I saw that levoleucovorin, which is (6S)-5-formyltetrahydrofolate, tablets are probably going to become available (http://www.reuters.com/article/pressRelease/idUS106792+05-Jun-2008+BW20080605), and that's the type of thing that could conceivably be an alternative to (6S)-5-methyltetrahydrofolate (L-methylfolate). L-methylfolate is available by prescription, but I'm not sure what the status is with coverage by insurance carriers. L-methylfolate is also available over-the-counter under the "trade" name Metafolin. Again, I have no financial interest whatsoever in any of these products, but these types of details have the potential to become "locked away," etc. I don't know if insurance carriers would all immediately cover levoleucovorin, but it seems to me that the coverage might be more durable? Obviously, a person's doctor would have to prescribe it for an off-label use, in this case, but levoleucovorin is probably going to be approved for use in the treatment of methotrexate toxicity. I'm not saying the uses for L-methylfolate are any less serious than for the treatment of methotrexate toxicity, but not everyone would agree with me. Whatever way one wants to view it, the coverage of levoleucovorin might be "durable."
The significance of the potential approval of levoleucovorin is that L-leucovorin (a.k.a. L-folinic acid) is the natural diastereomer of 5-formyltetrahydrofolate, and the natural diastereomer has been shown to produce more potent effects than the mixture of natural and unnatural diastereomers have been shown to produce. In my opinion, L-leucovorin would be expected to have some safety-related advantages over racemic leucovorin (such as in people who have immunological disorders or who are predisposed to experiencing allergic reactions), even though many people obviously have taken racemic leucovorin safely. The leucovorin that is available now is half (6R)-leucovorin and half (6S)-leucovorin [it's "racemic leucovorin" and is also called D,L-leucovorin or D,L-folinic acid or (6R,6S)-leucovorin or just "leucovorin"]. But the point is that even that racemic leucovorin has been used in most of the applications that L-methylfolate has been used in. In my opinion, the key point is that both L-methylfolate and L-leucovorin are reduced folates (meaning that the hydride transfer reactions, etc., have already been "taken care of" and don't need to be performed in the body), and this is thought to allow more of a dose of a reduced folate, in comparison to a dose of folic acid, to enter the brain. Reduced folates also tend to have higher bioavailabilities than folic acid does, in my opinion, although researchers keep coming out with articles that compare tiny dosages of folic acid to tiny dosages of reduced folates and that sometimes show equivalent bioavailabilities. These articles seem to only confuse people and perpetuate the problems with inadequate dosages, neglect of the importance of cobalamin (vitamin B12) repletion, etc.
I'm just going to say this, and, if anyone's reading this blog, hopefully communicate my subjective sense of things. I don't have time to go through a lot of citations, and the research on folates (and forms of vitamin B12) and cancer prevention seems to still be stuck, somewhat, in problems with dosages and bioavailability, related to the use of folic acid (as only one factor explaining the problems), and so on. But the DNA damage that can result from depletion of intracellular folates tends to be very severe, and there's a lack of appreciation for how severe it is. More importantly, the uracil misincorporation into DNA that results from intracellular depletion of folates is only the "first layer" of damage. Uracil misincorporation can lead to double-strand breaks of DNA, and double-strand breaks can lead to large deletions. In my opinion, maximizing the folate cycle in a systematic and, arguably, pharmacologically-aggressive manner is likely to be of significant importance for strategies aimed at cancer prevention. In a person who has previously had cancer or who has major risk factors for certain cancers, however, something like a reduced folate could, in my opinion, conceivably increase the risk of cancer recurrence or produce other, undesirable effects. A person should always check with his or her doctor before taking any nutritional supplements, given that a person's individual medical history can drastically change the effects that folates or other supplements might have. Reduced folates could increase angiogenesis, or new blood vessel growth, around a nascent tumor or could, in my opinion, in a manner that would depend on the rates of cell proliferation and the intracellular folate levels and the cellular context, increase tumor growth. I know some would argue that I'm "getting ahead of myself" by expressing my subjective opinion about the role that the thymidylate cycle or DNA methylation or histone methylation may play in the development of some cancers, but here's a crude search on "breast cancer" and "prevent" and (folate OR folic OR tetrahydrofolate) that gives 15,700 results (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22breast+cancer%22+prevent+folate+OR+folic+OR+tetrahydrofolate). I just do that to give anyone reading this a sense of things. I could go through all the mechanisms and important articles and flaws in all the studies using microgram dosages of folic acid that never have a hope of elevating the levels of intracellular total folates in mammary epithelial cells or colonocytes, in the colon, or other cell types. But I've discussed the problems with all these aspects of the pharmacology of folates in many other postings.
I remember reading an article that discussed the likelihood that different factors, such as environmental toxins or nutrient depletion, might contribute to the development of cancers in people. Although avoidable radiation exposure (avoidable exposure to sources of *radiation*), in my opinion, could be one factor that could become important for some people (I'm not talking about "solar radiation" in this case, but I guess everyone knows that that is important to be aware of, too, and doesn't need to hear me repeat the standard refrain on that). But, at least in terms of the comparison of environmental toxins to the depletion of things like intracellular folates (and the article didn't even refer to them specifically, as I recall), the authors of the article concluded that environmental toxins were unlikely, in many people, to accumulate to an extent that would be significant enough to produce major DNA damage or other changes that could result in cancers. An environmental toxin has to really build up and be ingested for a long time, to produce cancers. I'm not discounting the damaging effects of airborne pollution or methylmercury in the food supply, etc. I'm just saying that, in my opinion, many of these mechanistic explanations for the ways in which environmental toxins would produce cancers are not plausible, in the sense that the chemicals either are not concentrated enough or do not exert consistent-enough effects on cells that they do become concentrated in. But it is well-known, in my opinion, that intracellular folate depletion can lead to significant DNA damage and potentially predispose to the development of cancers by altering DNA methylation and histone methylation, producing uracil misincorporation and secondary, more severe forms of DNA damage, etc. It is clear to me that there are still major problems with the interventions using miniscule dosages of folic acid or giving inadequate attention to bioavailability issues. I'm not making any kinds of claims or guarantees, and all I can offer is my opinion on this type of thing. Obviously, a person should talk with his or her doctor before taking any supplements and should make sure that his or her past medical history is not going to make the intake of reduced folates or methylcobalamin unsafe, etc. Obviously, even the most systematic and pharmacologically-sound approach should not be *expected* or assumed to have the capacity to prevent any disease or cancer or anything else, and the factors leading to the development of cancers are very complex.
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