Does 5-Fluorouracil cause Macrocytic megaloblastic anemia or just macrocytic ?

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whatdidigetinto

whatdidigetinto

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I was watching pathoma when he said that non-megaloblastic macrocytic anemia is caused by 5-Fluorouracyl, however in rapid review pathology and through common sense i realized that 5-FU does in fact cause megaloblastic anemia to occur since it interferes with DNA synthesis.
Your thoughts?
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Why would 5-FU produce megaloblastic anemia? It does not cause folate deficiency.
A drug like MTX, on the other hand, would cause folate deficiency.
 
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Myxedema said:
Why would 5-FU produce megaloblastic anemia? It does not cause folate deficiency.
A drug like MTX, on the other hand, would cause folate deficiency.
Click to expand...
5-FU would definitely cause megaloblastic anemia since it interferes with pyrimidines synthesis.
 
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whatdidigetinto said:
5-FU would definitely cause megaloblastic anemia since it interferes with pyrimidines synthesis.
Click to expand...

Pathologies that interfere with pyrimidine synthesis do not necessarily cause megaloblastic anemia. If that were true, conditions like orotic aciduria would have caused megaloblastic anemia as well. Let me ask you this: Would you expect to see macrocytic anemia in a patient treated with hydroxyurea? Would a patient treated with hydroxyurea have folate deficiency?

I've checked this in UpToDate as well and it does not list 5-FU as a cause of folate deficiency. Drugs associated with folate deficiency are: 1) MTX and other DHFR inhibitors, 2) Ethanol, 3) Phenytoin
 
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Myxedema said:
Pathologies that interfere with pyrimidine synthesis do not necessarily cause megaloblastic anemia. If that were true, conditions like orotic aciduria would have caused megaloblastic anemia as well. Let me ask you this: Would you expect to see macrocytic anemia in a patient treated with hydroxyurea? Would a patient treated with hydroxyurea have folate deficiency?

I've checked this in UpToDate as well and it does not list 5-FU as a cause of folate deficiency. Drugs associated with folate deficiency are: 1) MTX and other DHFR inhibitors, 2) Ethanol, 3) Phenytoin
Click to expand...

Orotic aciduria does cause a megaloblastic anemia.
and 5FU would also cause it.
folate is needed for synthesis of thymidine,which is required for dna synthesis,a disruption in dna synthesis is the mechanism involved in megaloblastic anemia.
 
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chaotic mind said:
Orotic aciduria does cause a megaloblastic anemia.
Click to expand...

No: http://tinyurl.com/d6kgsbb

and 5FU would also cause it.
folate is needed for synthesis of thymidine,which is required for dna synthesis,a disruption in dna synthesis is the mechanism involved in megaloblastic anemia.
Click to expand...

N5,N10-THF is indeed needed for the synthesis of dTMP. Does 5-FU interfere with THF? Does it cause a shortage of THF? "Folate deficiency" and "alteration in DNA synthesis" are not interchangeable; they are different concepts. 5-FU causes an alteration in DNA synthesis and produces a non-megaloblastic macrocytic anemia. MTX, on the other hand, would decrease the amount of available THF and cause folate deficiency, which would produce megaloblastic anemia.
 
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Myxedema said:
No: http://tinyurl.com/d6kgsbb



N5,N10-THF is indeed needed for the synthesis of dTMP. Does 5-FU interfere with THF? Does it cause a shortage of THF? "Folate deficiency" and "alteration in DNA synthesis" are not interchangeable; they are different concepts. 5-FU causes an alteration in DNA synthesis and produces a non-megaloblastic macrocytic anemia. MTX, on the other hand, would decrease the amount of available THF and cause folate deficiency, which would produce megaloblastic anemia.
Click to expand...
if you were to block thymedilate synthase with 5FU, then you wont be able to process n5n10 methylene THF which then gives you DHF. without the DHF you cant make THF using the enzyme dihydrofolate reductase. so basically if you use 5-FU then dihydrofolate reductase cannot synthesize THF, leading to megaloblastic anemia.
 
