Cancer chemotherapy

Question 1

What is metastasis?

Answer 1

When cancer cells spread to other parts of the body through the blood and lymph systems.

Question 2

What is a tumour?

Answer 2

An abnormal mass of tissue that may be solid or fluid-filled.

Question 3

What are the 4 main types of cancer?

Answer 3

Carcinoma- tumours derived from the skin or lining tissues (epithelial cells).
Sarcoma- tumours that start off in connective tissue (cartilage/bones/fat/nerves).
Blastoma- tumours derived from embryonic or immature cells (quite rare).
Lymphoma/leukaemia- arises from the blood forming cells originiating in bone marrow and matures in the blood/ lymph nodes, leukaemia is thought to be the only cancer where tumours are not formed.

Question 4

List some of the causes of cancer

Answer 4

Environmental/lifestyle, radiation, genetic factors, viral/bacteria, chemicals, age etc.

Question 5

What are the treatments available for cancer?

Answer 5

Surgery, chemotherapy, radiation therapy and newer approaches involving biologics.

Question 6

What are the reasons radiotherapy is used in cancer treatment nowadays?

Answer 6

As a stand alone treatment, to shrink a tumour before surgery, to reduce the risk of a cancer coming back after surgery, to complement chemotherapy.

Question 7

When were nitrogen mustard gases developed and what is their general formula?

Answer 7

During WW2, RN(CH2CH2Cl)2

Question 8

How do nitrogen mustards work?

Answer 8

They alkylate and cross-link DNA, preventing further replication.

Question 9

Name a successful structural analogue of sulfonamide

Answer 9

Methotrexate

Question 10

What does DEPT stand for and aim to do?

Answer 10

Directed enzyme prodrug therapy aimed at improving the targeting of drugs to the tumour and minimising side effects, eg ADEPT- uses antibodies to direct the drug to the tumour.

Question 11

What is the general ring structure for steroids?

Answer 11

6, 6, 6, 5

Question 12

Name 2 anti-cancer drugs that have been developed based on the estrogen receptor and explain whether each one is an agonist or an antagonist

Answer 12

Stilboestral- agonist- similar carbon framework and oxygen functionality.
Tamoxifen- antagonist- similar carbon framework so binds, but lack of oxygen functionality.

Question 13

Describe the general structure of DNA

Answer 13

Phosphate-sugar backbone, complementary H-bonding between the bases (which have nucleophillic N/O functionality). DNA forms duplexes (anti-parallel double helix).

Question 14

What is the obvious limitation to developing a drug that interferes with the production/operation of DNA?

Answer 14

We are biosynthesising/replicating DNA constantly, therefore if that is targeted there will be likely toxicity.

Question 15

How do nitrogen mustards work?

Answer 15

Interstrand crosslinking agents (crosslink DNA), therefore preventing replication as the 2 strands can’t unwind to generate 2 new DNA molecules.

Question 16

What is the name and formula for the most useful nitrogen mustard?

Answer 16

Mustine, MeN(CH2CH2Cl)2

Question 17

How was uramustine designed?

Answer 17

So that the uracil provided stabilisation and the aim was also that the uracil portion would enhance takeup by the rapidly growing cancer cells in mistake for uracil itself- ie aiming for better selectivity.

Question 18

Define prodrug

Answer 18

Inactive compound that is metabolised in the body to give the active form.

Question 19

What is cyclophosphamide and why is it less reactive than earlier mustards?

Answer 19

Pro-drug analogue of nitrogen mustard; nitrogen is now tied up as an amide so can be taken orally (big advantage over injection).

Question 20

What enzyme transforms cyclophosphamide in the liver to the active form?

Answer 20

Cytochrome p450 (oxidase enzyme).

Question 21

What is the issue with the side product produced from cyclophosphamide and how can it be resolved?

Answer 21

ACROLEIN- accumulates in the bladder and can cause bleeding etc. Co-administer with a sulfur compound which mops up acrolein, giving a highly water-soluble adduct for excretion.

Question 22

How does ADEPT work and how is selectivity achieved?

Answer 22

An antibody linked to the key enzyme is developed against a tumour antigen and injected into the blood, aiming to selectively bind to the tumour. Then, the prodrug is administered into the blood circulation and hopefully converted into an active cytotoxic drug by the enzyme, only within the tumour. Selectivity is achieved by the tumour specificity of the enzyme.

Question 23

What does carboxypeptidase enzyme convert an amide prodrug into?

Answer 23

An active cross-linking agent.

Question 24

What does the beta-lactamase enzyme cleave?

Answer 24

The peptide bond in a beta-lactam ring- ie it opens the strained 4-membered ring.

Question 25

What is a DNA intercalating agent and how does it work as a cancer treatment?

Answer 25

A substance that inserts itself into DNA and binds by NON COVALENT MEANS, may kill cancer cells by altering the helical structure of DNA and so stopping them from dividing.

Question 26

Name examples of major and minor groove binders

Answer 26

Major= doxorubicinm and pixanthrone
Minor= distamycin

Question 27

What is the general required structure of DNA intercalators?

Answer 27

Often based on flat aromatic or heteroaromatic compounds that can fit in a groove of DNA between 2 base pairs, thus disrupting the replication process.

Question 28

What non-covalent interactions help to ‘lock’ the intercalating agent into the DNA?

Answer 28

Ionic bonds/interactions (drugs often have at least 1 N-group which once protonated can form ionic bonds to the negatively charged phosphate DNA backbone), pi-stacking.

Question 29

Name the enzyme that reduces folic acid in its biosynthetic pathway

Answer 29

Dihyrdofolate reductase (DHFR).

Question 30

What does THF stand for?

Answer 30

Tetrahydro-folic acid

Question 31

Compare folic acid and methotrexate, suggesting a mode of action for methotrexate

Answer 31

Methotrexate is accepted by DHFR then binds to hydroxymethyl transferase, but can’t undergo formylation so blocks folic acid turnover. Acts as an ANTAGONIST.

Question 32

Describe the mode of action of 5-fluorouracil

Answer 32

Principally interferes with the biosynthetic route leading to the DNA building block based on thymine, the nucleotide thymidine. It acts as an irreversible inhibitor of thymidylate synthase, blocking the biosynthesis of the key nucleotide thymidine monophosphatase needed for DNA replication. So rapidly dividing cancer cells undergo ‘thymineless cell death’.

Question 33

Describe the simplified biosynthetiic route to thymidine

Answer 33

Thymidylate synthetase acts as a catalytic nucleophile in a Michael reaction (nucleophillic addition to an alpha,beta-unsaturated ketone) with 10-formyl-THF providing the one carbon electrophile (Me+). Then, loss of a proton regenerates the enzyme catalyst and re-installs the alkene.

Question 34

Why does 5-fluorouracil irreversibly inhibit thhymidylate synthase?

Answer 34

Because (after the addition) the fluorine can’t be removed by a base.

Question 35

What are the major structural elements of the mitotic spindle and what are they formed from?

Answer 35

Microtubule polymer, formed from tubulin proteins.

Question 36

What was the drug Taxol extracted from?

Answer 36

The bark of Pacific yew trees

Question 37

Describe the mode of action of taxol

Answer 37

Stabilises the microtubule polymer and protects it from disassembly so cell division is prevented further down the line.

Question 38

What alternative tree was used to extract taxol and why?

Answer 38

European yew, as isolation of the pacific yew tree bark killed the tree (not very sustainable).

Question 39

What closely-related compound to taxol is found in the needles of the European yew tree?

Answer 39

10-deacetylbaccatin