Arginine Depletion May Be A Viable Approach For Cancer

haidut

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Ray is not a big fan of certain amino acids like arginine due to its role as a nitric oxide (NO) precursor. I posted a study several weeks ago showing that supplemental arginine greatly boosted tumor growth while supplemental glycine halted it. This latest study seems to take the arginine depletion approach to its extreme and it is showing promising results.

http://www.neomatica.com/2014/08/21/chr ... -eats-dna/
Novel drug action against solid tumors explained

"...Scientists based in the U.S. at the University of California Davis, and in Taiwan at Taipei Medical University as well as the National Health Research Institutes have simultaneously discovered a new process of “chromatophagy” cellular suicide and shed light on the way a “starvation” drug deprives cancer cells of arginine, a necessary amino acid."

"...The drug examined in the study is ADI-PEG20, developed by Polaris Pharmaceuticals of San Diego. ADI-PEG20 is an enzyme that degrades arginine, which normally would be available to the cell, breaking it down into its precursors. The agent is currently in phase III clinical trials in liver cancer, phase II in melanoma and phase I in prostate cancer."

The drug ADI-PEG20 is nothing but the enzyme arginine deaminase (ADI) combined with polyethylene glycol (PEG). ADI converts arginine to citrulline and ammonia.
Arginine deiminase - Wikipedia, the free encyclopedia

Given the tumor promoting effects of ammonia on cancer, I wonder if safer methods of arginine depletion would be more viable. Cascara, niacinamide, methylene blue, and vitamin B12 should lower NO directly and provide the same benefit, since NO depletion is what the arginine depletion therapy seems to be relying upon for effectiveness.
 
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Birdie

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Thanks for this article haidut. I'd known about the arginine reduction to help herpes outbreaks, so this is fascinating.

Well, we know cascara contains emodin..but I don't see a connection to the starvation of cancer cells in the same way. The cascara, niacinamide and B12 are always part of the Peat anti-estrogen, anti-inflammation, anti-aging... all would help in the overall cancer approach.
 

jyb

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haidut said:
Ray is not a big fan of certain amino acids like arginine due to its role as a nitric oxide (NO) precursor. I posted a study several weeks ago showing that supplemental arginine greatly boosted tumor growth while supplemental glycine halted it. This latest study seems to take the arginine depletion approach to its extreme and it is showing promising results.

http://www.neomatica.com/2014/08/21/chr ... -eats-dna/

"...Scientists based in the U.S. at the University of California Davis, and in Taiwan at Taipei Medical University as well as the National Health Research Institutes have simultaneously discovered a new process of “chromatophagy” cellular suicide and shed light on the way a “starvation” drug deprives cancer cells of arginine, a necessary amino acid."

If the positive effects are due mainly to lowering NO due to arginine depletion, I wonder if cascara, niacinamide and vitamin B12 would have similar effects...

There are consistent internet anecdotes with people doing well restricting arginine for infections. It's even a standard recommendation for a viral infection like herpes, people report good results when avoiding arginine rich foods such as chocolate, while supplementing lysine. This gives a good lysine to arginine ratio.

But nowhere do people seem to take these amino experiment to the extreme, for example a complete arginine restriction for a few days. I think that, like for tryptophane/methionine restriction, there could be a trade-off...because these amino acids are very common in good foods, so to restrict them would mean basically eating a low protein diet. But presumably the liver and immune system might get adversely affected by protein deficiency? Maybe it's only workable for a few days duration.
 
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Birdie said:
Thanks for this article haidut. I'd known about the arginine reduction to help herpes outbreaks, so this is fascinating.

Well, we know cascara contains emodin..but I don't see a connection to the starvation of cancer cells in the same way. The cascara, niacinamide and B12 are always part of the Peat anti-estrogen, anti-inflammation, anti-aging... all would help in the overall cancer approach.

Arginine is a precursor to NO, so the less arginine you ingest the less NO you produce. Peat has written about the role of NO in cancer and has stated that methylene blue has major cancer fighting abilities due to being able to lower NO synthesis as well as scavenge free NO. So, IF we assume that arginine depletion starves cancer through reduced raw materials for NO synthesis, all other agents that inhibit NO should be helpful as well. Emodin, niacinamide, B12 are already mentioned but others include zinc, magnesium, copper, selenium, etc.
Does that make sense?
 