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Myxedema said:
No: http://tinyurl.com/d6kgsbb



N5,N10-THF is indeed needed for the synthesis of dTMP. Does 5-FU interfere with THF? Does it cause a shortage of THF? "Folate deficiency" and "alteration in DNA synthesis" are not interchangeable; they are different concepts. 5-FU causes an alteration in DNA synthesis and produces a non-megaloblastic macrocytic anemia. MTX, on the other hand, would decrease the amount of available THF and cause folate deficiency, which would produce megaloblastic anemia.
Click to expand...

:)
folate deficiency causes altered dna synthesis.
5 fu also interferes with dna synthesis.
a disturbance in the dna synthesis is the FINAL COMMON PATHWAY for megaloblastic anemia.thats why the nucleus of rbcs(and other rapidly dividing cells) is immature (BLAST) like and the cytosol can continue to mature.
Orotic aciduria causes a megaloblastic anemia which responds to uridine.
 
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whatdidigetinto said:
if you were to block thymedilate synthase with 5FU, then you wont be able to process n5n10 methylene THF which then gives you DHF. without the DHF you cant make THF using the enzyme dihydrofolate reductase. so basically if you use 5-FU then dihydrofolate reductase cannot synthesize THF, leading to megaloblastic anemia
Click to expand...

There are alternative pathways of folate metabolism. If methylene THF levels were to be elevated, then they would be reduced by N5-N10-methylene-THF reductase enzyme into N5-methyl-THF, which is the reduced storage form. From this reduced form, THF itself can be synthesized by the enzyme homocysteine methyl transferase, which would transfer the methyl group from the reduced THF to homocysteine and form methionine (which would later form SAM to act as a carrier for methyl groups).

In summary, if there were an increase in oxidized form of THF, it would be reduced into the storage form. From the reduced form, THF can be re-formed by donating the methyl group to homocysteine.

http://bloodjournal.hematologylibrar.../1535.abstract
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Here's a list of possible etiologies of folate deficiency, taken from Cecil Medicine, 24th edition (p. 1076):
II. Folate deficiency
A. Nutritional causes
1. Decreased dietary intake—poverty and famine, institutionalization (psychiatric facilities, nursing homes), chronic debilitating disease, prolonged feeding of infants
with goat’s milk, special slimming diets or fad foods (folate-rich foods not consumed), cultural or ethnic cooking techniques (food folate destroyed)
2. Decreased dietary intake and increased requirements
a. Physiologic—pregnancy and lactation, prematurity, hyperemesis gravidarum, infancy
b. Pathologic
(1) Intrinsic hematologic diseases involving hemolysis with compensatory erythropoiesis, abnormal hematopoiesis, or bone marrow infiltration by malignant
disease
(2) Dermatologic disease—psoriasis
B. Folate malabsorption
1. With normal intestinal mucosa
a. Drugs—sulfasalazine, pyrimethamine, proton pump inhibitors (via inhibition of proton-coupled folate transporters)
b. Hereditary folate malabsorption (mutations in proton-coupled folate transporters) (rare)
2. With mucosal abnormalities—tropical/nontropical sprue, regional enteritis
C. Defective CSF folate transport—cerebral folate deficiency (autoantibodies to folate receptors) (rare)
D. Inadequate cellular utilization
1. Folate antagonists (methotrexate)
2. Hereditary enzyme deficiencies involving folate
E. Drugs (multiple effects on folate metabolism)—alcohol, sulfasalazine, triamterene, pyrimethamine, trimethoprim-sulfamethoxazole, phenytoin, barbiturates
Click to expand...

Did they just forget 5-FU? Like I've said before, I've also checked this on UpToDate and it also doesn't list 5-FU among drugs causing folate deficiency.
 
