Brainscape's Knowledge GenomeTM

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


See full index

Canc > Cancer 9: Biological basis of cancer therapy > Flashcards

Cancer 9: Biological basis of cancer therapy Flashcards

1
Q

Which old drugs are being looked at for cancer treatment

A

Aspirin and

metformin (to reduce tumour glycolysis)

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

What is the most common cause of cancer death in the UK for male and female

A

Both lung

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

What are the 4 pillars of cancer theerapy

A

Surgery

Radiotherapy

Chemotherapy

Immunotherapy

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

What are the 6 most common cancers worldwide

A

Six most common cancers worldwide are lung, breast, bowel, prostate, and stomach

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

State the types of genetic mutations causing cancer

A

Chromosome translocation

Gene amplification (copy number variation)

Point mutations within promoter or enhancer regions of genes

Deletions or insertions

Epigenetic alterations to gene expression

Can be inherited

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the 2 types of systemic therapy

A

Cytotoxic chemotherapy

Targeted therapies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Give examples of cytotioxic chemotherapy

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are the target therapies

A

Small molecule inhibitors

Monoclonal antibodies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

How do cytotoxics work generally

A

Cytotoxics “select” rapidly dividing cells by targeting their structures (mostly the DNA)

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

….

A

…..

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

How can cytotoxic chemo be given

A

Given intravenously or by mouth (occasionally)

Non “targeted” – affects all rapidly dividing cells in the body

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

When can cytotoxic chem be given

A

Given post-operatively: adjuvant

Pre-operatively: neoadjuvant

As monotherapy or in combination with curative or palliative intent

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

How do alkylating agents work

A

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

Cross-link (intra, inter, DNA-protein) DNA strands and prevents DNA from uncoiling at replication

Trigger apoptosis (via checkpoint pathway)

Encourage miss-pairing - oncogenic

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

What are pseudo-alkylating agents

A

Add platinum to guanine residues in DNA

Same mechanism of cell death as akylating agents

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Give examples of pseudo-alkylating episodes

A

carboplatin, cisplatin, oxaliplatin

sounds like platin-um

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Give examples of alkylating agens

A

Chlorambucil, cyclophosphamide, dacarbazine, temozolomide.

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

What are the side effects of Alkylating and pseudoalkylating agents

A

cause hair loss (not carboplatin),

nephrotoxicity,

neurotoxicity,

ototoxicity (platinums),

nausea,

vomiting,

diarrhoea,

immunosuppression,

tiredness

BrainEarTirednessHairlossImmunosuppressionNauseaKidneys

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

How does cisplatin work

A

Enters through copper channel (CTR1)

Hydrolises in low Cl- environment, then binds guanine residues cross links DNA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are the effects of intra- and inter-strand cross-links created by cisplatin

A

At the DNA damage checkpoin,

nucleotide excision repair attempts to excise the lesions

Mismatch repair pathway activated (these are a type of during, or post replication repair)

At the DNA damage checkpoimnt, apoptotic cell death due to p53

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

How do antimetaboites work

A

Masquerade as purine or pyrimidine residues leading to inhibition of DNA synthesis, DNA double strand breaks and apoptosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Which checkpoints are involve in detecting damage due to cancer drugds

A

anti-metabolites: DNA checkpoint –> apoptosis

same for alkylating

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What do anti-metabolites block

A

Block DNA replication (DNA-DNA) and transcription (DNA –RNA)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What can anti-metabolites be antagonsits of

A

Purine antagonist (adenine and guanine)

Pyrimidine antagonist (thymine/uracil and cytosine)

Folate antagonists (which inhibit dihydrofolate reductase required to make folic acid, building block for all nucleic acids – especially thymine)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Give examples of anti-metabolites

A

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

(mostly -bine, or has base name…. for folate it has -ate at the end)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
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
26
Q

How do anthracyclins work

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 and cell membrane damaging free oxygen radicals

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Give examples of anthracyclines

A

doxorubicin, epirubicin

-cin (remember cos cyclin has c)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
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
29
Q

What vinca alkaloids and taxanes. How does each work

A

Work by inhibiting assembly (vinca alkaloids) or disassembly (taxanes) of mitotic microtubules causing dividing cells to undergo mitotic arrest

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What are the side effects of microtubule targeting drugs (eg. vinca alkaloids and taxanes)