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jyb said:
haidut said:
Ray is not a big fan of certain amino acids like arginine due to its role as a nitric oxide (NO) precursor. I posted a study several weeks ago showing that supplemental arginine greatly boosted tumor growth while supplemental glycine halted it. This latest study seems to take the arginine depletion approach to its extreme and it is showing promising results.

http://www.neomatica.com/2014/08/21/chr ... -eats-dna/

"...Scientists based in the U.S. at the University of California Davis, and in Taiwan at Taipei Medical University as well as the National Health Research Institutes have simultaneously discovered a new process of “chromatophagy” cellular suicide and shed light on the way a “starvation” drug deprives cancer cells of arginine, a necessary amino acid."

If the positive effects are due mainly to lowering NO due to arginine depletion, I wonder if cascara, niacinamide and vitamin B12 would have similar effects...

There are consistent internet anecdotes with people doing well restricting arginine for infections. It's even a standard recommendation for a viral infection like herpes, people report good results when avoiding arginine rich foods such as chocolate, while supplementing lysine. This gives a good lysine to arginine ratio.

But nowhere do people seem to take these amino experiment to the extreme, for example a complete arginine restriction for a few days. I think that, like for tryptophane/methionine restriction, there could be a trade-off...because these amino acids are very common in good foods, so to restrict them would mean basically eating a low protein diet. But presumably the liver and immune system might get adversely affected by protein deficiency? Maybe it's only workable for a few days duration.

Arginine is a non-essential amino acid for adults. Only babies seem to need it, and even that is questionable:
https://en.wikipedia.org/wiki/Arginine
So, we should be able to restrict it freely with little ill effect. Alternatively, blocking the enzyme NOS (and/or scavenging existing NO) should reduce the harm from arginine if restriction is impractical.
Another pathway through which arginine may do harm is the urea cycle through the enzyme arginase.
https://en.wikipedia.org/wiki/Arginase

Arginase is strongly stimulated in tumors by lactic acid, and inhibiting arginase effectively blocks tumor growth.
https://en.wikipedia.org/wiki/Arginase#Pathology

One of the most potent arginase inhibitors is caffeine, which explains some of its strong anti-cancer effects. Of course, inhibiting arginase will tend to increase ammonia which is a known side effect of high doses of caffeine. So it seems there is an optimal amount of caffeine so that we don't end up with ammonia overload, which itself promotes cancer growth. I think individual doses of 400mg are the maximum that can be handled safely by most humans. The optimal daily dose seems to be in the range of 1,200mg - 1,500mg so taking 400mg several times a day is probably the most practical option.
 

jyb

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haidut said:
Arginine is a non-essential amino acid for adults. Only babies seem to need it, and even that is questionable:
https://en.wikipedia.org/wiki/Arginine
So, we should be able to restrict it freely with little ill effect. Alternatively, blocking the enzyme NOS (and/or scavenging existing NO) should reduce the harm from arginine if restriction is impractical.
Another pathway through which arginine may do harm is the urea cycle through the enzyme arginase.
https://en.wikipedia.org/wiki/Arginase

Yeah but I mean, nutritious foods usually have some arginine. For example if I drop milk, then I need to start thinking about calcium, potassium, various amino acids, etc. and I'm not sure if my immune system would be as good without the real food - after a while. Part of Lysine's goodness seems to be restriction of arginine uptake so that seems to be an alternative to severe arginine restriction.

And if it is true that arginine restriction works for the same reason as NO restriction, then yes all any anti-NO measure would be relevant. Clearly Peat thinks that (cf Nitric Oxide interview).
 

jyb

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haidut said:
One of the most potent arginase inhibitors is caffeine, which explains some of its strong anti-cancer effects. Of course, inhibiting arginase will tend to increase ammonia which is a known side effect of high doses of caffeine. So it seems there is an optimal amount of caffeine so that we don't end up with ammonia overload, which itself promotes cancer growth. I think individual doses of 400mg are the maximum that can be handled safely by most humans. The optimal daily dose seems to be in the range of 1,200mg - 1,500mg so taking 400mg several times a day is probably the most practical option.

