MT L1 Antimetabolites - Folate & pyramidine "antagonists"

Question 1

Name the 4 main groups of antimetabolite

Answer 1

Folate "antagonists"
Pyramidine "antagonists"
Purine "antagonists"
Sugar modified nucleoutides
("antagonists" are all enzyme inhibitors)

Question 2

Antimetabolites inhibit one or more steps in the

Answer 2

biosynthesis of DNA

Question 3

Name the 3 enzymes in the folate cycle. Which do we not target?

Answer 3

TS - thyamidylate synthetase
DHFR - dihydrofolate reductase

we don’t target as not rate limiting:
SHMT - serine hydroxymethyltransferase

Question 4

action of methotrexate?

where does it bind?

Answer 4

analogue of dyhydrofolate.

inihibits DHFR at folate binding site

Question 5

How does methotrexate get into the cell?

Answer 5

too polar for passive diffusion so taken up through reduced folate carrier (RFC)

Question 6

How is methotrexate metabolised once in the cell?

Answer 6

polyglutmated - prevents it leaving the cell so it can accumulate

Question 7

when is methotrexate used?

Answer 7

many cancer types and often in high dose regimen with leucovorin

Question 8

what are the three mechanisms of resistance against methotrexate

Answer 8

1. mutations to RFC - most common
2. multidrug resistance phenotype - pGP causing efflux of drug - looks for aromatic rings and basic centres
3. mutation of folate binding site on DHFR

Question 9

name the four lippophilic antifolates - inhibitiors of DHFR

Answer 9

pyrimethamine - antibacterial
methylbenzoprim - experimental
piritrexim
nolatrexed - also inhibits TS

Question 10

How have the newer inhibitors of DHFR attempted to overcome the methothrexate resistance?

Answer 10

lippohpilic so can diffuse into the cell (don’t require the RFC)

Question 11

How do pemetrexed and ralitrexed act and where?

Answer 11

competative inhibitors of TS.

bind at the 5,10CH2-tetrahydrofolate-binding site

Question 12

How does 5-FU inhibit the folate cycle

Answer 12

metabolinte binds at dUMP site on TS.

Mechanism based irriversible inhibitor

Question 13

5-FU: why is it such a good inhibitor

Answer 13

Beta eleimination cannot take place due to presence of F. (F+ cannot come off as it’s too electronegative).

Enzyme must be broken down and resynthesised.

Question 14

Name the metabolites of 5-FU

Answer 14

5FU ->
FdURD ->
FdUMP -> into the folate cycle

Question 15

What is cytidine?

modes of action (2)

Answer 15

weak inhibitor or TS (binds at the dUMP site).

has other mechanisms of action - encorporated into RNA mimicing cytosine but makes RNA unstable (stronger action)

Question 16

What is cytidine metabolised into before action

Answer 16

azacytidine

Question 17

name the three pyramidine “antagonists”

Answer 17

5FU
FdURD
azacytidine

Question 18

What is the problem with 5FU

Answer 18

v insoluble and hard to formulate

Question 19

outline mechanism of TS normally

Answer 19

1. Conjugate addition of TS to dUMP to make enolate.
2. 5,10CH2-THF is delivered as an electrophile (imminium)
3. beta elimintion regenerates the double bond (releasing DHF and dTMP)