Nick (anti-cancer drugs)

Question 1

Cancer treatment

Answer 1

There are three traditional approaches to the treatment of cancer:
- Surgery
- Radiotherapy
- Chemotherapy
Chemotherapy is often used alongside surgery and radiotherapy.

Combination therapy is used as this has increase efficacy of action, decreased toxicity and evasion of drug resistance.
As cancer cells are derived from normal cells, identifying targets unique to cancer cells is not easy.
Most traditional anticancer drugs work by disrupting the function of DNA and are classed as cytotoxic.

Question 2

Mechanisms of action

Answer 2

There are various anti-cancer drugs with different mechanisms of action. These include:
- Alkylating and metalling agents
- Intercalating agents
- Topoisomerase poisons
- Chain cutters
- Chain terminators

These interact directly with DNA to inhibit its various functions.

Question 3

Antimetabolites

Answer 3

Another way to disrupt DNA function is to inhibit the enzymes involved in the synthesis of DNA. These are antimetabolites. They include:
- Dihydrofolate reductase inhibitors
- Thymidylate syntheses inhibitors
- Ribonucleotide reductase inhibitors
- Adenosine deaminase inhibitors
- DNA polymerase inhibitors

Question 4

Other types of chemotherapy

Answer 4

Anti-cancer drugs can also act on structural proteins such as tubulin, a structural protein crucial in cell division.

Paclitaxel binds to tubulin and causes cell division cycle to be halted. Used to treat cervical cancers.

Question 5

Enzyme inhibition

Answer 5

Anti-cancer drugs can also inhibit enzymes involved in angiogenesis (formation of new blood vessels), metastasis and apoptosis.
These include matrix metalloproteinase inhibitors and many others.
MMPs are zinc dependant enzymes that degrade extracellular matrix and encourage angiogenesis, tumour propagation, and metastasis.

Question 6

Receptor inhibition

Answer 6

Anti-cancer drugs can be used to inhibit receptors for growth hormones and the various signal proteins and kinases in the signal transduction pathways
Hormone based therapies, monoclonal antibodies, and gene therapy have also been used as anti-cancer agents

Question 7

Alkylating agents

Answer 7

Contains highly electrophilic groups that form covalent bonds to nucleophilic groups in DNA.
They prevent replication and transcription and are useful anticancer agents. However, there can be toxic side effects.
Alkylating agents can cause interstrand (between bases on both strands) and intrastrand (between bases on the same strand) crosslinking if two electrophilic group present.
Alkylation of nucleic acid basses can result in miscoding.

Question 8

Examples of alkylating agents

Answer 8

Nitrogen mustards are example of alkylating agents that cause interstrand and intrastrand crosslinking and prevents replication.

Question 9

Nitrogen mustards mechanism of action

Answer 9

Chloromethine loses -Cl to become Aziridinium ion.
Lone pair on N in guanine attracted to C in ion.
Loses another -Cl.
Lone pair on N on guanine on other strand attracted to positive charge to form cross linked DNA.

Question 10

Chlormethine

Answer 10

Chlormethine is highly reactive and can react with water, blood and tissues. It is too reactive to survive the oral route and must be administered intravenously.
Other nitrogen mustards used an anti-cancer drugs include:
- Melphalan
- Uracil mustard
- Estramustine
- Chlorambucil
- Ifosamide

Question 11

Melphalan

Answer 11

Melphalan doesn’t undergo the side reactions like chlormethine because the benzene ring in melphalan is electron withdrawing via resonance so the lone pair on N is less available.

Melphalan’s structure mimics the amino acid phenylalanine meaning it is more likely to be recognised as an amino acid and get taken into cells by transport proteins.

Question 12

Metallating agents

Answer 12

Metallation is a chemical reaction that forms a bond to a metal. Cis-platin is a metallating agent used to treat cancer.

Question 13

Cisplatin

Answer 13

‘Cis’ is from the arrangement of the chlorines and ammonias (cis/trans).
It is activated in cells with low chloride concentration, causing chloroformed substituents to be replaces with neutral water ligands, forming a positively charged species.
Cl leaves molecules. Lone pair on O in H2O attracted to Pt and replaces that ligand. Same thing happens with other Cl and a 2+ species is formed. DNA replaces the water ligands.