Actually, I've read studies showing arginase inhibitors like caffeine could promote NO. An explanation is that more arginine becomes available for NO production.

However...I also read that one way caffeine works for infections is by killing infected cells, which are weaker. So, anti-viral action not necessarily incompatible with increased NO production killing weaker cells?
 
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haidut

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jyb said:
haidut said:
One of the most potent arginase inhibitors is caffeine, which explains some of its strong anti-cancer effects. Of course, inhibiting arginase will tend to increase ammonia which is a known side effect of high doses of caffeine. So it seems there is an optimal amount of caffeine so that we don't end up with ammonia overload, which itself promotes cancer growth. I think individual doses of 400mg are the maximum that can be handled safely by most humans. The optimal daily dose seems to be in the range of 1,200mg - 1,500mg so taking 400mg several times a day is probably the most practical option.

Actually, I've read studies showing arginase inhibitors like caffeine could promote NO. An explanation is that more arginine becomes available for NO production.

However...I also read that one way caffeine works for infections is by killing infected cells, which are weaker. So, anti-viral action not necessarily incompatible with increased NO production killing weaker cells?

Except that caffeine actually decreases NO in humans and rodents:
http://thorax.bmj.com/content/57/4/361.full
http://www.vcu.edu/csbc/bbsi/people/stu ... pharma.pdf

So, while it may increase arginine bioavailability it seems to prevent it from turning into NO.
 

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I'm surprised I never see manganese supplementation mentioned in relation to NO reduction. It should be the most powerful supplement in this regard.
 
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Pet Peeve

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Manganese is a cofactor of arginase which converts arginine to ornithine. Without enough arginase arginine will be converted to NO. In my personal experience the effect increased according to the amount taken, I took 3 x 8 mg per day at most. Here is the article that got me supplementing manganese for asthma. I had the idea to reduce NO before I even heard of Ray Peat:

http://www.ncbi.nlm.nih.gov/pubmed/15621923
 
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Pet Peeve said:
post 109837 Manganese is a cofactor of arginase which converts arginine to ornithine. Without enough arginase arginine will be converted to NO. In my personal experience the effect increased according to the amount taken, I took 3 x 8 mg per day at most. Here is the article that got me supplementing manganese for asthma. I had the idea to reduce NO before I even heard of Ray Peat:

http://www.ncbi.nlm.nih.gov/pubmed/15621923

Interesting, but please keep in mind that this study talks about relationship, not cause-effect. Increased arginase is also a hallmark of cancer and inhibiting arginase greatly reduces tumor growth. So, I think we need more info before we can recommend manganese for lowering NO.
https://en.wikipedia.org/wiki/Arginase
"...Recent work at Yale University shows that arginase1 is activated by lactic acid in tumors to stimulate macrophages to help a tumor grow as if it were poorly healing tissue. When arginase1 was inhibited in a mouse model tumor size was greatly reduced."
http://www.ncbi.nlm.nih.gov/pubmed/25043024
 
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aguilaroja

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haidut said:
.... So, I think we need more info before we can recommend manganese for lowering NO.
https://en.wikipedia.org/wiki/Arginase

It's an interesting point about shuttling arginine away from nitric oxide via the urea cycle. I share haidut's concern. There are other studies suggesting excess manganese may be increasing nitric oxide synthase activity. It could be that manganese has a narrow window of safety, even as a "trace element".

http://www.ncbi.nlm.nih.gov/pubmed/24777576
Alpha-synuclein oligomerization in manganese-induced nerve cell injury in brain slices: a role of NO-mediated S-nitrosylation of protein disulfide isomerase.Xu B1, Jin CH, Deng Y, Liu W, Yang TY, Feng S, Xu ZF.
Mol Neurobiol. 2014 Dec;50(3):1098-110. doi: 10.1007/s12035-014-8711-z.
"...findings revealed that Mn induced nitrosative stress via the activation of iNOS and subsequent S-nitrosylation of PDI in cultured slices."

http://www.ncbi.nlm.nih.gov/pubmed/15601679
Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism.
Filipov NM1, Seegal RF, Lawrence DA.
Toxicol Sci. 2005 Mar;84(1):139-48.
"Within the context of inflammation, increased production of proinflammatory cytokines and NO by Mn could be an important part of the mechanism by which Mn exerts its neurotoxicity."

