folic acid too much?

[mpbser]

I have an inherited genetic mutation related to folic acid and I was reading about overdose/toxic levels of folic acid the other morning. (My husband is the one with cancer.) As folinic acid (not folic acid but a bioavailable form of it) is standardly given with chemo ("Leucovorin") at a dose of 400 mg/m2 IV, I am now wondering how safe it is for my husband who has heart disease (narrowed cardiac artery). Research suggests that taking folic acid in doses of 800-1200 mcg might increase the risk of heart attack in people who have heart problems. Also, folic acid intravenously (by IV) or by mouth might worsen narrowed arteries. I know that Leucovorin supposedly increases the absorption time of the chemo but do the benefits outweight the risks in people such as my husband?

And is that even the reason why it is given? Our local cancer center oncologist said it was but now that I am trying to confirm, I can't find substantiation.

On a site note, found some interesting information about a relationship between folic acid to cancer. First, at https://www.webmd.com/vitamins/ai/ingre ... folic-acid a number of the references cite studies that show a connection between folic acid and colon cancer. I have also read that a high daily dose of folic acid from a supplement has been associated with a more than doubling of the risk of prostate cancer. https://www.consumerlab.com/answers/is- ... olic_acid/

I see an interesting coincidence between the recent explosion of numbers of young people with colon cancer, the ubiquitous supplementation of folic acid in US wheat products (starting in 1998), and genetically-engineered foods that are causing genetic mutations to the human microbiome (starting in past decade).

[mpbser]

Obviously, we will avoid folic acid during chemo, both in supplemental and dietary form. In fact, I plan on buying only imported pasta and other wheat product foodstuff.

[rp1954]

Folic acid is the industrial garbage form of vitamin B9, especially with 5FU and for MTHFR variants; we avoid it. I can't directly address your husband's particular heart issues - they can be manifold - possibly calcium or iron excess; deficient C, D3, K2 (MK4) or magnesium, homocysteine, diabetes, Apo B1 etc.

As for leucovorin(LV) with 5FU, we titrated LV with 15mg oral tablets, split daily, and only needed 8-19 mg per day (vs 75 - 90 mg/d for standard oncology). You would need a different dose schedule for cyclical IV chemo.

Then my wife used 1-2 tablespoons of liver for natural folate to feed the good cells. We were able to use PSK, WGP and/or MK4 to pick up the slack if any more LV effect was needed to boost the daily 5FU's efficacy. The oncologists sometimes try to just use 5FU without LV (like the shortages) but that is not as good as chemo.

[mpbser]

I finally got around to looking up the specifics of Leucovorin and learned that it is actually folinic acid. Interestingly, it's actually 5-methyl-tetrahydrofolate, a metabolite of folinic acid, that does the activity on the chemo (FU). 5-methyl-tetrahydrofolate is the last step in the folate methylation cycle. I know this from my studies on the subject.

I have always wondered if my husband has an inherited MTHFR mutation like I do. So, I am glad to see that leucovorin is not folic acid (I agree with rp1954 that it's industrial garbage... Americans seem not to mind about eating waste. Look at antifreeze in American food!) but folinic acid.

How it it works:

Fluorouracil inhibits nucleic acid synthesis by several mechanisms, including binding to thymidylate synthetase. A leucovorin metabolite (5-methyl-tetrahydrofolate [5-MTHF]) stabilizes the bond formed between a fluorouracil
metabolite (fluorodeoxyuridine monophosphate) and thymidylate synthetase. This causes a decrease in intracellular levels of that enzyme and a resulting decrease in the production of thymidylate. In this way, leucovorin can enhance or modulate the activity of fluorouracil.

I still don't really get the issue with avoiding folic acid during/based on chemo/leucovorin though, considering leucovorin isn't folic acid. In other words, it's not like leucovorin adds to the amount of folic acid one is taking -- it's not folic acid.