A

Nerve damage: peripheral neuropathy, autonomic neuropathy

Hair loss

Nausea

Vomiting

Bone marrow suppression (neutropenia, anaemia etc)

Arthralgia

Allergy

31
Q

What are topoisomerases. How do they 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

32
Q

Which drugs have anti-topoisomerae effets

A

Drugs such as anthracyclines have anti-topoisomerase effects through their action on DNA

33
Q

As well as anthracyclines, which other drugs also have anti-topoisoerase effects

A

Specific topoisomerase inhibitors include Topotecan and irinotecan (topo I) and etoposide (topo II) alter binding of the complex to DNA and allow permanent DNA breaks

34
Q

What are the side effects of topositomerase

A

(irinotecan): Acute cholinergic type syndrome – diarrhoea, abdominal cramps and diaphoresis (sweating).

Hair loss

Nausea, vomiting

Fatigue

Bone marrow suppression

35
Q

Which drug might help with side effects of topoisomerase inhibitors

A

Atropine

36
Q

What must be watched out for with patients on chemotherapy

A

Septic neutropaenia

If a patient with cancer has fever, they would need antibiotics immediately

37
Q

What are the methds of cancer cell resistance to chemo drugs

A

Drug effluxed from the cell by ATP-binding cassette (ABC) transporters

DNA adducts replaced by Base Excision repair (using PARP)

DNA repair mechanisms upregulated and DNA damage is repaired (so no DNA double strand breaks)

38
Q

What are targeted therapies

A

monoclonal antibodies and small molecule inhibitors

39
Q

Why can monogenic cancers be treated easier

A

You can “cut the wiring” (mutation) in monogenic cancers but for others, parallel pathways or feedback cascades are activated

40
Q

How can dual kinase inhibitors help

A

Prevent feedback loops (which could compensate fr the blocked muation) but increase toxicities – new therapeutic strategies required

41
Q

What arethe 6 hallmarks of cancer

A 
Self –sufficient
Insensitive to anti-growth signals
Anti-apoptotic
Pro-invasive and metastatic
Pro-angiogenic
Non-senescent
42
Q

What are the 4 new hallmarks of cancer

A

Dysregulated metabolism
Evades the immune system
Unstable DNA
Inflammation

43
Q

What must normal cells have to divide (move out of G0)

A

Growth factor binding

44
Q

What percentage of receptor tyrosine kinases are assoiated with human malignancies

A

> 50% associated with human malignancies

45
Q

In which cancers are receptors over expressed

A

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

EGFR – over-expressed in breast and colorectal cancer

PDGFR- glioma (brain cancer)

46
Q

Give an example of when a receptor tyrosine kinase LIGAND ie overexpressed

A

VEGF – prostate cancer, kidney cancer, breast cancer

47
Q

Give examples of faulty receptors leading to constitutive (ligand independent) receptor activation

A

EGFR (lung cancer)

FGFR (head and neck cancers, myeloma)

48
Q

State three ways in which receptors can lead to unregulated proliferation

A

Over expression of receptor tyrosine kinase

Faulty receptor sleading to constitutive receptor activation

Overexpression of receptor ligand

49
Q

Outline what each of the following suffixes mean

  • momab
  • ximab
  • zumab
  • mumab
A

-momab (derived from mouse antibodies)

-ximab (chimeric= from animal) e.g
cetuximab

  • zumab (humanised) e.g. bevacizumab trastuzumab
  • mumab (fully human) e.g. panitumumab
50
Q

Differentiate humanised monoclonal antibodies and chimeric monoclonal antibodies

A

HUMANISED:

Murine (i.e. rodent) regions insterpsed with the heavy and light chains of the Fab portion of the antibody

CHIMAERIC antibody

Murine compoent of the variable region of the Fab section is maintained integrally (not interspersed)

51
Q

How do mAbs work

A

Target the extracellular component of the receptor

Neutralise the ligand

Prevent receptor dimerisation

Cause internalisation of receptor

52
Q

In addition to targeting the EC component of the receptor, what else can mABs do?

A

mAbs also activate Fcγ-receptor-dependent phagocytosis or cytolysis

induces complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC).

