Basics Of Chemotherapy, Anti-malarials & HIV Treatment Part 1

Question 1

What were the observations of Paul Ehrlich?

Answer 1

During his research, he observed that certain dyes only bound to bacteria whereas others only bound to human tissue

Question 2

What did Paul Ehrlich’s observations lead him to theorise?

Answer 2

The concept of ‘magic bullets’

If an organism was infected by a certain bacterial species…
Then substances with a specific affinity to these bacteria and not for the host tissue would provide an effective cure - acting on the bacteria alone

Question 3

What organisms are considered parasites in chemotherapy? (6)

Answer 3

Bacteria
Fungi
Protozoa
Helminths (worms)
Viruses
Cancer cells

Question 4

What is the concept of chemotherapy?

Answer 4

To identify a (preferably) qualitative biochemical difference between the host and the parasite

This difference can then be targeted in the parasite by a selective drug

Causing a cytotoxic effect in the parasite but no effect in the host

Question 5

What are the 3 different situations in which there could be a biochemical difference between the host tissue and the parasite (in chemotherapy)?

Answer 5

Situation 1:
- Target is only present in the parasite and not the host
- Drug selects against this target
- Leading to a cytotoxic effect in the parasite and no effect in the host

Situation 2
- Target is present in both the parasite and host but there is a sufficient difference in structure between the two
- Selective drug only targets the protein in the parasite
- Leading to a cytotoxic effect in the parasite and no effect in the host

Situation 3
- Target is present in both the parasite and host but the host contains an escape mechanism / alternative pathway which protects against the target being modulated
- Both targets inhibited but due to escape mechanism in host, this leads to a cytotoxic effect in parasite but no effect in the host

Question 6

What is the therapeutic index? (TI)

Answer 6

A measure of drug safety based on populations

Question 7

What can the therapeutic index (TI) be used for?

Answer 7

Evaluating the safety of a drug

Question 8

What is the ED50 (median effective dose)?

Answer 8

Dose that produces the therapeutic effect in 50% of the population

Question 9

What is the TD50 (median toxic dose) ?

Answer 9

Dose that produces the toxic effect in 50% of the population

Question 10

What is the LD50 (median lethal dose) ?

Answer 10

Dose that produces the lethal effect in 50% of the population
Previously tested on animals, but now it is rarer

Question 11

How do you calculated the therapeutic index (TI) in humans?

Answer 11

TI = TD50 / ED50

Therapeutic index = median toxic dose / median effective dose

Question 12

How do you calculate the therapeutic index (TI) in animals?

Answer 12

TI = LD50 / ED50

Therapeutic index = median lethal dose / median effective dose

Question 13

What does a higher TI mean?

Answer 13

The safer the drug

Question 14

What organisms have many differences to human cells? (4)

Answer 14

Fungi
Helminths
Bacteria
Protozoa

Question 15

What is an example of a (qualitative) difference between human and bacterial cells?

Answer 15

Bacterial cell walls

Therefore targeting cell wall synthesis is a selective drug target and will not produce an effect in humans

Question 16

What is a potential problem in chemotherapy?

Answer 16

Development of resistance (adaptation / mutation)

Question 17

Why do viruses have fewer biochemical differences?

Answer 17

• they hijack (some of) the host’s biochemistry
• therefore drugs need to selectively target biochemical pathways encoded for by the viral genome and not hijacked pathways of the host

Question 18

Why is it harder to find qualitative differences with cancer cells?

Answer 18

They are essentially self-cells

Have to rely on quantitative differences - between the normal host cell phenotype and the cellular phenotype of the cancer cell

Question 19

What are the 3 classes of biochemical reactions targeted by chemotherapy?

Answer 19

1. Class 1 - energy production
2. Class 2 - small molecule synthesis
3. Class 3 - macromolecule production, polymers

Question 20

Why are energy production biochemical reactions generally not targeted by chemotherapy?

Answer 20

They are fundamental for cell biology

Question 21

What is an example of drugs which target (class 2) small molecule synthesis biochemical reactions?

Answer 21

Anti-malarial drugs

Question 22

What biochemical reactions are a good sources of chemotherapeutic targets?

Answer 22

Class 3 - macromolecule production, polymers

Question 23

What are examples of biochemical reactions for energy production (class 1) (7)

Answer 23

Glycolysis
Catabolism of polysaccharides
Production of NADPH via pentose phosphate pathway
Pyruvate oxidation
Citric acid cycle
Fermentation
Respiration - including oxidative phosphorylation

Question 24

What are examples of biochemical reactions for small molecule synthesis (class 2) (5)

Answer 24

Biosynthesis of amino acids
Lipids
Coenzymes (e.g. Tetrahydrofolate)
Purines & pyrimidines (for DNA synthesis)
Haem catabolism / metabolism

Question 25

What are examples of biochemical reactions for macromolecule / polymer production? (Class 3) (4)

Answer 25

Biosynthesis of DNA, RNA, proteins, lipoproteins
Peptidoglycan protein degradation
Cytoskeleton assembly
Glycogen synthesis