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Myxedema said:
No: http://tinyurl.com/d6kgsbb



N5,N10-THF is indeed needed for the synthesis of dTMP. Does 5-FU interfere with THF? Does it cause a shortage of THF? "Folate deficiency" and "alteration in DNA synthesis" are not interchangeable; they are different concepts. 5-FU causes an alteration in DNA synthesis and produces a non-megaloblastic macrocytic anemia. MTX, on the other hand, would decrease the amount of available THF and cause folate deficiency, which would produce megaloblastic anemia.
Click to expand...
dude check this pic, this should end the discussion i think:

http://imgur.com/BBJsr

As you can see from the diagram, a deficiency in b12 or the addition of 5FU or methotrixate will all affect the pool of THF. You can even see that 5-FU causes both a decrease in pyrimidine synthesis and a decrease in THF since dihydrofolate reductase will not have a subtrate since thymedilate synthase will be inhibited.
 
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whatdidigetinto said:
dude check this pic, this should end the discussion i think:

http://imgur.com/BBJsr

As you can see from the diagram, a deficiency in b12 or the addition of 5FU or methotrixate will all affect the pool of THF
Click to expand...

That diagram has something missing: Draw an arrow from N5-N10-methylene-THF (active form) to THF-CH3 (storage form). There's a diagram in Kaplan Biochemistry LN if you have access to it.
 
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Myxedema said:
That diagram has something missing: Draw an arrow from N5-N10-methylene-THF (active form) to THF-CH3 (storage form). There's a diagram in Kaplan Biochemistry LN if you have access to it.
Click to expand...
I know what you are referring too. This diagram is from First Aid and they just kept it short (by not showing the enzyme you are talking about). But regardless of the latter, we will obtain LESS THF when 5-FU is administered. Dude 5-FU is a double edged sword: 1- It decreases the pool of available THF and 2 -It decreases amount of DNA produced. Now, are you telling me that a compound that decreases amount of DNA produced and decreases the pool of THF will not cause megaloblastic anemia? I highly doubt it.
 
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whatdidigetinto said:
I know what you are referring too. This diagram is from First Aid and they just kept it short (by not showing the enzyme you are talking about). But regardless of the latter, we will obtain LESS THF when 5-FU is administered. Dude 5-FU is a double edged sword: 1- It decreases the pool of available THF and 2 -It decreases amount of DNA produced. Now, are you telling me that a compound that decreases amount of DNA produced and decreases the pool of THF will not cause megaloblastic anemia? I highly doubt it.
Click to expand...

OK, I see your logic, but think about this: The function of THF is to donate one-carbon groups. That's why the carbon group in serine is transferred to THF to form N5,N10-methylene-THF: That carbon group is the primary source of donation. So, by the blockage of the enzyme, there would be an increase in the THF form more capable of donating carbon groups.

Also, these THF forms can be converted into one another using other enzymes as well. For example, N5,N10-methylene-THF can donate its carbon group back to glycine to form serine and THF. So, I don't think there would be a decrease in THF pool. If it were, I would have expected 5-FU to be listed among the causes of folate deficiency.

As for the second point, it does alter DNA synthesis, hence the macrocytosis. But altering DNA synthesis is not enough to create megaloblastic anemia.

Btw N5-N10-methylene-THF is not the active form, THF is
Click to expand...

Now about this I'm sure. THF is the basic form. It doesn't have the carbon group to donate yet. It can get it from serine to form the methylene form, or it can get it from formate to form the formyl form. After several reactions (hydrolation, dehydrogenation, reduction etc.), these carbon groups are changed. But plain THF is the one that doesn't have those carbon groups.
 
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Bro i'm done arguing with you. I presented my explanation and you can chose to accept it or not, that is your right, but unfortunately i dont want to waste any more time on this subject.

Also: ''Tetrahydrofolate (THF), a biologically active form of the vitamin" from this journal http://www.pnas.org/content/early/2011/08/15/1111701108.full.pdf

quick question as long as we are on this subject. it says in first aid that on page 103, ''THf is a 1 carbon unit carrier'' while it also states that ''SAM is a methyl group donor''. I saw the structure of homcysteine and methionine, and i also saw the structures of norepinephrine and epinehprine. The thing is they ALL have an extra CH3 group. So what exactly is the difference between THF and SAM? Function wise that is.
 
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whatdidigetinto said:
Bro i'm done arguing with you. I presented my explanation and you can chose to accept it or not, that is your right, but unfortunately i dont want to waste any more time on this subject.