[LPL]

Hm..? Am I misunderstanding?
I thought Folinic acid was 5-formyltetrahydrofolate.
That the steps in coverting Folic acid and folate was like this:
“Tetrahydrofolate (THF)
5-formyltetrahydrofolate (Folinic acid)
5-10-methylenetetrahydrofolate
5-methyltetrahydrofolate (Methylfolate)”
From http://mthfr.net/folic-acid-awareness-w ... 014/01/08/

[LPL]

Sorry I did misunderstand.
Well since the needed MTHFR comes in to make the last step “Methylfolate”.. why can’t they have that in the Leucovorin?
My husband is compound heterozygous (and so am I). A lot of people have problems with this ‘last step’.

[rp1954]

Levo 5,10-methylenetetrahydrofolate (L 5,10-MeTHF, aka Cofactor aka ANX-510) is the leucovorin metabolite that reacts with 5FU to inhibit colon cancer cells. The 5,10 MeTHF binds 5FU ~100x stronger than with natural folate. Ca 2006-2008 AdventRX attempted to trial and market Cofactor at high doses and high prices, but didn't get FDA approval due to surprisingly more side effects over leucovorin. The FDA also had another new high pay client lined up with Levoleucovorin.

Natural folate is what normal cells need. The preferred human form, natural folate is 5-methyltetrahydrofolate, L 5-MTHF.
MTHFR allows the conversion of 5,10 MeTHF to 5 MTHF, variant MTHFR slower or less efficient.

My surmise is that AdventRX thought the conversion of leucovorin to L-5,10 MeTHF would be an improvement, bypassing that first conversion, but instead overdosed MTHFR variant patients with IV bolus treatments of 5,10 MeTHF (Cofactor). Leucovorin requires conversion time and so might be less toxic, especially to MTHFR variants. Our daily dosing of LV spreads leucovorin conversion out even more, more closely matches 5FU use to LV/Cofactor conversion, and can be finely (reduced) dosed for toxicity.

We also use liver products for their L5MTHF content to reduce 5FU-LV toxicity effects on the CBC differentials.

I more suspect the accumulation of unconverted folic acid in the blood maybe a critical association with CRC.

[LPL]

Interesting!?

Folate gene prediction of treatment response to 5-FU and leucovorin in advanced colorectal cancer. (2018) http://ascopubs.org/doi/abs/10.1200/JCO ... suppl.3550

CRguy posted about this trial - Feb 15 2019
http://coloncancersupport.colonclub.com ... 38#p488411
”Looking for patients with advanced colorectal cancer to a test two different treatment combinations.
https://medivizor.com/view_article/2326 ... dium=email
This phase 3 trial is examining the effectiveness of arfolitixorin versus leucovorin (folinic acid) when added to a combined treatment with 5-fluorouracil, oxaliplatin, and bevacizumab (FOB) to treat advanced colorectal cancer. The main outcome to be measured is the cancer response to the treatment.”

From http://isofolmedical.com/modufolin/about-arfolitixorin/
”ARFOLITIXORIN CONTAINS THE KEY ACTIVE METABOLITE OF ALL CLINICALLY USED FOLATE-BASED DRUGS
arfolitixorin is Isofol’s clinical lead candidate, a novel folate-based therapy developed to increase the efficacy and reduce the side effects of antimetabolites used in cancer treatment. The active pharmaceutical ingredient (API) of arfolitixorin is the key active metabolite of all clinically used folate-based drugs today, including leucovorin and levoleucovorin, and does therefore not require metabolic activation to exert its action. As part of their cancer treatments, more than 500 000 patients are treated with folate-based therapies annually, in the US, Europe and Japan – more than any other single cancer drug.”

[mpbser]

rp1954 and LPL, thanks so much for the input! This is truly fascinating on so many different levels for me.

I see that arfolitixorin is [6R]-5,10-methylene-tetrahydrofolate. This makes so much sense, to use it. Funny how leucovorin has been used for so many years and the industry is only now getting around to studying this.

[mpbser]

tangentially related... would love to have more time to get a full grasp on the folate-protein connection:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946189/

[LPL]

tangentially related... would love to have more time to get a full grasp on the folate-protein connection:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946189/

mpbser, I read your article. Interesting.
Then I found myself reading this http://www.brendadavisrd.com/methionine ... cted-diet/
I don’t know how I feel about it... remembering reading conflicting ’stuff’ about this some years ago.
Yes agree - I also wish I had more time!