http://www.ncbi.nlm.nih.gov/pubmed/19812365
Developmental exposure to manganese increases adult susceptibility to inflammatory activation of glia and neuronal protein nitration.
Moreno JA1, Streifel KM, Sullivan KA, Legare ME, Tjalkens RB.
Toxicol Sci. 2009 Dec;112(2):405-15. doi: 10.1093/toxsci/kfp221.
"Chronic exposure to manganese (Mn) produces a neurodegenerative disorder affecting the basal ganglia characterized by reactive gliosis and expression of neuroinflammatory genes including inducible nitric oxide synthase (NOS2)."
 

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Metabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages

“The role of arginine in metabolic physiology was first demonstrated in 1932, when Krebs and Henseleit discovered the urea cycle. In 1981, Windmueller and Spaeth reported that the small intestine is the major source of citrulline for synthesis of arginine by the kidneys, now called the intestinal–renal axis for arginine synthesis on an organismal level (9).”

“The importance of arginine has still risen since then, it is now clear that immune cell arginine metabolism is fundamentally involved in cancer, inflammation, infections, fibrotic diseases, pregnancy, and immune regulation in general (1621).”

“(i) Glutamine can be converted to ornithine via glutaminase (yielding glutamate), pyrroline-5-carboxylate synthetase (P5CS), which is almost exclusively expressed in the intestinal mucosa, and ornithine aminotransferase (OAT). (ii) Ornithine transcarbamylase (OTC) and carbamoyl phosphate synthetase (CPS) are involved in the formation of citrulline from ornithine. The enzymes are restricted to the mitochondrial matrix of hepatocytes and epithelial cells of small and (to a minor extent) large intestine. This reaction is therefore a part of the hepatic urea cycle and also involved in intestinal synthesis of citrulline, which is released into the circulation.”

“Murine macrophages have long been known to (i) upregulate ***** and constitutively express ASL* when stimulated with the NOS-inducing agents lipopolysaccharide (LPS) and IFN-γ (24) and (ii) to partially rescue NO synthesis via citrulline uptake and ****-mediated recycling to arginine (25). This set of reactions via **** and ASL forms the so-called citrulline–NO cycle (26). The importance of this pathway for the resynthesis of arginine to ensure sufficient substrate supply for prolonged NO synthesis under arginine limitation has been recently demonstrated in vivo in murine mycobacteria infection (27).”

*Argininosuccinate synthetase (****) and argininosuccinate lyase (ASL) are cytosolic enzymes responsible for the biosynthesis of arginine from citrulline (and aspartate as a co-substrate).

“In contrast to murine macrophages, arginine transport is based on system y+L [amino-acids transporters] in IFN-γ-activated human primary monocytes (39) or LPS-stimulated alveolar macrophages (40), another example of interspecies differences, which are so prominent in various aspects of arginine metabolism in the immune system (17, 41, 42).”

“Most prominently known as microbicidal and inflammatory effector pathway in macrophages (22), iNOS activity has also been demonstrated in a variety of other cell types, e.g., hepatocytes (55), pulmonary epithelium (56), and colon epithelium (57). A variety of pro-inflammatory cytokines (e.g., IL-1β, IFN-γ, or TNF-α), microbial products (e.g., LPS), and hypoxia can induce macrophage iNOS transcription, whereas other cytokines (e.g., IL-4, IL-10, TGF-β) suppress iNOS gene transcription (58). Additive or synergistic activities of combinations of multiple cytokines are most efficient in inducing or suppressing iNOS gene expression. NO synthesis can also be limited by arginine availability and/or on the level of iNOS protein expression (59).”

“Ornithine, via the enzyme OAT, is also a precursor amino acid for the synthesis of proline, which itself is essential for the synthesis of collagen. Accordingly, arginase-derived ornithine might be important in tissue (re-)modeling processes. This hypothesis was supported by studies that demonstrated an increase in arginase levels in fibrotic lung disease (74) or allergic asthma (75, 76).”