53
Q

mABs can also target what, other than receptors

A

The ligand

54
Q

Give 2 examples of monoclonal antibodyes

A

Bevacizumab binds and neutralises VEGF. Improves survival in colorectal cancer

Cetuximab targets EGFR

55
Q

What do small molecule ihibitors do

A

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

56
Q

What was the first targeted therapy

A

Glivex (i.e. imatinib) to work on CML due to BCR-ABL

57
Q

How does glivec work

A

Glivec is a small molecule inhibitor and targets the ATP binding region within the kinase domain

58
Q

T/f small molecule inhibiors only act on receptor TKs

A

F

Small molecule inhibitors act on receptor TKs but also intracellular kinases – therefore can affect cell signalling pathways

59
Q

Give examples of SMI inhibiting receptors

A

erlotinib (EGFR), gefitinib (EGFR), lapatinib (EGFR/HER2), sorafinib (VEGFR)

60
Q

Give examples of SMIs affecting intracelllar kinases

A

Sorafinib (Raf kinase)
Dasatinib (Src kinase)
Torcinibs (mTOR inhibitors)

61
Q

How can SMIs work, by acting on receptors

A

block cancer hallmarks (e.g VEGF inhibitors alter blood flow to a tumour, AKT inhibitors block apoptosis resistance mechanisms)

62
Q

T/F targeted therapy has slightly reduced toxicity relative to systemic therapy

A

F

By acting on receptors (either externally or internally), targeted therapies block cancer hallmarks (e.g VEGF inhibitors alter blood flow to a tumour, AKT inhibitors block apoptosis resistance mechanisms) WITHOUT the toxicity observed with cytotoxics

63
Q

What is advantage of mABs compared to SMI

A

mABs:
High specificity, caused ADCC, complement mediated cytotoxicity and apopotisis induction, can be radiolabelled, longer half life

SMI:
Can target TKs without EC domain or which are constitutively actiated (ligand independent), pleiotropic targets, oral administration, good penetration, cheap

64
Q

mABs is especially good for which malignancies

A

Haem

65
Q

What are disadvantages when comapirng mABs and SMIs

A

mABs:

Large/comlex structure (low tumour/BBB penetration), less usefula gainst bulky tumours, only useful against targets with EC domains, not useful for constitutivel activated receptors, cause allergy, IV admin, risky, expensive

SMI:
Shorter half life, more frequent admin. , mor eunexpected toxiity due to pleiotropic targets

66
Q

Outline the mechanism of resistance to targeted therapies

A

Mutations in ATP-binding domain (e.g BCR-Abl fusion gene and ALK gene, targeted by Glivec and crizotinib respectively)

Intrinsic resistance (herceptin effective in 85% HER2+ breast cancers, suggesting other driving pathways)

Intragenic mutations

Upregulation of downstream or parallel pathways

67
Q

How are anti-sense oligonucelotides useful in cancer treatment

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

68
Q

How might RNA interference be useful in cancer therapy

A

Single stranded complementary RNA

Compounds have to be packaged to prevent degradation - nanotherapeutics

69
Q

What are the obstacles in the way o fthe targeted approach

A

Tumour heterogeneity is a major obstacle to the targeted approach

70
Q

Outline the success story involving b-RAF

What are the side effects of the drug

A

Activating mutations of
B-Raf identified in 60%
melanomas

B-Raf inhibitor (vemurafenib)
showed dramatic Phase I activity
in melanoma (80% PR or CR)
Extends life span of mutation holders by 7 months

arthralgia, skin rash and photosensitivity

71
Q

Which mutation of b-RAF is commonly found in melanoma

A

Substitution of glutamic acid
for valine (V600E) causes a
500-fold increase in activity

72
Q

Outline the success story involving immune modulation via programmed cell death 1 (PD-1)

A

PD1 present on tumour cell surface

Required to maintain T cell activation

But after binding to the ligand PDL1, the body’s T cell could not recognise the tumour as foreign anymore

Blocking PDL1 or its receptor PD-1, immune system is stimulated again

Nivolumab (developed by BMS) is anti-PD1 antibody

73
Q

What is nivolumab, is it effective?

A

anti-PD1 antibody

delivered lasting responses

74
Q

What could be new therapeitoc avenes in cancer therapy

A

Nanotherapies – delivering cytotoxics more effectively

Virtual screening technologies to identify “undruggable” targets

Immunotherapies using antigen presenting cells to present “artificial antigens”

Targeting cancer metabolism

Canc (16 decks)

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