Folinic acid (also known as leucovorin) is a prescription medication used in cancer chemotherapy along with the drugs methotrexate or 5-fluorouracil.
The rationale for using it in the GBM trial is that folates can act as DNA methylating agents, increasing MGMT methylation for example, which in turn could reduce the expression of MGMT and improve sensitivity to alkylating chemotherapy (such as TMZ).
An interesting aspect in all this is that the preclinical studies mentioned in the trial description did not actually use folinic acid, but ordinary folic acid (vitamin B9) supplied in the drinking water. A couple different models of gliomagenesis in rodents showed that folic acid supplementation led to smaller tumors which was associated with increased DNA methylation and decreased expression of genes such as MGMT, and tumor-promoting genes such as survivin and PDGF-B.
http://www.ncbi.nlm.nih.gov/pubmed/22325970 (will upload to the Brain Tumor Library)
Unfortunately this study does not discuss the fact that IDH1-mutant gliomas are characterized by pathological DNA hypermethylation, and for such tumors the value of folate supplementation is highly doubtful.
On the other hand MGMT unmethylated, IDH non-mutant tumors could conceivably benefit from folate supplementation, especially during chemotherapy.
To repeat, while the clinical trial is using folinic acid, the preclinical work that preceded this trial used ordinary folic acid (vitamin B9).
Doses of folic acid for the mice and rats were 4-40 micrograms per millilitre of drinking water. However, rodent doses should never be literally applied to humans.
The phase 1 trial of folinic acid, when completed, should give us an idea of what an effective dose (if effective at all) might be, keeping in mind that folinic acid is not the same compound as folic acid. The recommended daily intake of folic acid is several hundred micrograms per day (about half a milligram).
I read something long time ago about methylation and folic acid. Something about people who can not convert folic acid into something and that for those people folic acid supplementation is not advisable and that they should get some other form instead that is already converted into something. Sorry about being so unspecific. 2 kids at home don't let me check all that and figure it out. I will try to check it out once I have a chance.
What is the relationship between folinic acid and folic acid. Is folinic acid a more 'activated' form of folic acid in the sense that it breaks down more quickly into 5-methyltetrahydrofolate (5-MTHF)?
"Folate is the generic term for a family of compounds including folic acid and its derivatives which include 5- methyltetrahydrofolate (5-MTHF), 5-formyltetrahydrofolate (5-FTHF or folinic acid), 10-formyl-THF, 5,10-methyleneTHF and unsubstituted THF"
"Folinic acid is a 5-formyl derivative of THF (Figure 1B). Unlike the synthetic folate, folinic acid is naturally found in food. It is readily converted to THF without requiring the action of the enzyme dihydrofolate reductase (DHFR). Therefore its function as a vitamin is unaffected by drugs inhibiting this enzyme, such as methotrexate (Rajagopalan et al., 2002). 5-MTHF (Figure 1C) is a biologically active form of folate and is the most abundant form found in plasma, representing >90% of folate and is the predominant active metabolite of ingested folic acid."
According to wikipedia folinic acid is a "vitamer" for folic acid.
"A vitamer of a particular vitamin is any of a number of chemical compounds, generally having a similar molecular structure, each of which shows vitamin-activity in a vitamin-deficient biological system."
From what I read half of people of european decent and many others can't convert folic acid to the active form of 5-mthf and in those people after supplementation with folic acid high level of folic acid in the blood results which can cause health problems. Bellow is some article I found. "That folic acid may interfere with cancer has been known since the 1940’s. The chemotherapy drug methotrexate is an antifolate agent that blocks the metabolism of folic acid, developed after it was noted that a diet deficient in folic acid helped patients with leukemia. Studies of folic acid supplementation are raising flags about the potential risks of therapy, possibly as a result of excessive consumption. One of the most startling was a study that looked at folic acid supplementation in patients with colorectal adenomas, which are cancer precursors. Participants were randomized to folic acid 1mg or placebo for up to six years. While it was hypothesized that folic acid would provide a protective effect, the results were disappointing. Not only did folic acid have no effect on adenoma incidence (even in those with low folate status), there was a significant increase in the risk of non-colorectal cancers (10.5% vs. 6.3%), due mainly to an excess of prostate cancers. Futher worrying evidence emerged in 2009, when a Norwegian study of heart failure patients was published. Researchers randomized almost 7000 patients to folic acid and vitamin B12 versus other vitamins or placebo. The vitamins significantly raised the risks of both cancer and all-cause mortality, driven mainly by more cases of lung cancer. "
I was considering supplementation but now I'm not sure.
They also sell 5-MTHF without prescription maybe I should get that instead of folic acid. I am wondering if that would be helpful. I think that was a suggestion of one of the doctors on some site I encountered who wrote a lot about normalizing the methylation cycle.
