Principles Of Selective Toxicity Flashcards
What is the principal of selective toxicity?
First principle is there must be difference between the biochemistry of host and infectious agents.
Second, there’s must must be difference between normal and cancer cells
There must be difference in metabolic pathway between normal, tumours and invading species
There must be a high degree of discrimination so the ratio of therapeutic to toxic effect must be wide.
What biological capabilities must cancer cells acquire?
It must sustain proliferating signalling
It must evade growth suppressor
It must activate invasion and metastasis
It must enable replicating immortality
It must induce angiogenesis
It must resist cell death
Why do we want to achieve selective cancer chemotherapy?
Because cancer cells have high rate of cell division so we want to target cancerous cells
What must we observe to help us achieve selectivity in cancer chemotherapy?
The cellular, biochemical and molecular difference between cancer cells and healthy cells.
Drugs can be singly or via combined therapy, what are the criteria for drug combination?
What else does successful treatment require?
- Is the drug active when used alone?
- Does the drug all have different mechanism of action, to prevent enzyme competition.
- Drugs with different toxicity profile
- Use the drug dose close to their maximum tolerated level
Psychological and social support is also needed
What characteristics do cytotoxic drugs have?
They are active against proliferating cells.
These types of drugs have less activity against non dividing cells which is great as normal host cells are not affected.
Problem is cancer cells in resting phase are also not affected and can cause remission later on.
What are phase specific drugs?
They are drugs that only affect certain part of the cell cycle
What are cycle specific drugs?
They are drugs that affect cycling cells throughout the cell cycle and finally affecting DnA synthesis
What happens in the G0 part of the cell cycle?
G0 describe the cell to be in the testing phase, before replication and division start
What does G1 phase do?
G1 phase is the pre DNA synthesis phase, its when cells synthesis components needed for DNA synthesis. G1 phase account for 40% of drugs. Cycle specific drugs act on the second half f the G1 phase.
What is the S phase in cell cycle?
It describe the phase when DNA is synthesised. 30% of drugs act in the part of the cycle.
What is G2 phase of the cell cycle ?
This is pre mitosis and when cell components and synthesised for mitosis. 19% of drugs act at this point.
What is the mechanism action of alkylating agents?
When you give a patient a alkylating agent it form a highly reactive carbonyl ion which transfer alkyl groups to nucleophilic sites on DNA bases which result in cross linkage, abnormal base pairing and DNA strand breakage. All three of these result in a decrease in cell proliferating.
On a side note it also damage RNA and proteins.
What does therapeutic index of 1 mean?
It means the concentration that cause toxicity is the same of the concentration that cause cancer cell death.
Do you want the therapeutic index to be wide or narrow? And why?
You want it wide as a narrow therapeutic index means the difference between dose to cause harm and dose to kill cancer cell is narrow. So if it was narrow then all dividing cells are affected and narrow side effects.
You want some degree of selectivity so only hurt harmful cells.
What do you have to consider when prescribing antibiotics?
Route of admission Broad spectrum? Previous antibiotics prescription Allergies Other medication for contraindications Other ongoing medical conditions
Targets of antibodies
It goes from bacterial cell wall - peptidoglycan
To things like protein synthesis, intermediary metabolism and biosynthesis of DNA and RNA and cell membranes
What is peptidoglycan made out of and what is its structure
Bacterial cell wall peptidoglycan is made out of sugars and amino acids.
It’s structure is semi rigid, tight knit molecular complex. It’s function is to resist lysis.
What is LPS and where can you find it?
LPS is lipopolysaccharide and it is made up of a lipid portion and lipid A and a polysaccharide portion. LPS can be found on the outer membrane of a gram negative bacteria. Lipid A is endocrine which triggers fever and shock.
What does benzylpenicillin do?
It is an antibiotic also known as penicillin, it is active against aerobic gram positive and gram negative cocci and many anaerobic microbes.
It is bactericidal which is it prevent the growth of bacteria. The binding of penicillin binding proteins on susceptible microbes lead to inhibition of peptide cross linking within the microbial cell wall. It utilise auto lyric enzymes to kill it self.
What are adverse effects of penicillin?
Hypersensitivity reaction such as rash, anaphylactic reactions , neurotoxicity and GI disturbances
How are some bacteria resistant to penicillin?
Some bacteria can produce beta lactamase which break down the beta lactam ring.
Which antibiotic do you prescribe if the bacteria have beta lactamase?
Give them fluloxacillin as they are resistant to beta lactamase this is because beta lactam ring on flucloxcilin is pent shaped not square like the rest.
Examples of antibiotics that inhibit protein synthesis and how?
Aminoglycosides such as gentamicin and streptomycin
A bacteria make protein via 7os prokaryotic ribosome. Antibiotic can act on the larger portion (5os) and inhibit the formation of peptide bond between the amino acids
They can also interfere with attachment of tRNA to mRNA-ribosome complex.
They can also bind to the 5os portion but prevent the movement of ribosome across/translocate along the mRNA.
Lastly they can bind to the 3os portion causing code on mRNA to be read incorrectly