Also: ''Tetrahydrofolate (THF), a biologically active form of the vitamin" from this journal http://www.pnas.org/content/early/2011/08/15/1111701108.full.pdf

quick question as long as we are on this subject. it says in first aid that on page 103, ''THf is a 1 carbon unit carrier'' while it also states that ''SAM is a methyl group donor''. I saw the structure of homcysteine and methionine, and i also saw the structures of norepinephrine and epinehprine. The thing is they ALL have an extra CH3 group. So what exactly is the difference between THF and SAM?
Click to expand...

SAM: Methyl (-CH3)
THF: All other one-carbon groups (-CH2OH, -COH, ...)
 
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''THF: All other one-carbon groups (-CH2OH, -COH, ...)''
Does that include CH3? because if you check the structures of homocysteine and methionine, the difference is an extra methyl group only.
 
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"As for the second point, it does alter DNA synthesis, hence the macrocytosis. But altering DNA synthesis is not enough to create megaloblastic anemia."

thats where you are wrong.
defective dna synthesis leads to megaloblastic anemia.the nucleus cannot mature and stays large hence the name megaloblastic.
macrocytes means the rbc is large.megaloblast =nuclear maturation defect.
 
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chaotic mind said:
As for the second point, it does alter DNA synthesis, hence the macrocytosis. But altering DNA synthesis is not enough to create megaloblastic anemia.

thats where you are wrong.
defective dna synthesis leads to megaloblastic anemia.the nucleus cannot mature and stays large hence the name megaloblastic.
macrocytes means the rbc is large.megaloblast =nuclear maturation defect.
Click to expand...


The question is, do you agree that 5FU causes megaloblastic macrocytic anemia or not? your input will be much appreciated.
 
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whatdidigetinto said:
''THF: All other one-carbon groups (-CH2OH, -COH, ...)''
Does that include CH3? because if you check the structures of homocysteine and methionine, the difference is an extra methyl group only.
Click to expand...

That is the one exception. There is only one reaction where a methyl group in THF would be donated: Homocysteine methyl transferase. Other than this, THF does not transfer methyl groups, SAM does.

thats where you are wrong.
defective dna synthesis leads to megaloblastic anemia.the nucleus cannot mature and stays large hence the name megaloblastic. macrocytes means the rbc is large.megaloblast =nuclear maturation defect.
Click to expand...

If this were true, then there would be no such thing as a "non-megaloblastic macrocytic anemia". For example, in MDS, there's ineffective erythropoiesis. As a of this lack of maturation, macrocytosis is seen. By your standard, anemia seen in MDS should be megaloblastic. However, it's not.
 
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whatdidigetinto said:
The question is, do you agree that 5FU causes megaloblastic macrocytic anemia or not? your input will be much appreciated.
Click to expand...

sorry..I forgot to quote myxedema.thats why i didnt make sense.
5FU does cause megaloblastic anemia.
the only point I want to make is that there are causes of megaloblastic anemia other than b12 and folic acid deficiency eg. orotic aciduria and drugs like hydroxyurea and cytarabine.

megaloblast=macrocyte with immature nucleus
and there are macrocytic anemias without the nuclear defects-the rbcs are just larger in size ,no megaloblasts in bone marrow eg.hypothyroidism,liver disease

about myelodysplasia....some cases are associated with megaloblastic anemia.
 
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Myxedema said:
That is the one exception. There is only one reaction where a methyl group in THF would be donated: Homocysteine methyl transferase. Other than this, THF does not transfer methyl groups, SAM does.



If this were true, then there would be no such thing as a "non-megaloblastic macrocytic anemia". For example, in MDS, there's ineffective erythropoiesis. As a of this lack of maturation, macrocytosis is seen. By your standard, anemia seen in MDS should be megaloblastic. However, it's not.
Click to expand...


ineffective erythropoiesis can be due to defect in hemoglobin synthesis (thalassemia)so i wouldnt expect a megaloblastic anemia there cause nothing is wrong in the dna synthesis.
 
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