“The same two macrophage phenotypes were then also correlated with tumor growth (arginase/ornithine) or tumor killing (NOS/NO) (79).”

“Clearly, arginine depletion does not inhibit immune responses broadly and indiscriminately: important activation aspects of T cells (91, 94) and granulocytes (95) are preserved in an arginine-depleted milieu and other cellular responses, e.g., induction of arginine transport protein CAT-1 (33), are even enhanced in eukaryotic cells under arginine nutrient deprivation.”

“In human tuberculosis, the distribution of M1 (iNOS) and M2 (arginase) macrophages is spatially organized within granulomas: M1 macrophages can preferentially be found in the inner region closer to viable mycobacteria, whereas a higher frequency of M2 macrophages is detectable on the outer “healing” margins. This clearly forms an organized microenvironment in which antibacterial (M1) responses are physically separated by M2-based anti-inflammation and fibrosis from uninvolved tissue (96).”

“..it was shown that arginase I expression in granuloma-associated macrophages restricts immune pathology since macrophage-specific deletion of arginase I led to larger granulomas and bacterial burden load (115). These discrepant study results clearly demonstrate the fundamental importance of the microenvironment and the multitude of potential factors that act on macrophages in vivo and which can simply not be mimicked in vitro.”

“The arginase/iNOS dichotomy of macrophage amino acid metabolism has counterparts in the other major components of cellular metabolism: (a) genes of fatty acid oxidation are preferentially expressed in M2 macrophages and inhibition of fatty acid oxidation leads to an abrogation of M2 activation (116); (b) M1 macrophages preferentially use glycolysis and glutamine anaplerosis while M2 macrophages preferentially use oxidative metabolism (117).”

--
So, even if you restrict, it's still able to be recycled. Both pathways have important functions, hence the inner and outer actions in infections, and more than supressing inflammation by trying to manipulate those pathways, the focus should be on diminishing what's causing it. However, it seems that dietary restriction can help the body control better the inflammatory process. At least this is what I understood from the review.
 
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Birdie

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Arginine is a precursor to NO, so the less arginine you ingest the less NO you produce. Peat has written about the role of NO in cancer and has stated that methylene blue has major cancer fighting abilities due to being able to lower NO synthesis as well as scavenge free NO. So, IF we assume that arginine depletion starves cancer through reduced raw materials for NO synthesis, all other agents that inhibit NO should be helpful as well. Emodin, niacinamide, B12 are already mentioned but others include zinc, magnesium, copper, selenium, etc.
Does that make sense?
Yes. :)
 

< Rain

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Interesting, but please keep in mind that this study talks about relationship, not cause-effect. Increased arginase is also a hallmark of cancer and inhibiting arginase greatly reduces tumor growth. So, I think we need more info before we can recommend manganese for lowering NO.
Arginase - Wikipedia
"...Recent work at Yale University shows that arginase1 is activated by lactic acid in tumors to stimulate macrophages to help a tumor grow as if it were poorly healing tissue. When arginase1 was inhibited in a mouse model tumor size was greatly reduced."
Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. - PubMed - NCBI
Question on Ornithine to Reduce Ammonia.


Recently heard Haidut on Generative Energy #10 (Danny Roddy) mentioning a study in Japan using amino acid Ornithine to excrete ammonia thru the urea cycle.

Q: Does Ornithine require concurrent Lysine. Any thoughts on need to avoid NO production; would Aspirin/Niacinamide/P5P work for that purpose? Thank You!



This is what Hulda Clark says: “Another sleep disturbance is waking in the night and not being able to go back to sleep for hours. Or not being able to get to sleep.



I believe these problems are caused by a high ammonia level in the brain. This belief is based on two observations. Ornithine, an ammonia reducer, induces a wonderful sleep in sleep-deprived persons. It is also observed that after killing parasites, which produce ammonia, sleep is much improved. Our metabolism does not produce ammonia. We produce urea which is excreted by the kidneys along with water and then called urine. When we are parasitized, our metabolism is burdened with ammonia, though, made by the parasites. We have to turn it into urea in the liver and kidneys so we can excrete for them. But this can't be done in the brain! The brain lacks an essential enzyme, ornithine curbamyl-transferase, for this bit of biochemistry. The brain was never meant to be parasitized or infected and has no defense. Most of our parasites come from animals we associate with. We weren't meant to live with horses, cows, sheep, pigs, monkeys, guinea pigs, cats, dogs and chickens nor to come in contact with dozens more at a zoo. We do so at our own peril.