So in this article it indirectly says that supplementing with 5-MTHF would be better than with folic acid and that the study was done on glioblastoma. I already bought yet another form of folate. I will have to buy this one now. http://www.lifeextension.com/protocols/cancer/brain-tumor/page-01
The differences in survival between people who can convert folate and not are big. So I would assume that supplementation with 5-MTHF would have significant impact on survival.
The Neuro-Oncology study is interesting, and does suggest that people with defects in the conversion of precursor folates to active 5-MTHF might benefit by supplementation with 5-MTHF. Unfortunately the study does not mention what percentage of the 214 GBM patients had the normal genotype (CC), and what percentage had less functional genotypes (CT, TT) for the MTHFR gene at that location. It would have been nice to know what percentage might benefit from supplementation.
Anyhow, hypomethylated gliomas probably will have more benefit from folate or 5-MTHF supplementation than hypermethylated gliomas (ie most IDH1 mutant gliomas).
Any further comment on this? I have the question into a new ND I will consult with. I was drawn to the topic initially because a year ago a doctor I was working with was starting to suspect I had the MTHFR mutation. I haven't used synthetic folate since but from my understanding people with the mutation can produce a weakened version of the enzyme that breaks down folate, leading to a build up in the blood. Which I had a year ago. 5-MTHF helps to better break down folate and regulate the enzyme. Stephen, can you tell me why you think this would benefit IDH1 mutated glioma less?
The MTHFR enzyme converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF). 5-MTHF is the "predominant active metabolite of ingested folic acid" and is an important co-factor for remethylation of homocysteine to methionine. Methionine in turn is the ultimate source of methyl groups for DNA methylation.
Consequently folate analogs (such as folinic acid) are being used with the rationale of methylating DNA, including the MGMT gene, in the hopes of sensitizing tumors to TMZ https://clinicaltrials.gov/ct2/show/NCT01700569
In contrast to glioblastoma, IDH1-mutated gliomas are typically already pathologically hypermethylated, so I reason that taking drugs or folates to increase DNA methylation for a tumor that is characterized by pathological hypermethylation might not be the greatest idea.
However, there could be other valid reasons to supplement with 5-MTHF (L-methylfolate), for example those who have mutations that severely compromise the function of the MTHFR enzyme.
Folinic acid (also known as leucovorin) is a prescription medication used in cancer chemotherapy along with the drugs methotrexate or 5-fluorouracil.
ReplyDeleteThe rationale for using it in the GBM trial is that folates can act as DNA methylating agents, increasing MGMT methylation for example, which in turn could reduce the expression of MGMT and improve sensitivity to alkylating chemotherapy (such as TMZ).
An interesting aspect in all this is that the preclinical studies mentioned in the trial description did not actually use folinic acid, but ordinary folic acid (vitamin B9) supplied in the drinking water. A couple different models of gliomagenesis in rodents showed that folic acid supplementation led to smaller tumors which was associated with increased DNA methylation and decreased expression of genes such as MGMT, and tumor-promoting genes such as survivin and PDGF-B.
http://www.ncbi.nlm.nih.gov/pubmed/22325970 (will upload to the Brain Tumor Library)
Unfortunately this study does not discuss the fact that IDH1-mutant gliomas are characterized by pathological DNA hypermethylation, and for such tumors the value of folate supplementation is highly doubtful.
On the other hand MGMT unmethylated, IDH non-mutant tumors could conceivably benefit from folate supplementation, especially during chemotherapy.
To repeat, while the clinical trial is using folinic acid, the preclinical work that preceded this trial used ordinary folic acid (vitamin B9).
Wondering the mg of folinic acid used in the preclinical work preceding the trial?
DeleteDoses of folic acid for the mice and rats were 4-40 micrograms per millilitre of drinking water. However, rodent doses should never be literally applied to humans.
ReplyDeleteThe phase 1 trial of folinic acid, when completed, should give us an idea of what an effective dose (if effective at all) might be, keeping in mind that folinic acid is not the same compound as folic acid. The recommended daily intake of folic acid is several hundred micrograms per day (about half a milligram).
I read something long time ago about methylation and folic acid. Something about people who can not convert folic acid into something and that for those people folic acid supplementation is not advisable and that they should get some other form instead that is already converted into something. Sorry about being so unspecific. 2 kids at home don't let me check all that and figure it out. I will try to check it out once I have a chance.
ReplyDeleteWhat is the relationship between folinic acid and folic acid. Is folinic acid a more 'activated' form of folic acid in the sense that it breaks down more quickly into 5-methyltetrahydrofolate (5-MTHF)?
ReplyDeleteThe following is taken from this study:
ReplyDeletehttp://www.ncbi.nlm.nih.gov/pubmed/24494987
"Folate is the generic term for a family of compounds
including folic acid and its derivatives which include 5-
methyltetrahydrofolate (5-MTHF), 5-formyltetrahydrofolate
(5-FTHF or folinic acid), 10-formyl-THF, 5,10-methyleneTHF
and unsubstituted THF"
"Folinic acid is a 5-formyl derivative of THF (Figure 1B).
