Basics Of Chemotherapy, Anti-malarials & HIV Treatment Part 1 Flashcards
What were the observations of Paul Ehrlich?
During his research, he observed that certain dyes only bound to bacteria whereas others only bound to human tissue
What did Paul Ehrlich’s observations lead him to theorise?
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
What organisms are considered parasites in chemotherapy? (6)
Bacteria
Fungi
Protozoa
Helminths (worms)
Viruses
Cancer cells
What is the concept of chemotherapy?
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
What are the 3 different situations in which there could be a biochemical difference between the host tissue and the parasite (in chemotherapy)?
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
What is the therapeutic index? (TI)
A measure of drug safety based on populations
What can the therapeutic index (TI) be used for?
Evaluating the safety of a drug
What is the ED50 (median effective dose)?
Dose that produces the therapeutic effect in 50% of the population
What is the TD50 (median toxic dose) ?
Dose that produces the toxic effect in 50% of the population
What is the LD50 (median lethal dose) ?
Dose that produces the lethal effect in 50% of the population
Previously tested on animals, but now it is rarer
How do you calculated the therapeutic index (TI) in humans?
TI = TD50 / ED50
Therapeutic index = median toxic dose / median effective dose
How do you calculate the therapeutic index (TI) in animals?
TI = LD50 / ED50
Therapeutic index = median lethal dose / median effective dose
What does a higher TI mean?
The safer the drug
What organisms have many differences to human cells? (4)
Fungi
Helminths
Bacteria
Protozoa
What is an example of a (qualitative) difference between human and bacterial cells?
Bacterial cell walls
Therefore targeting cell wall synthesis is a selective drug target and will not produce an effect in humans
What is a potential problem in chemotherapy?
Development of resistance (adaptation / mutation)
Why do viruses have fewer biochemical differences?
- 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
Why is it harder to find qualitative differences with cancer cells?
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
What are the 3 classes of biochemical reactions targeted by chemotherapy?
- Class 1 - energy production
- Class 2 - small molecule synthesis
- Class 3 - macromolecule production, polymers
Why are energy production biochemical reactions generally not targeted by chemotherapy?
They are fundamental for cell biology
What is an example of drugs which target (class 2) small molecule synthesis biochemical reactions?
Anti-malarial drugs
What biochemical reactions are a good sources of chemotherapeutic targets?
Class 3 - macromolecule production, polymers
What are examples of biochemical reactions for energy production (class 1) (7)
Glycolysis
Catabolism of polysaccharides
Production of NADPH via pentose phosphate pathway
Pyruvate oxidation
Citric acid cycle
Fermentation
Respiration - including oxidative phosphorylation
What are examples of biochemical reactions for small molecule synthesis (class 2) (5)
Biosynthesis of amino acids
Lipids
Coenzymes (e.g. Tetrahydrofolate)
Purines & pyrimidines (for DNA synthesis)
Haem catabolism / metabolism
What are examples of biochemical reactions for macromolecule / polymer production? (Class 3) (4)
Biosynthesis of DNA, RNA, proteins, lipoproteins
Peptidoglycan protein degradation
Cytoskeleton assembly
Glycogen synthesis
