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Mack
Member since Jan-9-09
25 posts
Feb-05-09, 06:01 AM (PST)
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"DCA and the MAAI pathway"
 
   The following is all highly speculative and a bit rushed. I've tried to find a reason as to why some people have done really really well on dca at the start but recently the cancer has come back at a later stage. I've been hopping from study to study on pubmed today, just taking notes rather than the links but the keyword search function can be used to find the papers again fairly easily.

From my scribbled notes on the research, mostly in animals:

There is no alternative pathway for DCA clearance other than the MAAI (also known as GSTZ1-1) mediated transformation.

Prolonged continued use of dca will deplete MAAI

MAAI pathway is also used to breakdown tyrosine catabolites. If MAAI is depleted/inhibited, toxic concentrations of tryosine intermediates such as maleylacetone and succinylacetone accumulate.

Patients with acquired deficiency of MAAI via dca are at increased risk of drug & chemical induced toxicity

DCA indiced inactivation of MAAI leads to formation of MAA derived intermediate, maleylaceton which is a biomarker for dca associated toxicities

Urinary excretion of unchanged dca increased with age. Oxalate (the end product of DCA metabolism) decreases. Plasma and urinary levels of maleylacetone (natural substrate for MAAI enzyme increases with age. Liver MAAI activity inhibited equally by DCA in all age groups.

In animals it took 8 weeks for MAAI to return to control levels after chronic administering of dca.

Hypothetically, chronic dca could mimic the symptoms of Tyrosinemia type 1. The catabolite succinylacetone is an irreversible inhibitor of aminolevulinic acid dehydratase ALAD. This depletes Heme - required by enzymes synthesizing vascular modulators leading to decreased renal NOS activity and increased kidney microsomal heme oxygenase activity by 27%. (But in animals this did not increase blood pressure)

Delta aminolevulinic acid (delta ALA) implicated in neurological complications of porphyria & tyrosinemia type 1 & elevated in urine of dca treated animals - delta ALA reduced myelin lipids and proteins

Melatonin protects against oxidative stress caused by delata ALA.

DCA itself directly induces reversible inhibition of myelin related proteins

*** This could be interesting - heriditary tyrosinemia type 1 leads to chronic stress which activates Akt survival signal - inhibits apoptosis in liver - inhibits mitochondrial mediated apoptosis through BAD & Bcl-X(l) & Bcl-2

In a nutshell, chronic prolonged use of dca can dominate and exhaust a chemical pathway used to breakdown phenylalanine and tyrosine, accumulating poisonous catabolites in the body. If this mimics heriditary tyrosinemia type 1 it might lead to the shutdown of the mitochondrial mediated apoptopic pathway.

Again I stress this is a hypothesis only. We would need to somehow check the dca resistant people for increased maleylacetone and succinylacetone and come up with a fix for it - somehow increasing MAAI, or a drug that breaksdown the tyrosine catabolites. Alternatively we need a dosing and time regimen for dca that ensures MAAI does not get depleted. I welcome all comments and opinions.

Regards to you all

Mack


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Sandra
Member since Feb-27-07
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Feb-05-09, 08:33 AM (PST)
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1. "RE: DCA and the MAAI pathway"
In response to message #0
 
Great post Mack,

I'm wondering if there might be a secondary effect here. Tyrosine is the precursor amino acid for thyroxin (the thyroid gland hormone). I wonder if DCA use could cause hypothyroidism, slowing metabolism (cellular energy production) possibly inhibiting apoptosis... Just my rambling here, at 1:30am my time...

Sandra


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Sandra
Member since Feb-27-07
687 posts
Feb-05-09, 08:22 PM (PST)
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2. "RE: DCA and the MAAI pathway"
In response to message #1
 
Check out THIS clinical trial with DCA, NTBC and a low tyrosine diet!!! I'm going to try to find out if these results are published yet or not!!!

What is NTBC?