It is known that ammonia is a strong brain irritant. In fact, a person can be awakened from a coma by being made to smell ammonia "smelling salts." Omithine reacts with ammonia, mopping it up like a sponge. Arginine, another amino acid, also reacts with ammonia, but does not put you to sleep. So there is more to insomnia than mere inability to reduce ammonia levels. Arginine results in alertness and therefore should be used in the morning, when needed. Ornithine, given at bedtime, may take 1/2 hour to do its magic. Both are perfectly safe, since they are natural to your body, and a food constituent.



Start by taking two ornithine capsules (each 500 mg.) on the first night. Take four the next night. Take six the night after and choose the dose you like best. Sometimes it takes five days to "catch up" on everything that needs to be done for the brain and get you sleeping. Meanwhile, of course, you are planning to kill your parasites and be done with insomnia in the most effective way of all.”
 

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Thanks for posting this study (and all others), @haidut.

For a discussion with a related person, I needed some statements on arginine/NO and cancer from "offical studies", and found the following pieces of information. Probably boring for people following RP, but maybe useful for copy/paste purposes.

"Tumour cells are particularly dependent on arginine for growth [1,2], although the reasons for this requirement are not completely clear. Dietary supplementation with arginine has been shown to stimulate tumour growth in patients with breast cancer [3] as well as to stimulate the growth of some experimental tumours [4–10] [...] Synthesis of NO from arginine, which is mediated by the NOS (NO synthase) enzyme family, has [...] been demonstrated in several tumour cells [15–17] and solid human tumours [18–20]." (Caso et al. (2004) Tumour cell growth in culture - Dependence on arginine [Tumour cell growth in culture: dependence on arginine. - PubMed - NCBI])

"Arginine has been known to influence the growth of transplantable mice tumor since 1930 (1). Diet supplemented with arginine enhances tumor growth in mice. Conversely, dietary restriction of arginine inhibits growth of metastatic tumor (2)." (Cheng et al. (2007) Pegylated recombinant human arginase (rhArg-peg5,000mw) inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through arginine depletion [Pegylated recombinant human arginase (rhArg-peg5,000mw) inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through a... - PubMed - NCBI])

"BALB/c mice fed with supplemented arginine developed subcutaneous growth of EMT-6 tumors at a much faster rate than control mice (47). Similarly, an arginine supplemented diet increased metastatic murine colon tumor growth by 55%, whilst restriction of arginine inhibited the growth by up to 78% (48)." (Fultang et al. (2016) Molecular basis and current strategies of therapeutic arginine depletion for cancer [Molecular basis and current strategies of therapeutic arginine depletion for cancer. - PubMed - NCBI])


And this one is on inducing pancreatitis:

"Administration of L-arginine in rats produced pancreatitis by various mechanisms such as increased production of nitric oxide (NO) (thereby inducing oxidative and nitrosative stress), increased levels of inflammatory mediators, and inducing metabolic acidosis [10]. The current study used L-arginine to induce experimental acute necrotising pancreatitis and to evaluate the putative role of M. pudica in treating pancreatitis." (Kaur et al. (2016) Protective effect of Mimosa pudica L. in an L-arginine model of acute necrotising pancreatitis in rats [Protective Effect of Mimosa Pudica L. In an L-Arginine Model of Acute Necrotising Pancreatitis in Rats])
 

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But how do yo suppress arginine from your diet?
 

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I'm not knowledgable enough to answer your question, but in my case it was simple: The person I'm trying to convince currently takes 6 g - 12 g supplemental arginine per day!!!! Personally I just aim at reducing my intake of arginine from artificial sources such as certain tooth pastes (e.g., Elmex sensitive and the like). And I take low dose methylene blue in an attempt to reduce my NO burden.
 

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But how do yo suppress arginine from your diet?
There are lists of foods to avoid. A search for arginine/lysine ratio or low arginine foods would be a start.

There are a lot of people using low arginine diets for herpes or shingles.
 

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