Block E - lecture one

Question 1

immunopharmacolgy ?

Answer 1

Immunopharmacolgy is the modification of immune cell activities by pharmacological agents or exogenous compounds.

Question 2

what do all non specific immunosuppression drugs target ?

Answer 2

All target DNA stage of cell cycle leading to immunosuppression.

Question 3

3 types of non specific ?

Answer 3

false metabolites

alkalyating agents

inhibitors of nucleotide synthesis

Question 4

False metbaolites ?

Answer 4

false metabolites – compounds that will substitute for the normal nucleotide which stops the DNA chain forming.

Question 5

alkylating agents ?

Answer 5

alkylating agents - affects the stage of DNA unwinding which covalently binds nucleotides to either side of the chain to stop the unwinding and DNA synthesis at that stage.

Question 6

inhibitors of nucleotide synthesis ?

Answer 6

inhibitors of nucleotide synthesis - use compounds which stop nucleotide flux into DNA synthesis

Question 7

side effect of hair loss ?

Answer 7

Hair loss – as follicles are fast dividing cells, if cut off then hair is lost.

Question 8

GI damage ?

Answer 8

Gastrointestinal damage – the cells that line the GI tract have a very fast turn over, if cell death occurs then GI damage occurs.

Question 9

skin damage?

Answer 9

Skin damage - skin contain a high turnover, these compounds lead to death of these cells and skin damage

Question 10

how does cytotoxicity happen ?

Answer 10

Cytotoxicity leading to cell death by inhibiting DNA synthesis affecting the turnover of cells.

Question 11

describe azathioprine ( imuran) ?

Answer 11

False metabolite is azathioprine (Imuran) which is a pro drug of an old compound called 6-mercaptopurine which is used in cancer chemotherapy. Imuran above the line, the nitrogen group is cleaved to yield 6 mercaptopurine once digested orally. Once cleaved it is the active false metabolite 6- mercaptopurine.

Question 12

once in the cells what does 6 mercaptopurine have as options ?

Answer 12

Once in cells, 6 mercaptopurine can go down 2 pathways. The pathway that we want it to go down is the purine synthesis where it acts as a false metabolite leading to cell death. However, it can also go down the xanthine oxidase route which is an enzyme normally present in the metabolism of nucleotides, it converts the 6 – mercaptopurine to thiobarbituric acid, which isn’t active, but it excreted very quickly via urine. To try and prevent this from occurring allopurinol is used which is an enzyme inhibitor of xanthine oxidase and prevents the conversion of 6 mercaptopurine into thiobarbituric acid , so most of it goes into purine synthesis and maintain a high concentration of 6-mercaptopurine which can be used as a false metabolite leading to cell death.

Question 13

cyclophosphamide ?

Answer 13

An example of an alkylating agent is cyclophosphamide, used as an anti-cancer compound. It contains 2 chlorines in its structure which is the bifunctional group, they are a set distance apart which allows them to intercalate into DNA and covalently bind to the nucleotides. Cyclophosphamide is a prodrug and is not active in it’s own right , after oral administration it is converted by the liver cytochrome P450 enzyme into 4 hydroxy cyclophosphamide which has been hydroxylated which allows the ring to open up and form an aldehyde group called aldophosphamide which is now active. Following this the aldophosphamide is metabolised into an inactive form, the carboxylic acid form which is excreted by the urinary route.

Question 14

active form of aldophosphamide has the ability to do ?

Answer 14

Aldophosphamide , the active form has the ability to intercalate into DNA and covalently bind to the strands of DNA. As it unwinds the chlorine groups can interact with the guanosine bases of DNA. The 2 positive charges on the nitrogen (N7) of guanine covalently bind to the chlorines on aldophosphamide, this has been irreversibly linked and cannot unwind to continue the process of DNA replication , cell cycle is arrested and cell death occurs.

Question 15

mycophenolate ?

Answer 15

This is the inhibition of nucleotide synthesis, mycophenolate mofetil is quite a modern drug. It is a pro drug and once administered , it is hydrolysed to produce mycophenolic acid, a carboxylic acid.

Question 16

de novo pathway of nucleotide synthesis ?

Answer 16

The de-novo pathway of nucleotide synthesis is shown above, the MPA has a target of IMP dehydrogenase (IMPD), MPA inhibits the enzyme IMPD and prevents the production of guanosine by preventing inosine being dehydrogenated. There is no guanosine which feeds into the pathways above, so it isn’t incorporated into the DNA. This leads to cell death.

Question 17

mechanism of action for MPA ?

Answer 17

Non-competitive enzyme inhibitor – isn’t acting on active site of enzyme

Allosteric regulator of activity – not affecting the active site directly but acts on another site which affects the active site and changes it’s ability to bind to the substrate.

Adjacent to the active site is where MPA binds, and this alters the conformation of the active site and its ability to bind to inosine. This leads to inhibition of enzyme activity and guanosine is not produced from inosine and results in cell death.

Question 18

what do all 3 pathways of non specific immunosuppresion lead to ?

Answer 18

All 3 pathways lead to Cytotoxic cell death, this is targeted at the stage of clonal expansion of T cells. This prevents the production of immune responsive T cells.