Cancer Chemotherapy

Question 1

What type of medication targets Proliferation Signalling

Answer 1

EGFR inhibitors

Question 2

What type of medication targets Evading growth suppressors

Answer 2

Cyclin-Dependent kinase inhibitors

Question 3

What type of medication targets Enabling Replicative immortality

Answer 3

Telomerase Inhibitors

Question 4

What type of medication targets Inducing angiogenesis

Answer 4

Inhibitors of VEGF signalling

Question 5

What type of medication targets Genome instability and Mutation

Answer 5

PARP inhibitors

Question 6

What type of medication targets Resisting cell death

Answer 6

Proapoptotic BH3 mimetic

Question 7

What do Anti-mitotics target?

Answer 7

Targets microtubules

Question 8

What are microtubules formed of?

Answer 8

alpha and beta tubulin dimers

Question 9

How do anti-mitotics target microtubules?

Answer 9

Disrupt assembly- Bind to free alpha-beta tubulin dimers
or
disrupt disassembly- stabilises microtubules and prevents cell division

Question 10

Give an example of a disrupting assembly anti-mitotic

Answer 10

Vinblastine- amine protonated
vincristine- amide not protonated - slightly more potent

Question 11

Give an example of a disrupting DISassembly anti-mitotic

Answer 11

Paclitaxel- most common
or
Docetaxel- more soluble

Question 12

How can resistance be developed for anti-mitotics?

Answer 12

Overexpression of p-glycoproteins
Mutations in tubulin gene

Question 13

What is an anti-metabolite?

Answer 13

An analogue of precursors for macromolecules
They inhibit essential enzymes

Question 14

How does poisoning Thymidylate synthesis work?

Answer 14

5Fu -> FDUMP inhibits dUMP -> dTMP
Poisons enzyme
Michael addition
Causes DNA damage

Question 15

What is an Alkylator?

Answer 15

Nitrogen mustards

Question 16

How do alkylators work?

Answer 16

Crosslink DNA- Prevents DNA polymerase from separating strands.
Crosslink between N7 of Guanine (interstrand crosslink)

Question 17

What chemical group is reactive on an alkylator?

Answer 17

The highly reactive aziridinium ion (N containing three membered ring)

Question 18

Give an example of an Alkyl nitrogen mustard

Answer 18

melphalan (L-PAM)
Chlorambucil
cyclophosphamide (prodrug)

Question 19

How are aniline mustards better?

Answer 19

Less side effects due to Lone pair on N delocalised into ring

Question 20

Explain how cyclophosphamide is a good drug (nitrogen mustard)

Answer 20

Prodrug
Not active in body- has to be activated- less TOXICITY
Has to be activated by cytochrome P450

Question 21

How can resistance be developed in relation to Nitrogen Mustards?

Answer 21

Increased expression of glutathione-S-transferase & levels of glutathione (thiol will substitute with triangle N group)
Can administer glutathione-S-transferase inhibitors^
Increased expression of excision repair enzymes
Changes in drug repair

Question 22

What are DNA platinating agents?

Answer 22

Cisplatin anti-tumour drug

Question 23

What chemical changes happen to cisplatin in the body?

Answer 23

the 2 chlorine groups are displaced with water (OH groups in turn)

Question 24

How do platinating agents work? suspectedly….

Answer 24

Inhibit DNA Polymerase
Target N7 Guanine

Question 25

How can resistance develop for DNA platinating agents?

Answer 25

Increase repair mechanism for intrastrand crosslinks (on same strand) over expression of glutathione

Question 26

How do Topoisomerase inhibitors work?

Answer 26

Intercalate into DNA, causes shape of helix to change- therefore enzymes cant process DNA well- Prevents cell replication and causes cell death Prevents topoisomerase from fixing double strand break

Question 27

examples of DNA intercalators (anthracyclines)

Answer 27

Doxorubicin Daunorubicin

Question 28

How do anthracyclines work

Answer 28

Amino sugar sits in minor groove of DNA Planar aromatic structure fit into DNA 3 rings, 2 aromatic, middle has 2 c=o which are parallel

Question 29

Whats the difference between DNA topoisomerase 1 and 2?

Answer 29

Topo 1 cuts 1 strand Topo 2 cuts 2 strands- also fixes double strand break

Question 30

What do anthracyclines do in relation to Topoisomerases?

Answer 30

Inhibits topo 2 by preventing the fix of a double strand break

Question 31

What are the modern approaches to chemo

Answer 31

PARP inhibitors Tyrosine Kinase Inhibitors

Question 32

How do PARP inhibitors work

Answer 32

Inhibits PARP (Poly ADP ribose polymerase) which fixes single strand breaks caused by topoisomerase 1 leads to cell death as fix is prevented and double strand break may occur instead.

Question 33

What are the genes that are targeted by PARP inhibitors?

Answer 33

BRCA1 AND BRCA2 - Fix double strand break, if mutation than this cannot be fixed. In healthy cells- can undergo normal homologous recombination.

Question 34

What is Olaparib?

Answer 34

BRCA PARP Inhibitor

Question 35

What are tyrosine Kinase Inhibitors?

Answer 35

NIBS- target proteins

Question 36

What are BCR and ABL?

Answer 36

2 genes- chromosome 9 and chromosome 22

Question 37

What forms the Philadelphia chromosome

Answer 37

translocation between bcr and abl (9 and 22)

Question 38

What does the Philadelphia (BCR-ABL) chromosome do?

Answer 38

Protein is always on- proliferation Acts as a tyrosine kinase Found in CML

Question 39

What was the first tyrosine kinase inhibitor? (BCR-ABL kinase inhibitor)

Answer 39

Imatinib

Question 40

What about Imatinib makes it a tyrosine kinase inhibitor?

Answer 40

Methyl group caused selectivity for ABL kinase Piperidine means water soluble 2-phenylaminopyrimidine initial structure

Question 41

What does the BRAF pathway cause?

Answer 41

Cell proliferation Gene expression Mitosis Differentiation

Question 42

What does a mutation in BRAF protein cause?

Answer 42

Constant signalling and activation Causes uncontrolled cell proliferation

Question 43

What are vemurafenib , dabrafenib and sorafenib examples of?

Answer 43

BRAF inhibitors

Question 44

what are erlotinib or gefitinib

Answer 44

EGFR for NSCLC inhibits ras

Question 45

Cetuximab is for what

Answer 45

CRC blocks egfr (HER1)

Question 46

What is the mutation for Braf inhibitors

Answer 46

single mutation of V600E