Principles Of Selective Toxicity

Question 1

What is the principal of selective toxicity?

Answer 1

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.

Question 2

What biological capabilities must cancer cells acquire?

Answer 2

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

Question 3

Why do we want to achieve selective cancer chemotherapy?

Answer 3

Because cancer cells have high rate of cell division so we want to target cancerous cells

Question 4

What must we observe to help us achieve selectivity in cancer chemotherapy?

Answer 4

The cellular, biochemical and molecular difference between cancer cells and healthy cells.

Question 5

Drugs can be singly or via combined therapy, what are the criteria for drug combination?

What else does successful treatment require?

Answer 5

1. Is the drug active when used alone?
2. Does the drug all have different mechanism of action, to prevent enzyme competition.
3. Drugs with different toxicity profile
4. Use the drug dose close to their maximum tolerated level

Psychological and social support is also needed

Question 6

What characteristics do cytotoxic drugs have?

Answer 6

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.

Question 7

What are phase specific drugs?

Answer 7

They are drugs that only affect certain part of the cell cycle

Question 8

What are cycle specific drugs?

Answer 8

They are drugs that affect cycling cells throughout the cell cycle and finally affecting DnA synthesis

Question 9

What happens in the G0 part of the cell cycle?

Answer 9

G0 describe the cell to be in the testing phase, before replication and division start

Question 10

What does G1 phase do?

Answer 10

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.

Question 11

What is the S phase in cell cycle?

Answer 11

It describe the phase when DNA is synthesised. 30% of drugs act in the part of the cycle.

Question 12

What is G2 phase of the cell cycle ?

Answer 12

This is pre mitosis and when cell components and synthesised for mitosis. 19% of drugs act at this point.

Question 13

What is the mechanism action of alkylating agents?

Answer 13

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.

Question 14

What does therapeutic index of 1 mean?

Answer 14

It means the concentration that cause toxicity is the same of the concentration that cause cancer cell death.

Question 15

Do you want the therapeutic index to be wide or narrow? And why?

Answer 15

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.

Question 16

What do you have to consider when prescribing antibiotics?

Answer 16

Route of admission 
Broad spectrum?
Previous antibiotics prescription
Allergies
Other medication for contraindications
Other ongoing medical conditions

Question 17

Targets of antibodies

Answer 17

It goes from bacterial cell wall - peptidoglycan

To things like protein synthesis, intermediary metabolism and biosynthesis of DNA and RNA and cell membranes

Question 18

What is peptidoglycan made out of and what is its structure

Answer 18

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.

Question 19

What is LPS and where can you find it?

Answer 19

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.

Question 20

What does benzylpenicillin do?

Answer 20

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.

Question 21

What are adverse effects of penicillin?

Answer 21

Hypersensitivity reaction such as rash, anaphylactic reactions , neurotoxicity and GI disturbances

Question 22

How are some bacteria resistant to penicillin?

Answer 22

Some bacteria can produce beta lactamase which break down the beta lactam ring.

Question 23

Which antibiotic do you prescribe if the bacteria have beta lactamase?

Answer 23

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.

Question 24

Examples of antibiotics that inhibit protein synthesis and how?

Answer 24

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

Question 25

What are fungi?

Answer 25

Fungi are eukaryotes which live as saprophytes or parasites.

Question 26

What can be named after fungi infections?

Answer 26

Mycosis

Question 27

How does fungi infect people?

Answer 27

They either infect superficially or systematically

Question 28

What are the three main groups of fungi that cause disease to us?

Answer 28

1. Mound such as athletes foot or ringworm
2. True yeasts: it can cause cryptococcal meningitis and lung infection in immunocompromised.
3. Yeast like fungi: they cause oral and vaginal thrush and septicaemia

Question 29

What are examples of other actions of fungal agents?

Answer 29

It can act on the cell membrane and alter membrane integrity.

It also act on nuclear division and inhibit fungal mitosis by binding to intracellular micro tubular protein

It can also destroy nucleus acid synthesis, a example is flucytosine which gets converted in fungal cells into 5-flurouracil which is potent inhibitor of DNA synthesis.

Question 30

What is polyene macrolides?

Answer 30

A example is amphotericin B and nystatin

It’s mechanism of action is to interact hydrophobically with ergosteril in fungal cell membrane and forms pores in it.cell death ensues. This has good toxic selectivity as humans have cholesterol not ergosterol

Amphotericin is a broad spectrum which is used for serious systemic infections

Nystatin is used to treat thrush which is a oral and vaginal infection.

Question 31

What is zidovudine? What is its mechanism of action

Answer 31

It is a drug shown to inhibit HIv.
Still a pro drug that is phosphorylated to form ZDVTP
It competes with thymidine for the same enzyme and is incorporated into growing DNA strand and terminates synthesis due to lack of Oh groups. It cause selective inhibitor of RT enzymes it have high affinity for it compare to other mammalian polymerase enzymes.

Question 32

What is antifolate?

Answer 32

It’s a drug used to treat malaria it have specific DHFR inhibition. Humans have DHFR as well which is why high dose of this drug inhibit the same enzyme within the host. It generate pseudo folate which doesn’t act like folate

Question 33

What is proguanil?

Answer 33

It is a selective inhibitor of plasmodium DHFR (dihydrofolate reductase) and thymus you’re synthase. It have intrinsic anti malarial activity. It provide control with acute malarial attacks and can eradicate infection. It causes fertilised gametes in mosquitos to not develop.