NTBC is a drug that has recently been approved for children and adults with a rare metabolic disease called Hereditary Tyrosinemia Type I (HT). Persons with HT build up some of the same toxic chemicals in the blood and urine that persons taking DCA accumulate. Studies have shown that giving NTBC to persons with HT prevents the build up of these chemicals. We think NTBC will reduce the toxicity of DCA in patients with CLA. However, we cannot be sure that NTBC is effective for CLA patients who are taking DCA unless we conduct what is called a "double-blind", parallel study. This means NTBC is compared to a "placebo." A placebo is a chemical that is safe to take but has absolutely no therapeutic benefit. NTBC may also have toxic side effects if the person has large amounts of tyrosine in his or her diet. NTBC is not harmful if it is given with a diet low in tyrosine. All patients enrolled in this study will receive a diet low in tyrosine and phenylalanine (low tryosine diet, or LTD).

http://www.gcrc.ufl.edu/dca/NTBC/index.html



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Sandra
Member since Feb-27-07
687 posts
Feb-05-09, 08:30 PM (PST)
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3. "RE: DCA and the MAAI pathway"
In response to message #2
 
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T4P-4JMKMPC-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=96e3d28d7a2e6e35d1a611e2b7c5c1b5

Evaluation of dichloroacetate treatment in a murine model of hereditary tyrosinemia type 1.

Langlois C, Jorquera R, Finegold M, Shroads AL, Stacpoole PW, Tanguay RM.
Laboratory of Cellular and Developmental Genetics, CREFSIP, Department of Medicine, University Laval, Que., Canada G1K 7P4.
Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease severely affecting liver and kidney and is caused by a deficiency in fumarylacetoacetate hydrolase (FAH). Administration of 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC) improves the HT1 phenotype but some patients do not respond to NTBC therapy. The objective of the present study was to evaluate whether administration of dichloroacetate, an inhibitor of maleyl acetoacetate isomerase (MAAI) to FAH-knockout mice could prevent acute pathological injury caused by NTBC withdrawal. DCA (0.5 and 5g/L) was given in combination with a standard diet or with a tyrosine-restricted diet. With the low-tyrosine diet body weight loss and most of hepatic and renal injuries were prevented regardless the DCA dose. The administration of DCA with a standard diet did not prevent damage nor the oxidative stress response nor the AFP induction seen in FAH-knockout mice. DCA was shown to inhibit hepatic MAAI activity to 86% (0.5g/L) and 94% (5g/L) of untreated wild-type mice. Interestingly, FAH(-/-) mice deprived of NTBC (NTBC-OFF) and NTBC-treated FAH-knockout mice had similar low hepatic MAAI activity levels, corresponding to 10-20% of control. Thus the failure of DCA treatment in FAH(-/-) mice seems to be attributed to the residual MAAI activity, high enough to lead to FAA accumulation and HT1 phenotype.


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Sandra
Member since Feb-27-07
687 posts
Feb-05-09, 08:38 PM (PST)
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4. "RE: DCA and the MAAI pathway"
In response to message #3
 
Info on NTBC (Orfadin)
http://www.rxlist.com/orfadin-drug.htm


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Sandra
Member since Feb-27-07
687 posts
Feb-05-09, 08:55 PM (PST)
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5. "RE: DCA and the MAAI pathway"
In response to message #4
 
Probably good for DCA uses to AVOID tyrosine and phenylallanine sources in their diets.

http://www.nutritional-supplements-health-guide.com/tyrosine-foods.html


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Sandra
Member since Feb-27-07
687 posts
Feb-05-09, 11:22 PM (PST)
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6. "RE: DCA and the MAAI pathway"
In response to message #5
 
Foods lowest in tyrosine and phenylallanine:

http://www.nutritiondata.com/foods-000000000000087086000-w.html


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Sandra
Member since Feb-27-07
687 posts
Feb-06-09, 00:05 AM (PST)
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8. "RE: DCA and the MAAI pathway"
In response to message #6
 
Tyrex 2 and Tyros 2 are protein powders (low in tyrosine and phylallanine) formulated for people with Tyrosinemia.


