5-fu: how does it work?

[TommyGunn04]

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How would you answer this type of question?

999) How does 5-FU work?

(a) binds to/complexes dihydrofolate
(b) inhibits thymidylate synthetase
(c) blah blah
(d) blah blah

How would you respond?

My understanding is that it binds to folic acid; does folic acid = dihydrofolate? First Aid says it inhibits thymidylate synthase; does synthASE = synthETASE? It gets turned into 5F-dUMP, which binds folic acid, and this complex in turn inhibits thymidylate synthase, so I'm unclear on what the answer here should be.

 

[HiddenTruth]

How would you answer this type of question?

999) How does 5-FU work?

(a) binds to/complexes dihydrofolate
(b) inhibits thymidylate synthetase
(c) blah blah
(d) blah blah

How would you respond?.

First of all 5-FU is a pyrimidine analog, and not a folic acid analog.
The answer would be "B". 5-FU (like Flutocytosine) are bioactivated to 5-fdUMP through a serious of enzymatic reactions. 5FduMP inhibits thymidylate syntheTase. Blockade of TS inhibits DNA synthesis. THis is referred to as "thymineless" death, which is basically that 5FdUMP is an irreversible inhibitor of TS. It doesn't have anything to do with the enzyme DHFR (that is the enzyme used in the pathway of folic acid synthesis, which is only associated with methotrexate and SMX/Trim). I really don't know what role folic acid plays in the mechanism of this drug. Also, as a side note, if you give Leucovorin (reduced folate) with 5-FU, it increase the activity of 5-FU reuslting in an extednded time of depletion of thymidine nucleotides with a subsequent increase in cell death.

Don't get this confused with giving Leucovarin in patients who are on Methotrexate. In this case, Leucovarin is used as a "rescue" drug. It is a fully reduced functional folate coenzyme, which is directly converted to FH4 without the need of DHFR (the enzyme requied in the synthesis of FH4, whic is inhibited by methotrexate). It is basically another way to get to the end product without using the enzyme inhibited by methotrexate. So, essentially it's use is opposite in 5-FU (where it enhances cell death).

 

[TommyGunn04]

I didn't say it was a folic acid analog, I was basically re-phrasing what it says on pg 334 of First Aid 2004: "pyrimidine analog bioactivated to 5F-dUMP, which convalently COMPLEXES FOLIC ACID. This complex inhibits thymidylate synthase, resulting in decreased dTMP and the same effects as methotrexate."

So, the key to this question is as I asked above, is syntheTASE the same as SYNTHASE? (in which case I'd choose "B") Or is saying that it "binds dihydrofolate" basically the same as saying that it complexes folic acid, as First Aid states. My issue here is that these answers both seem right-ISH but I can't figure out which is THE correct one. Sorry if that wasn't clear before.

 

[HiddenTruth]

I didn't say it was a folic acid analog, I was basically re-phrasing what it says on pg 334 of First Aid 2004: "pyrimidine analog bioactivated to 5F-dUMP, which convalently COMPLEXES FOLIC ACID. This complex inhibits thymidylate synthase, resulting in decreased dTMP and the same effects as methotrexate."

So, the key to this question is as I asked above, is syntheTASE the same as SYNTHASE? (in which case I'd choose "B") Or is saying that it "binds dihydrofolate" basically the same as saying that it complexes folic acid, as First Aid states. My issue here is that these answers both seem right-ISH but I can't figure out which is THE correct one. Sorry if that wasn't clear before.

Ok, so here are some points which may clear things.
I checked a couple of places and actualy synthase is the same as syntheTase. But, most of the places I read it says syntheTase. So, answer B is indeed correct. Dyhidrofolate is considered to be a precursor to folic acid since the active form of folic acid is tetrahydofolate. I still don't know what the mechanims behind complexing with folic acid is. I read it in FA also. I don't know, but in the case of your question, it's irrelavant as there is a clear answer. Hope this help--