12. Biological basis of cancer treatment

Question 1

How is cytotoxic chemotherapy generally administered?

Answer 1

IV

Question 2

Recall the 6 types of non-targetted cytotoxic chemotherapy available

Answer 2

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

Question 3

Recall the MOA of alkylating agents

Answer 3

Add alkyl groups to guanine residues in DNA, producing cross-linking and therefore preventing DNA unravelling for replication. Triggers apoptosis.

Question 4

Recall an example of an alkylating agent

Answer 4

Chlorambucil

Question 5

Recall the MOA of pseudo-alkylating agents

Answer 5

Adds platinum to guanine residues in DNA - this creates cross-links between strands and prevents uncoiling for replication –> apoptosis

Question 6

Recall an example of a pseudo-alkylating agent

Answer 6

Cisplatin

Question 7

Recall the 2 classes of antimetabolite cytotoxic chemotherapy

Answer 7

1. Purine/pyrimidine analogues

2. Folate antagonists

Question 8

Recall the MOA of purine/pyrimidine analogues as a cytotoxic chemotherapy

Answer 8

By masquerading as a base they inhibit DNA synthesis - breaks DNA strand –> apoptosis

Question 9

Recall the MOA of folate antagonists as a cytotoxic chemotherapy

Answer 9

Inhibit dihydrofolate reductase, thus preventing nucleic acid production

Question 10

Recall an example of an anti-folate drug

Answer 10

Methotrexate

Question 11

Recall the MOA of anthracyclines as a cytotoxic chemotherapy

Answer 11

Intercalate between bases in DNA, producing free radicals and therefore causing damage to DNA and cell membrane

Question 12

Recall an example of an anthracycline drug

Answer 12

Doxorubicin

Question 13

Recall the MOA of vinca alkaloids as a cytotoxic chemotherapy

Answer 13

Inhibition of assembly of mitotic spindle

Question 14

Recall the MOA of taxanes as a cytotoxic chemotherapy

Answer 14

Inhibition of disassembly of mitotic spindle

Question 15

What is the normal function of topoisomerase?

Answer 15

DNA uncoiling: induces temporary strand breaks in the phosphodiester backbone to protect free ends of DNA from aberrant recombination events

Question 16

Recall the MOA of topoisomerase inhibitors as a cytotoxic chemotherapy

Answer 16

They alter the binding of the topoisomerase complex to make breaks in phosphodiester backbone permanent

Question 17

Recall 3 possible mechanisms of resistance to chemotherapy

Answer 17

1. DNA-repair mechanisms upregulated
2. PARP excises faulty bases
3. Cell effluxes cell via ABC transporters (ATP-binding cassette)

Question 18

Recall 2 classes of targeted chemotherapy

Answer 18

1. Small molecule inhibitors

2. Monoclonal antibodies

Question 19

What type of malignancy are monoclonal antibody-based chemotherapies particularly effective against?

Answer 19

Blood malignancies

Question 20

Recall 3 advantages of small-molecule inhibitors as a chemotherapy

Answer 20

1. Cheap
2. Oral administration
3. Can target TKs with no EC domain

Question 21

Recall 3 useful comparisons of the usefulness of monoclonal antibodies vs small molecule inhibitors

Answer 21

1. Half life: much longer for Monoclonals
2. Ability to target TKs without EC domains: only SMIs
3. Cost: SMIs much cheaper

Question 22

Recall a disadvantage of monoclonal antibodies as a chemotherapy

Answer 22

Low penetration due to their bulky structure

Question 23

Recall a disadvantage of small molecule inhibitors as a chemotherapy

Answer 23

Unexpected toxicity due to pleiotropic targets

Question 24

Recall the MOA of small molecule inhibitors

Answer 24

They bind to the intracellular kinase of RPTKs leading to blockade of autophosphorylation and therefore downstream signalling

Question 25

Give an example of a small molecule inhibitor and its MOA

Answer 25

Glivec

Binds the ATP-binding region of the kinase domain of ABL1 - used to treat Philadelphia chromosome CML

Question 26

Recall the MOA of monoclonal antibodies as a chemotherapy

Answer 26

Bind the extracellualar domain of RPTKs, preventing dimerisation and leading to receptor endocytosis

Question 27

Recall a monoclonal antibody used in colorectal cancer

Answer 27

Bevacizumab - targets VEGF

Question 28

Recall 3 possible mechanisms of resistance to targeted chemotherapies

Answer 28

1. Heterogeneity of tumour
2. Mutation in ATP-binding region of RPTK
3. Upregulation of a different proliferation pathway to divide despite drug

Question 29

Recall 2 genome-related chemotherapy options

Answer 29

1. RNA interference

2. Anti-sense oligonucleotides

Question 30

What are anti-sense oligonucleotide therapies particularly useful for?

Answer 30

“undruggable” targets

Question 31

Recall 4 side effects that are common to most cytotoxic chemotherapies

Answer 31

1. Alopecia
2. Bone marrow suppression
3. Fatigue
4. Nausea and vomiting

Question 32

In which tissues are alkylating agents particularly toxic?

Answer 32

Kidneys, mouth, neurons

Question 33

In which tissues are anthracyclines particularly toxic?

Answer 33

Cardiac

Question 34

In which tissues are vinca alkaloids and taxanesparticularly toxic?

Answer 34

Nerves

Question 35

Recall 3 new therapeutic avenues being explored for cancer therapy

Answer 35

1. Nanotherapy for cytotoxic drug delivery
2. Immunotherapies
3. Targeting cancer metabolism