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Mack
Member since Jan-9-09
25 posts
Feb-05-09, 11:30 PM (PST)
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7. "RE: DCA and the MAAI pathway"
In response to message #5
 
   http://www.ncbi.nlm.nih.gov/pubmed/16399379?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=4&log$=relatedreviews&logdbfrom=pubmed

"Zeta-class glutathione transferases (GSTZs) were recently discovered by a bioinformatics approach and the availability of human expressed sequence tag databases. Although GSTZ showed little activity with conventional GST substrates (1-chloro-2,4-dinitrobenzene; organic hydroperoxides), GSTZ was found to catalyze the oxygenation of dichloroacetic acid (DCA) to glyoxylic acid and the cis-trans isomerization of maleylacetoacetate to fumarylacetoacetate. Hence, GSTZ plays a critical role in the tyrosine degradation pathway and in alpha-haloacid metabolism. The GSTZ-catalyzed biotransformation of DCA is of particular interest, because DCA is used in the human clinical management of congenital lactic acidosis and because DCA is a common drinking water contaminant. Substrate selectivity studies showed that GSTZ catalyzes the glutathione-dependent biotransformation of a range of dihaloacetic acids along with fluoroacetic acid, 2-halopropanoic acids, and 2,2-dichloropropanoic acid. Human clinical studies showed that the elimination half-life of DCA increases with repeated doses of DCA; also, rats given DCA show low GSTZ activity with DCA as the substrate. DCA was found to be a mechanism-based inactivator of GSTZ, and proteomic studies showed that Cys-16 of human GSTZ1-1 is covalently modified by a reactive intermediate that contains glutathione and the carbon skeleton of DCA. Bioinformatics studies also showed the presence of at least four polymorphic variants of human GSTZ; these variants differ considerably in the rates of catalysis and in their susceptibility to inactivation by DCA. Finally, Gstz1(-/-) mouse strains have been developed; these mice fail to biotransform DCA or maleylacetone. Although the mice have no obvious phenotype, a high incidence of lethality is observed in young mice given phenylalanine in their drinking water. Gstz1(-/-) mice should prove useful in expanding the role of GSTZ in alpha-haloacid metabolism and in the tyrosine degradation pathway."

So the more dca is used the less it is broken down and takes longer to remove from the body. How long I don't know but it needs to be considered for dosing regimens.

Secondly there are 4 or more variants of GSTZ(MAAI) which differ in the rate of dca inactivation - ie in some people the GSTZ pathway will not be degraded as much as others.

Mack


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davidportia
Member since Jul-23-08
66 posts
Feb-07-09, 08:58 AM (PST)
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9. "RE: DCA and the MAAI pathway"
In response to message #0
 
   This is a great post that explain my doubt. The result of the initial use of DCA for the first two months with my dad surprised me with exceptional good result. I was kind of suspect the report contain errors.
The second round (two month) the tumor grew back although a higher dose was maintained, together with more supplements. I thought maybe one of the supplements may cause this bad result, so I asked my dad going back to just take what he took during the first round. The result of this round turned out even worse.
Today we all know Oracle told us that Lien is also having bad result now.
So how can we overcome this if what you stated make sense?
Best regards,
David


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Sandra
Member since Feb-27-07
687 posts
Feb-07-09, 11:28 PM (PST)
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10. "RE: DCA and the MAAI pathway"
In response to message #9
 
>So how can we overcome this if what you stated make sense?
>Best regards,
>David

Hi David,

If this is true, thyroid hormones should be checked (and possibly thyroid hormone should be supplemented) a low-tyrosine diet should be used, and depending upon the results of the clinical trial with NTBC, maybe it should be added with DCA. Time off DCA will also help, allowing the body to process the tyrosine that has built up, and make the thyroid hormones.

http://en.wikipedia.org/wiki/NTBC

http://www.gcrc.ufl.edu/dca/NTBC/index.html

http://www.ncbi.nlm.nih.gov/pubmed/16706549

Take care,
Sandra


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Sandra
Member since Feb-27-07
687 posts
Feb-08-09, 04:50 PM (PST)
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11. "RE: DCA and the MAAI pathway"
In response to message #10
 
Hmmm.... I've been trying to understand the catabolism of tyrosine to thyroxine (a thyroid hormone) to see whether or not DCA would cause hypothyroidism. I now think that this is a separate pathway, and doesn't involve the MAAI one (which DCA inhibits). So, I don't believe DCA use would lead to hypothyroidism.

