallel pathways or feedback cascades are activated
  • Dual kinase inhibitors are being developed (block 2 pathways) – these prevent feedback loops
  • The problem with these inhibitors is increased toxicity – so new therapeutic strategies are required
29
Q

What are the 6 hallmarks of cancer?

A
  1. Self–sufficient
  2. Insensitive to anti-growth signals – survivals with minimal stimulation and grows regardless of intake
  3. Anti-apoptotic
  4. Pro-invasive and metastatic – spreads rapidly into the surrounding area
  5. Pro-angiogenic
  6. Non-senescent
30
Q

Growth signals and normal cells

A

Normal cells need growth signals to move from a quiescent (resting) to active proliferating state

These signals are transmitted into the cell via growth factors binding transmembrane receptors

This activates downstream signalling pathways

31
Q

How can over expression of Her-2 or EGFR cause cause cancer?

A

Over-expression -> increased kinase cascade à-> increased signal amplification

32
Q

In which cancers are HER2, EGFR and PDGFR overexpression implicated?

A

HER2 – amplified and over-expressed in 25% breast cancer

EGFR – over-expressed in breast and colorectal cancer

PDGFR – glioma (brain cancer)

33
Q

What can happen if there is over-expression of a ligand?

A

-> increased kinase cascade -> increased signal amplification

34
Q

Where may ligand-independent receptor activation be seen?

A

This is seen with EGFR in lung cancer and FGFR in head and neck cancers, and myeloma

35
Q

In which cancers are ligand overexpression (VEGF) implicated?

A

VEGF – prostate cancer, kidney cancer and breast cancer

36
Q

Monoclonal antibody suffixes meanings:

  • momab
  • ximab
  • zumab
  • mumab
A
  • momab (derived from mouse antibodies)
  • ximab (chimeric) e.g. cetuximab
  • zumab (humanised) e.g. Bevacizumab, trastuzumab
  • mumab (fully human) e.g. panitumumab
37
Q

What are humanised and chimeric antibodies?

A

Humanized monoclonal antibody,
- A type of antibody made by combining a human antibody with a small part of a mouse or rat monoclonal antibody. The mouse or rat part of the antibody binds to the target antigen, and the human part makes it less likely to be destroyed by the body’s immune system

Chimeric antibody
- Made by fusing the variable domains of the heavy and light chains from one species, with the constant domain from another

38
Q

How do monoclonal antibodies work?

A
  • Monoclonal antibodies target the extracellular domain of the receptor, and neutralise the ligand. The antibody therefore prevents dimerization of the receptor.
  • Antibodies cause the receptor to be internalised, into the cell
  • Monoclonal antibodies also activate Fcγ-receptor-dependent phagocytosis
  • Cytolysis induces complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity
39
Q

Give examples of monoclonal antibodies in oncology

A

Bevacizumab binds and neutralises VEGF -> improves survival in colorectal cancer

Cetuximab targets EGFR -> also used in colorectal cancer

40
Q

What are small molecule inhibitors?

How do they work and give an example?

A
  • Small molecule inhibitors bind to the kinase domain of the tyrosine kinase within the cytoplasm
  • They block auto-phosphorylation and downstream signalling
  • An example of a small molecule inhibitor is GLIVEC (imatinib)
41
Q

How does glivec (imatinib) work?

A
  • A small molecule inhibitor that targets the ATP binding region within the kinase domain
  • Targets BCR-ABL in CML (9,22)
  • Fantastic clinical results (90% complete response rates in patients with CML)
  • Small molecule inhibitors act on receptor TKs but also intracellular kinases
  • Therefore can affect cell signalling pathways
42
Q

Give examples of SMIs inhibiting receptors and intracellular kinases

A

SMIs inhibiting receptors: erlotinib (EGFR), gefitinib (EGFR), lapatinib (EGFR/HER2), sorafinib (VEGFR)

SMIs inhibiting intracellular kinases: Sorafinib (Raf kinase), Dasatinib (Src), Torcinibs (mTOR inhibitors)

43
Q

What are the advantages and disadvantages of monoclonal antibodies?

A

Advantages:

  • specific
  • can be radiolabelled
  • longer half life
  • good for haematological malignancies
  • cause target receptor internalisation

Disadvantages:

  • large and complex so low tumour of BBB penetration
  • cause allergies
  • expensive
  • parenteral administration
  • risky
44
Q

What are the advantages and disadvantages of SMIs?

A

Advantages:

  • can target TKs without extracellular domain
  • pleiotropic target so useful in heterogenic tumours
  • oral administration
  • cheap
  • good tissue penetration

Disadvantages;

  • shorter half life
  • pleiotropic targets
45
Q

How can resistance develop to therapies?

A
  • Mutations in ATP-binding domain (e.g. BCR-Abl fusion gene targeted by Glivec)
  • Intrinsic resistance (herceptin effective in 85% HER2+ breast cancers, suggesting other driving pathways)
  • Intragenic mutations
  • Upregulation of downstream or parallel pathways
46
Q

Use of anti-sense oligonucleotides treatment

A
  • Single stranded, chemically modified DNA-like molecules: 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
47
Q

RNAi treatment

A
  • Single stranded complementary RNA
  • Has lagged behind anti-sense technology –especially in cancer therapy
  • Compounds have to be packaged to prevent degradation – nano-therapeutics
48
Q

How can the immune system be modulated to treat cancer via PD-1?

A
  • PD-1 is a ligand that is present on the surface of cancer cells
  • It is required to maintain T cell activation
  • After binding the ligand PDL1, the body’s T cells can no longer recognise tumour cells as foreign
  • If either is blocked, the immune system is stimulated
  • Nivolumab is an anti-PD1 antibody
49
Q

Nivolumab - uses and effectivity

A
  • This had good results in lung cancer, melanoma and renal cell carcinoma
  • In treatment-refractory melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC)
  • We saw an overall response rate of 31% in melanoma (compared to the usual 5-15%)
  • Median survival of 16 months (incredible for a phase I trial)
50
Q

Sequencing tumours before theapy

A
  • Depends on reliable methods – currently not being done (risk of false negative results)
  • Used to provide treatment as well as prognostic information
  • Concentrate on particular pathways for certain cancers
  • Circulating biomarkers, tumour cells or DNA
51
Q

What are some new therapeutic cancer avenues?

A

Nano-therapies – delivering cytotoxics more effectively

Virtual screening technologies to identify “undruggable” targets

Immunotherapies using antigen presenting cells to present “artificial antigens”

Targeting cancer metabolism

52
Q

What is a major obstacle to a targeted approach?

A

Tumour heterogeneity is a major obstacle to the targeted approach. most solid tumours (not CML), we see tumour heterogeneity.

53
Q

Melanoma treatment - B Raf inhibitor

How does it extend life-span?

How can the effects be seen with a PET scan?

Side effects?

A
  • Activating mutations of B-Raf identified that 60% of melanomas have a B-Raf mutation
  • Substitution of glutamic acid for valine (V600E) causes a 500-fold increase in activity
  • B-Raf inhibitor (vemurafenib) showed dramatic Phase I activity in melanoma (80% PR or CR)
  • We see the effects on a PET scan (uses glucose as a marker)
  • Extends life span of mutation holders by 7 months
  • Side effects: arthralgia, skin rash and photosensitivity

Year 2 - Cancer (9 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions