Cancer

Question 1

Over 40% of cancers are preventable. True or false?

Answer 1

True

Question 2

Nitrogen mustard is more toxic than sulphur mustard. True or false?

Answer 2

False

Question 3

Nitrogen mustard is no longer used clinically. True or false?

Answer 3

False - used clinically in combination with other drugs

Question 4

What is the mechanism of action of alkylating agents (mustards)?

Answer 4

They attach an alkyl group to DNA (guanine base)

This causes linkages between the DNA strands, inhibiting DNA synthesis

Question 5

Alkylating agents only attack cancerous cells. True or false?

Answer 5

False - also attack normal cells that divide frequently - i.e. cells of GIT, bone marrow etc

Question 6

What is the least toxic alkylating agent that is used in chemotherapy?

Answer 6

Chlorambucil

Question 7

What are 3 ways in which toxicity of alkylating agents can be reduced?

Answer 7

Only form the electrophile slowly in the tumour
Attach alkylating agent to an “amino acid”
Pro-drug

Question 8

Why do tumours require amino acids?

Answer 8

For protein synthesis - so making a chemotherapeutic drug look like an amino acid, will allow it to be taken up by the cancerous cell

Question 9

Which alkylating agent gets taken up into the tumour cell by a phenylalanine amino acid transporter?

Answer 9

Melphalan

Question 10

Name an alkylating agent that is a prodrug

Answer 10

Mitomycin C

Question 11

Alkylating agents contain highly nucleophilic groups. True or false?

Answer 11

False - electrophilic

Question 12

Alkylating agents form hydrogen bonds with nucleophilic DNA bases. True or false?

Answer 12

False - covalent bonds

Question 13

Alkylating agents are carcinogenic themselves. True or false?

Answer 13

True - they produce long term side effects

Question 14

Name 3 alkylating agents

Answer 14

Chlorambucil
Mitamycin C
Melphalan

Question 15

Name a drug that involves the binding of metal complexes to DNA.

Answer 15

Cisplatin

Question 16

How do metal complexes that bind to DNA work?

Answer 16

Neutral inactive molecule acting as a prodrug
Platinum covalently binds to chloro-groups
Ammonia molecules act as ligands
Activated in cells with low chloride concentration
Chloride substituents are replaced with neutral water ligands, producing positively charged species

Question 17

Cisplatin binds to regions in DNA that are rich in cytosine. True or false?

Answer 17

False - guanine

Question 18

Doxorubicin is an alkylating agent. True or false?

Answer 18

False - intercalating agent

Question 19

What is the mechanism of action of doxorubicin?

Answer 19

the planar tetracyclic chromophore is inserted between adjacent pairs and is stabilised by electrostatic interactions between DNA phosphate groups and the positively charged amino group of the sugar. As a result inhibits action of topoisomerase II
Also generates oxygen free radicals which leads to DNA damage

Question 20

Which drug can be used to reduce the cardiotoxicity of doxirubicin?

Answer 20

Dexrazoxane

Question 21

Explain the action of topoisomerase II

Answer 21

It relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand.
Tyrosine (in the topoisomerase enzyme) are involved in the chain breaking process and form covalent bond with DNA

Question 22

Name a topoisomerase II inhibitor and outline its mechanism of action

Answer 22

Etoposide - forms a ternary complex with DNA and topoisomerase II and prevents the re-ligation of DNA and so the double strand breaks

Question 23

Which chemotherapeutic drug is a semi-synthetic derivative of podophyllotoxin poison, extracted from the Mandrake plant?

Answer 23

Etoposide

Question 24

Which drug is only effective in chemo-sensitive tumours such as leukaemias, testicular cancer and small cell lung cancer?

Answer 24

Etoposide

Question 25

Etoposide has less major long term irreversible organ specific toxicity compared to doxorubicin and cisplatin. True or false?

Answer 25

True

Question 26

What are the effects of vincristine and vinblastine on mitosis?

Answer 26

Prevent polymerisation of microtubules

Question 27

What is the effect of taxol on mitosis?

Answer 27

Binds and stabilises microtubules

Question 28

How do anti-metabolites work?

Answer 28

they interfere with the production of nucleic acids

Question 29

Give an example of an anti-metabolite drug

Answer 29

5-FU | Methotrexate

Question 30

What are the advantages of antisense therapy?

Answer 30

Has the same effects as enzyme inhibitors or receptor antagonists (i.e. same as conventional drugs) It is highly specific where the oligonucleotide is 17 nucleotides or more Smaller doses are required compared to inhibitors or antagonists

Question 31

What are the disadvantages of antisense therapy?

Answer 31

'Exposed' sections of mRNA must be targeted Instability and polarity of oligonucleotides Short lifetime of oligonucleotides and poor absorption across cell membranes

Question 32

What are the advantages of micro-RNA therapy?

Answer 32

siRNAs have potential to be used in gene therapy Greater efficiency in silencing mRNA than conventional antisense therapy One siRNA could lead to cleavage of many mRNA molecules

Question 33

What are the disadvantages of micro-RNA therapy?

Answer 33

siRNAs need to be metabolically stable Difficult to reach target cells Devise a mechanism to ensure entry to target cells

Question 34

What is micro-RNA?

Answer 34

short segments of double stranded RNA - recognised by RISC to to produce siRNA

Question 35

What are the 3 essential domains of tyrosine kinase receptors?

Answer 35

``` ligand binding site (extracellular domain) transmembrane domain (alpha helix) domain with tyrosine kinase activity (cytosolic) ```

Question 36

Name 2 drugs which target kinases by disrupting ligand-receptor interactions

Answer 36

Bevacizumab | Trastuzumab (Herceptin)

Question 37

How does bevacizumab work?

Answer 37

It binds to a growth factor (VEGF) therefore preventing its binding to TK receptors. This interferes with tumour blood vessel development

Question 38

Which drug is used first line for colorectal cancers?

Answer 38

Bevacizumab

Question 39

How does trastuzumab work?

Answer 39

targets HER2 receptor which is over expressed in late stage breast cancers. It prevents binding of EGF to the HER2 receptor and therefore prevents signal transduction

Question 40

Herceptin works on all cancers. True or false?

Answer 40

False - only HER2 positive cancers as it only works on tumours where this protein is over expressed

Question 41

Name 2 drugs which target kinases by blocking ATP binding

Answer 41

Imatinib | Gefitinib

Question 42

How does imatinib work?

Answer 42

Blocks ATP from binding to bcr/abl fusion protein

Question 43

How does gefitinib work?

Answer 43

Prevents ATP binding to EGFR

Question 44

EGFR is overexpressed in many solid tumours. True or false?

Answer 44

True - that is why it is a target for cancer therapy as binding of EGF to EGFR receptor causes dimerisation and tyrosine is phosphorylated as a result -> signalling

Question 45

What is one way in which oestrogen secretion can be reduced?

Answer 45

Surgery

Question 46

What drug can reduce oestrogen secretion?

Answer 46

Tamoxifen

Question 47

Tamoxifen is a non-competitive inhibitor. True or false?

Answer 47

False - competitive inhibition of oestrogen binding to its receptor

Question 48

Which two drugs can inhibit MAPK signalling?

Answer 48

Dabrafenib and vemurafenib

Question 49

What are the two ways in which inflammation in cancer can be targeted?

Answer 49

Inhibiting pro-tumour inflammation | Promoting anti-tumour inflammation

Question 50

Name the monoclonal antibody that is a CTLA4 inhibitor

Answer 50

Ipilimumab

Question 51

Name the monoclonal antibody that is a PD-1 inhibitor

Answer 51

Nivolumab