Here is the metabolic pathway for tyrosine:
http://www.genome.jp/kegg/pathway/map/map00350.html

You can see the path that leads from tyrosine to L-thyroxine is vertical. The one from tyrosine to Maleylacetoacetate is horizontal (to the left).

So, at this point probably the best thing to do is try to eat more foods lower in tyrosine when taking DCA (fruits and vegetables), and take time off DCA.


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davidportia
Member since Jul-23-08
66 posts
Feb-09-09, 06:01 AM (PST)
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14. "RE: DCA and the MAAI pathway"
In response to message #11
 
   >Hmmm.... I've been trying to understand the catabolism of
>tyrosine to thyroxine (a thyroid hormone) to see whether or
>not DCA would cause hypothyroidism. I now think that this
>is a separate pathway, and doesn't involve the MAAI one
>(which DCA inhibits). So, I don't believe DCA use would
>lead to hypothyroidism.
>
>Here is the metabolic pathway for tyrosine:
>http://www.genome.jp/kegg/pathway/map/map00350.html
>
>You can see the path that leads from tyrosine to L-thyroxine
>is vertical. The one from tyrosine to Maleylacetoacetate is
>horizontal (to the left).
>
>So, at this point probably the best thing to do is try to
>eat more foods lower in tyrosine when taking DCA (fruits and
>vegetables), and take time off DCA.

Hi, Sandra,
Yes, I am thinking of time-off on DCA, but not sure how long on the time-off. As per Mack, it took 8 weeks for animal model. I think it maybe too long for my dad if LDN does not work to curb the tumor growth. Right now, I think I should give LDN at least 20 days before cutting off DCA. What dosage would be the best if I pursue 8-weeks on and 8-weeks off on DCA?
I hope we can come up with a dosing and time regimen for DCA that ensures MAAI does not get depleted at least for now, if we do not have access to other proven alternative meds. Any suggestions?
Best regards,
David


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Sandra
Member since Feb-27-07
687 posts
Feb-09-09, 06:45 PM (PST)
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15. "RE: DCA and the MAAI pathway"
In response to message #14
 
Hi David,
In the case of the animal model, I don't believe they were giving ANY time off (most DCA users on the forum are taking either a couple days off a week, or a week off every 2 weeks) so it would take longer for the mice to clear DCA. In your father's case, I would be worried to take him off DCA for as long as 8 weeks because I know from a couple of cases with dogs that cancer can come back very quickly when DCA is stopped. I would suggest taking a week off, like Medicor advices, and then resume your regular DCA on/off cycle. But again, we are still learning here, so that is just my suggestion to you at this point.

Try also to read up on tyrosine in foods and adjust your father's diet a bit. I think this may help. But, if you do reduce tyrosine, you may still need to have his thyroid hormones checked to see that this doesn't lower them.

Best to you and your father,
Sandra


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davidportia
Member since Jul-23-08
66 posts
Feb-16-09, 06:40 AM (PST)
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19. "RE: DCA and the MAAI pathway"
In response to message #15
 
   >Hi David,
>In the case of the animal model, I don't believe they were
>giving ANY time off (most DCA users on the forum are taking
>either a couple days off a week, or a week off every 2
>weeks) so it would take longer for the mice to clear DCA.
>In your father's case, I would be worried to take him off
>DCA for as long as 8 weeks because I know from a couple of
>cases with dogs that cancer can come back very quickly when
>DCA is stopped. I would suggest taking a week off, like
>Medicor advices, and then resume your regular DCA on/off
>cycle. But again, we are still learning here, so that is
>just my suggestion to you at this point.
>
>Try also to read up on tyrosine in foods and adjust your
>father's diet a bit. I think this may help. But, if you do
>reduce tyrosine, you may still need to have his thyroid
>hormones checked to see that this doesn't lower them.
>
>Best to you and your father,
>Sandra
Dear Sandra,
Sorry reply you so late because I have been very busy with my dad's current situation. I have managed to get him Terceva, in an effort to stop the current trend, and I pray that Terceva will work to correct the situation. He ate very little, and lost nearly 15 pounds already in about 3 weeks. He can hardly walk now, and always complains pains all over his body. I have asked him to stop DCA as soon as he started Terceva. I hope Terceva can give us some time that can make DCA work again for him. God bless,
Thank you, Sandra
David


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Jakke
Member since Feb-10-09
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Feb-19-09, 05:54 PM (PST)
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26. "RE: DCA and the MAAI pathway"
In response to message #15
 
   Could this be of any help?

http://www.phytochemicals.info/phytochemicals/genistein.php


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crono5
Member since Aug-2-07
66 posts
Apr-10-09, 07:42 AM (PST)
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32. "RE: DCA and the MAAI pathway"
In response to message #10
 
Recently i had receved an email from polish Lady who's Mom has got glioma, she said that in hospital doctors have discovered hypothyroidism, diabetics (due to steroids) - she doesn't follow low carb and sugar diet, and some other issues. But i think, that Sandra you were right hypothyroidism may be related with DCA intake due to inactivation of MAAI.

http://apoptoza.pl
http://nadzieja-glejak.pun.pl
http://glejak.pl/forum


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Mack
Member since Jan-9-09
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Feb-09-09, 01:04 AM (PST)
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12. "RE: DCA and the MAAI pathway"
In response to message #9
 
   Interference with the tyrosine degradation pathway may be just one way that dca can lose its effect and the cause may be quite subtle. For instance if not broken down, the tyrosine catabolite succinylacetone inhibits aminolevulinic acid dehydratase, which increases delta aminolevlinic acid (also known as 5-ALA) which induces iron release from ferritin via free radical production. High levels of iron are drivers of tumour growth and oxidative damage.

Most of us are aware that mainstream chemo also loses effectiveness and in some cases drives metastasis by upregulating the NF-KB pathway (which can hopefully be inhibited by taking alpha lipoic acid/curcumin. And of course individual responses may reflect subtles differences in our genes, ages, the food we eat. The amount we take...

So hard to know what to do, there is so much trial and error. But a first step should be to ask any long term good responders exactly what they are on in terms of as complete list of pharmaceuticals, supplements (incl brands), diet, their age, type of cancer if known. Something they are taking may be acting in concert to make dca more effective or it may be preventing a downstream pathway that ultimately leads to resistance in some people. Include the time of day drugs/supplements are taken.

If we compare the long terms responders to the resistant or non-responders something might just stand out. Also include side effects if any. For instance aminolevulinic acid accumulation might mimic the symptoms of Acute Intermittent Prophyria - constipation, abdominal pain, vomiting, hypertension, PN, seizures, delirium, coma, depression and it may give us the clue that dca has exhausted the MAAI/GSTZ pathway in these persons resulting in apoptosis inhibition via tyrosinemia triggered chronic stress via Akt, BAD & Bcl.

For dca to work there also needs to be an intact mitochondrian apoptopic pathway. One of the earlier discussion I had here was considering the use of acetyl l carnitine to boost cellular cardiolipin levels and also taking high dose DHA to load up the cardiolipin so that when dca restarts the mitochondria the free radicals generated within the cell by both energy pathways triggers apoptosis. The older you get the lower your cellular cardiolipin levels. If you also have diabetes you will have lower cardiolipin levels through a hypothesized upregulation of a cardiolipin digesting enzyme. But we don't have any data on whether this will work for cancer, although ALC has been trialled separately in chemo patients to reduce neuropathy.

Could you give us more data on your father? Please be aware I don't have any medical training but I hope we can make a difference and figure out why he stopped responding which would help us all. For example if he was on statins for chloresterol which can be cancer protective because of their anti inflammatory effects they also prevent production of coenzyme q10 a required co-enzyme for cellular energy production and which in breast cancer patients at least, has been shown to be at lower levels.

I'm assuming he was on alpha lipoic acid? Originally I was against its use as a potent anti-oxidant as I thought it would prevent ROS mediated apoptosis in the cell but Sandra has changed my mind and the studies seem to support its action as an anti cancer agent. Curcumin also has good NF-KB and apoptosis inducing effects. However it may have trouble being absorbed into the body.

http://www.febsletters.org/article/S0014-5793(08)00339-6/abstract
Abstract
We report here that alpha-lipoic acid (α-LA), a naturally-occurring antioxidant, scavenges reactive oxygen species (ROS) followed by an increase in apoptosis of human hepatoma cells. Apoptosis induced by α-LA was dependent upon the activation of the caspase cascade and the mitochondrial death pathway. α-LA induced increases in caspase-9 and caspase-3 but had no significant effect on caspase-8 activity. Apoptosis induced by α-LA was found to be mediated through the tensin homologue deleted on chromosome 10 (PTEN)/Akt pathway. Prior to cell apoptosis, PTEN was activated and its downstream target Akt was inhibited. Our findings indicate that increasing ROS scavenging could be a therapeutic strategy to treat cancer.

Also see this on chloroquine. Unfortunately the dose of its less effective counterpart quinine from Tonic Water probably wouldn't be effective (although if it doesn't hurt...)

http://www.ncbi.nlm.nih.gov/pubmed/19194831?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

The present study was to investigate the anticancer effect of chloroquine on proliferation of mouse colon cancer cell line CT26 in vivo and in vitro and the possible mechanism. We found that chloroquine inhibited CT26 proliferation by concentration- and time-dependent manner. This effect was associated with apoptosis induction and decreased level of phosphorylated p42/44 mitogen-activated protein kinase and phosphorylated Akt. The in vivo study showed chloroquine-reduced tumor volume and prolonged survival time in CT26-bearing mice. These observations indicated chloroquine could inhibit CT26 proliferation by inducing apoptosis both in vitro and in vivo, providing its chemotherapeutic potential of human cancers.

Mack


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didierphmartin
Member since Apr-16-08
15 posts
Feb-13-09, 01:58 PM (PST)
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16. "RE: DCA and the MAAI pathway"
In response to message #12
 
   Hello Mack

You brought me to a new possibility when you said:

"Interference with the tyrosine degradation pathway may be just one way that dca can lose its effect and the cause may be quite subtle. For instance if not broken down, the tyrosine catabolite succinylacetone inhibits aminolevulinic acid dehydratase, which increases delta aminolevlinic acid (also known as 5-ALA) which induces iron release from ferritin via free radical production. High levels of iron are drivers of tumour growth and oxidative damage."

This implies that DCA may icrease the effects of artesimin. The latter is susd mainly for malaria but some are experimenting it in the context of cancer. Artesimn uses iron as its main reactive component. I will explore further this path.

For reference on artesimn: http://www.nutritionaloncology.org/Artemisinin.html

Cheers
Didier PH Martin, PhD.


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parachute
Member since Mar-20-07
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Feb-14-09, 02:26 AM (PST)
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17. "RE: DCA and the MAAI pathway/artemisinin"
In response to message #16
 
   Didier,

The most interesting work with artemisinin compounds may be that of Drs. Lai and Singh at the University of Washington. Because cancer cells have an extraordinary number of transferrin receptors, their lab has developed a way to covalently tag artemisinin to transferrin. If memory serves, they indicate tagged artemisinin may be 2800 times more powerful than 100% pure extract.

No links at hand but googling 'Lai Singh cancer artemisinin" will keep you busy :-)

Since DCA appears to be metabolically self-limiting, I'm wondering about a higher dose of DCA interleaved with some combination of artemisinin and artesunate & possibly artemether during the time needed for DCA to clear blood plasma.