Unlike the synthetic folate, folinic acid is naturally found in
food. It is readily converted to THF without requiring the
action of the enzyme dihydrofolate reductase (DHFR).
Therefore its function as a vitamin is unaffected by drugs
inhibiting this enzyme, such as methotrexate (Rajagopalan
et al., 2002). 5-MTHF (Figure 1C) is a biologically active
form of folate and is the most abundant form found in plasma,
representing >90% of folate and is the predominant active
metabolite of ingested folic acid."
According to wikipedia folinic acid is a "vitamer" for folic acid.
ReplyDelete"A vitamer of a particular vitamin is any of a number of chemical compounds, generally having a similar molecular structure, each of which shows vitamin-activity in a vitamin-deficient biological system."
From what I read half of people of european decent and many others can't convert folic acid to the active form of 5-mthf and in those people after supplementation with folic acid high level of folic acid in the blood results which can cause health problems.
ReplyDeleteBellow is some article I found.
"That folic acid may interfere with cancer has been known since the 1940’s. The chemotherapy drug methotrexate is an antifolate agent that blocks the metabolism of folic acid, developed after it was noted that a diet deficient in folic acid helped patients with leukemia.
Studies of folic acid supplementation are raising flags about the potential risks of therapy, possibly as a result of excessive consumption. One of the most startling was a study that looked at folic acid supplementation in patients with colorectal adenomas, which are cancer precursors. Participants were randomized to folic acid 1mg or placebo for up to six years. While it was hypothesized that folic acid would provide a protective effect, the results were disappointing. Not only did folic acid have no effect on adenoma incidence (even in those with low folate status), there was a significant increase in the risk of non-colorectal cancers (10.5% vs. 6.3%), due mainly to an excess of prostate cancers.
Futher worrying evidence emerged in 2009, when a Norwegian study of heart failure patients was published. Researchers randomized almost 7000 patients to folic acid and vitamin B12 versus other vitamins or placebo. The vitamins significantly raised the risks of both cancer and all-cause mortality, driven mainly by more cases of lung cancer. "
I was considering supplementation but now I'm not sure.
They also sell 5-MTHF without prescription maybe I should get that instead of folic acid. I am wondering if that would be helpful. I think that was a suggestion of one of the doctors on some site I encountered who wrote a lot about normalizing the methylation cycle.
ReplyDeletehttp://www.drdebe.com/articles/l-5-mthf-new-supplement-that-could-save-your-life
ReplyDeleteSo in this article it indirectly says that supplementing with 5-MTHF would be better than with folic acid and that the study was done on glioblastoma. I already bought yet another form of folate. I will have to buy this one now.
ReplyDeletehttp://www.lifeextension.com/protocols/cancer/brain-tumor/page-01
Here is link to the study
Deletehttp://neuro-oncology.oxfordjournals.org/content/10/4/548.full
The differences in survival between people who can convert folate and not are big. So I would assume that supplementation with 5-MTHF would have significant impact on survival.
DeleteThe Neuro-Oncology study is interesting, and does suggest that people with defects in the conversion of precursor folates to active 5-MTHF might benefit by supplementation with 5-MTHF. Unfortunately the study does not mention what percentage of the 214 GBM patients had the normal genotype (CC), and what percentage had less functional genotypes (CT, TT) for the MTHFR gene at that location. It would have been nice to know what percentage might benefit from supplementation.
DeleteAnyhow, hypomethylated gliomas probably will have more benefit from folate or 5-MTHF supplementation than hypermethylated gliomas (ie most IDH1 mutant gliomas).
Any further comment on this? I have the question into a new ND I will consult with. I was drawn to the topic initially because a year ago a doctor I was working with was starting to suspect I had the MTHFR mutation. I haven't used synthetic folate since but from my understanding people with the mutation can produce a weakened version of the enzyme that breaks down folate, leading to a build up in the blood. Which I had a year ago. 5-MTHF helps to better break down folate and regulate the enzyme. Stephen, can you tell me why you think this would benefit IDH1 mutated glioma less?
ReplyDeleteThe MTHFR enzyme converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF). 5-MTHF is the "predominant active metabolite of ingested folic acid" and is an important co-factor for remethylation of homocysteine to methionine. Methionine in turn is the ultimate source of methyl groups for DNA methylation.
ReplyDeleteConsequently folate analogs (such as folinic acid) are being used with the rationale of methylating DNA, including the MGMT gene, in the hopes of sensitizing tumors to TMZ
https://clinicaltrials.gov/ct2/show/NCT01700569
In contrast to glioblastoma, IDH1-mutated gliomas are typically already pathologically hypermethylated, so I reason that taking drugs or folates to increase DNA methylation for a tumor that is characterized by pathological hypermethylation might not be the greatest idea.
However, there could be other valid reasons to supplement with 5-MTHF (L-methylfolate), for example those who have mutations that severely compromise the function of the MTHFR enzyme.
Delete