Cisplatin binds to DNA in regions rich in guanine units and causes intrastrand crosslinks rather than interstrand crosslinks.
This causes localised unwinding of DNa double helix and inhibits transcription.

Question 14

Alkylating and metallating agents summary points

Answer 14

Alkylating agents contain electrophilic groups that react with nucleophilic centres in DNA. If two electrophilic groups are present, interstrand crosslinking of the DNA is possible.
Nitrogen mustards react with guanine groups on DNA to produce crosslinking.
Nitrogen mustards reactivity can be lowered by adding electron withdrawing groups to the N.
Incorporation of biosynthetic building blocks aids the uptake into rapidly dividing cells.
Cisplatin and its analogues are metallating agents which cause intrastrand crosslinking. They are commonly used for the treatment of testicular and ovarian cancers.

Question 15

Intercalating agents

Answer 15

Intercalating agents contain planar aromatic or heteroaromatic ring systems. (Flat so it can get between layers and disrupt bonding in helix).
These planar systems slip between the layers of nucleic acid pairs and disrupt the shape of the helix.
Intercalation prevents replication and transcription.

Question 16

Examples of intercalating agents

Answer 16

Proflavine
Dactinomycin
Doxorubicin

Question 17

Bleomycin

Answer 17

Another intercalating agent.
Complex natural products that do not cause bone marrow depression. The bithiazole ring system intercalates with DNA and the N atoms in the molecule chelate a ferrous (Fe2+) ion.
This interacts with oxygen and is oxidised to a ferric (Fe3+) ion, leading to the generation of a superoxide (O2-) or hydroxyl radicals.
These highly reactive species abstract H atoms from DNA which results in DNA strands being cut.
Bleomycin also prevents the enzyme DNA ligase from repairing the damage caused.

Question 18

Chain cutters

Answer 18

Chain cutters are intercalating agents that cut stands of DNA and prevent the enzyme DNA ligase from repairing the damage.
They create radicals on the DNA structure that then react with oxygen leading to chain cutting.

A nucleophile attacks the trisulfide group and the free thiol then reacts via an intramolecular Michael addition with a reactive a-b- unsaturated ketone. The intermediate then cycloaromatises to produce an aromatic diradical species which snatches hydrogens from DNA. As a result the DNA becomes a diradical, and subsequent reaction with oxygen leads to chain cutting.

Question 19

Intercalating agents and chain cutters summary

Answer 19

Intercalating drugs contain planar aromatic or heteroaromatic ring systems which can slide between the base pairs of the DNA double helix.
Bleomycins are intercalating drugs which form complexes with Fe2+ ions. These complexes generate reactive oxygen species that cleave the strands of DNA.
Calichaemicin is a natural product which reacts with nucleophiles to produce a diradical species. Reaction with DNA ultimately lead to cutting of the DNA chains.

Question 20

Tertiary structure of DNA

Answer 20

DNA is an extremely long molecule. It must be coiled into a more compact 3D shape which can fit into the nucleus. This process is called supercoiling.
The double helix must unravel during replication. This unravelling leads to strain, the strain is relieved by enzyme catalysed cutting and repair of the DNA chain.

Question 21

Action of Topoisomerase II

Answer 21

Relieves the strain in the DNA helix by temporarily cleaving the DNA chain and crossing an intact strand through the broken strand.
Inhibition of these enzymes would block transcription and replication.

Question 22

Topoisomerase poisons- non-intercalating

Answer 22

Inhibition of these enzymes would block transcription and replication.
Examples include
- Etoposide
- Teniposide

They stabilise the covalent intermediate between DNA and topoisomerase II.

Question 23

Camptothecins

Answer 23

Camptothecins target the complex between DNA and topoisomerase I.
This leads to DNA cleavage and cell death if DNA synthesis is not in progress, however these agents are toxic to cancer cells if not synthesising new DNA.
This is due to an alternative mechanism of action.

Topotecan is another ani-cancer drug used in the treatment of advanced ovarian cancer. They are semi-synthetic and analogues of camptothecin.

Question 24

Topoisomerase poisons summary

Answer 24

Etoposide and teniposide are non-intercalating drugs that act as topoisomerase II poisons.
Camptothecins such as topotecan is a non-intercalating drug that acts as a topoisomerase I poison. It stabilises and enzyme-DNA complex where a single strand on DNA has been cleaved.