Biological Basis of Cancer Therapy

Question 1

Which of the pseudoalkylating agents does not cause alopecia?

Answer 1

Carboplatin

Question 2

Besides nausea and vomiting and tiredness, what side effects do alkylating and pseudoalkylating agents have?

Answer 2

Toxicity - Ototoxicity, neurotoxicity and nephrotoxicity
Diarrhoea
Alopecia (except for carboplatin)

Question 3

Besides nausea and vomiting and tiredness, what side effects do anti-metabolites have?

Answer 3

BM suppression; anaemia, neutropenia, thrombocytopenia 
Mucositis 
Diarrhoea 
Palmar-plantar erythrodysesthesia 
Alopecia

Question 4

Name an antimetabolite which pretends to be a purine

Answer 4

Dacarbazine
6-mercaptopurine
Fludarabine

Question 5

Name an antimetabolite which pretends to be a pyrimidine

Answer 5

5-Fluorouracil
Capecitabine
Gemcitabine

Question 6

Name two cytosine analogues

Answer 6

Capecitabine

Gemcitabine

Question 7

How does methotrexate work?

Answer 7

Folate antagonist therefore interferes with DNA synthesis

Question 8

Name two anthracyclines

Answer 8

Doxorubicin

Epirubicin

Question 9

Besides nausea and vomiting and fatigue, what side effects do anthracyclines cause?

Answer 9

Cardiac toxicity 
Alopecia 
Neutropenia 
Red urine 
Skin changes

Question 10

What is the anthracycline-induced cardiac toxicity thought to be due to?

Answer 10

Free radicals

Question 11

What side effects do vinca alkaloids and taxanes cause besides nausea and vomiting?

Answer 11

Peripheral and autonomic neuropathy 
Alopecia 
Arthralgia (joint pain)
BM suppression 
Allergic reaction

Question 12

What are the two topoisomerases and what do they do?

Answer 12

Topo 1 - normally prevents single stranded DNA tortional strain during replication and transcription

Topo 2 - prevents double stranded DNA torsional strain

Question 13

Give examples of topoisomerase 1 inhibitors

Answer 13

Topotecan

Irinotecan

Question 14

Give examples of topoisomerase 2 inhibitors

Answer 14

Etoposide

Question 15

What side effect does irinotecan specifically cause and what is the treatment for this?

Answer 15

Acute cholinergic syndrome (diarrhoea, cramping, diaphoresis)
Anticholinergics e.g. atropine

Question 16

What is diaphoresis?

Answer 16

Increased sweating

Question 17

Give three mechanisms of resistance to cancer therapy

Answer 17

Upregulation of DNA repair
Base excision repair (to remove drug) using ‘PARP’
Removal of drug from cell using ABC (ATP-binding cassette transporters)

Question 18

Which receptor is overexpressed in gliomas?

Answer 18

PDGFR

Question 19

Which receptor is overexpressed in breast and colorectal cancers?

Answer 19

EGFR

Question 20

VEGF is overexpressed in which cancers?

Answer 20

Prostate, kidney and breast cancer

Question 21

What name is given to the activation of receptors independent of ligands?

Answer 21

Constitutive receptor activation

Question 22

Give an example of two receptors in cancer which can be activated independent of ligands, and where these are found

Answer 22

EGFR - lung cancer

FGFR - head and neck cancers and myelomas

Question 23

What do the -momab suffix for monoclonal antibodies mean?

Answer 23

MOuse antibodies = MOmab

Question 24

What do the -zumab suffix for monoclonal antibodies mean?

Answer 24

Zumab = humaniZed

Question 25

What do the -mumab suffix for monoclonal antibodies mean?

Answer 25

MUmab = hUMan

Question 26

What do the -ximab suffix for monoclonal antibodies mean?

Answer 26

Ximab = chimeric antibodies

Question 27

How do monoclonal antibodies work in cancer?

Answer 27

``` They target the extracellular domain of receptors, thereby: Neutralising ligands Preventing receptor dimerization Causes internalisation of the receptor Stimulating cell death via complement or Antibody dependent cellular toxicity ```

Question 28

Which drug targets the EGFR receptor?

Answer 28

Cetuximab - for bowel cancer

Question 29

Which drug targets VEGF?

Answer 29

Bevacizumab - also for colorectal cancer

Question 30

How do small molecule inhibitors work?

Answer 30

They bind to tyrosine kinases and prevent phosphorylation and downstream signalling

Question 31

Give an example of a small molecule inhibitor

Answer 31

Glivec

Question 32

How does Glivec work and what is it used in?

Answer 32

It targets the ATP binding region within the kinase domain. Used in CML due to Bcr-Abl gene

Question 33

What are the mechanisms of resistance to targeted therapies?

Answer 33

Mutations in the ATP binding domain Intrinsic resistance e.g. the cancer produces a different product Intragenic mutations Upregulation of downstream pathways

Question 34

How do anti-sense oligonucleotides work?

Answer 34

They bind to completementary RNA sequence and prevent translation by recruiting RNAse H to cleave the target mRNA

Question 35

What mutation do 60% of melanomas have?

Answer 35

B-Raf mutation - substitution of glutamic acid for valine

Question 36

Why is this mutation in melanomas significant in therapy?

Answer 36

B-Raf inhibitors have been successful in treatment - life span extended by 7 months

Question 37

Give an example of a B-Raf inhibitor

Answer 37

Vemurafenib

Question 38

How does RNA interreference work?

Answer 38

Single stranded complementary RNA

Question 39

Name something which can bind to T-cells to prevent them from recognising cancer

Answer 39

PD-1 (programmed-death 1)

Question 40

Which drug has been used to block PD-1?

Answer 40

Nivolumab

Question 41

Which cancers have been targeted by Nivolumab?

Answer 41

Melanoma Non-small cell lung cancer Renal cell carcinoma

Question 42

What are humanised monoclonal antibodies?

Answer 42

Antibodies from non-human species are taken. Their protein sequences are modified to increase similarity ot human antibodies.

Question 43

Explain how humanised monoclonal antibodies work

Answer 43

The murine (mouse) regions are interspersed with light and heavy chains of Fab portion

Question 44

What are chimeric monoclonal antibodies?

Answer 44

Antibodies from various species are taken and spliced together

Question 45

What do mAbs activate which causes phagocytosis of the target cells?

Answer 45

Fc gamma-receptor

Question 46

What else can Fc gamma-receptor binding cause?

Answer 46

Cytolysis

Question 47

What are the two downstream effects of cytolysis or phagocytosis induced by Fc-gamma receptor binding of monoclonal antibodies?

Answer 47

Antibody-dependent cellular cytotoxicity | Complement dependent cytotoxicity