Randy


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Mack
Member since Jan-9-09
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Feb-16-09, 06:18 AM (PST)
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18. "RE: DCA and the MAAI pathway"
In response to message #16
 
   Hi Didier,

Been reading up on artemisinin. Sounds quite promising- yet another chink in the armour of cancer. I imagine the ideal cancer drug would actually be something containing 5 or so of these dca/artemisinin type non-toxic compounds with different mechanisms of action that would hopefully take out every single damn cancer cell in a single hit using one pathway or another. Of course always have to be mindful of haemorraging and toxicities from massive tumour necrosis- need to give the body time to remove the dead cells and heal.

I was meaning to ask you about inflammation but it slipped my mind. David related above that his father seemed to do very well on DCA for two months and then it returned to growing in spite of continued use of DCA.

Aside from possibly interfering with tyrosine breakdown, does DCA also promote an inflammatory state in the body, in the same way as some of the other chemo drugs do, thus making it necessary to specifically deal with the inflammation in order to ensure DCA continues to have an effect? Of course age and inflammatory diseases and conditions (obesity, diabetes, asthma etc) will play a part too but I was wondering if there is a test people can have before starting dca to test for inflammation and then again if it ceases to be effective? Or perhaps one should assume with an aggressive cancer there will always be systemic inflammation and take NF-KB inhibitors accordingly.

The other thing I was wondering about is the different responses between children and adults to DCA use, ie more toxic to adults. Is it possible that the MAAI clearance pathway is also affected by adult sex steroids/hormones?

Cheers

Mack


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didierphmartin
Member since Apr-16-08
15 posts
Feb-17-09, 05:49 PM (PST)
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22. "RE: DCA and the MAAI pathway"
In response to message #18
 
   Hello Mack,

No, DCA should not create inflammation but do not modulate it. This is why I think that peole having an anti-inflamatory strategy will do better on DCA. For example, people having a better omega6/omega 3 index will do better than the others. For instance, somebody having an index of 15 has definitively a pro-inflammatory environment. This would not be the case if the omega index is closer to 3 or 4.
You know, to the already known 6 properties of cancer, there is now consensus to add another one: inflammation. Without an inflammatory environment the tumor cannot induce enough angiogenesis (blood vessel growth). Without a proper vascularization, the tumor necroses. A tumor cross the angiogenic switch with the help of tumor associated macrophages.

Another problem some people may experience with DCA is internal tumor fluid pressure. In fact, DCA has the svery ame problems the cytotoxic drugs are have in terms of local bioavailability.

It is unfortunate that we do not have any data about the omega index of people having some success with DCA, as well as any more info about the tumor composition and tumor cell line. Otherwise we would progress more rapidly.

We should not forget than even in a single cancer we may face different type of cancer cells. Even more, some cases involve more than one cell line and hence are not homogeneous. And they are many more factors to consider....

This is why my personal belief is that it is better to attack the beast on more than one front. No general would do a war with only terrestrial forces. They would also add, air, sea to the terrestrial forces. Using a single drug for a complex and diverse disease is not a good idea. But using it in combination with other things increases the chances of success.

Cheers
Didier PH Martin, PhD.


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didierphmartin
Member since Apr-16-08
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Feb-17-09, 06:01 PM (PST)
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23. "RE: DCA and the MAAI pathway"
In response to message #18
 
   Hello Mack,

As you noticed in my last post, I agree with you that we need more than one weapon to beat that beast...

Yes there are two tests that could help tremendsouly to evaluate the success factor and the state of the tumoral environment:

a) 25(OH)D. Would indicate for tumor having working VDC receptors if there is enough 25(OH)D for autocrine processes that could lead to differentiation of apoptosis. Moreover, it can also help DCA end pathways involving the capsases.

b) omega 6/omega3 index. The higher the index and the more pro-inflammatory potential. Omega 6 is precursor of arachidonic acid and the latter an essential component of pro-inflammatory prostaglandins (cell signals). People having a western diet have a ratio close or higher than 15. Population with low cancer rates have a index closer to 4.

Maybe add to this thyroid endocrine system testing.

Cheers
didier PH Martin, PhD.


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davidportia
Member since Jul-23-08
66 posts
Feb-16-09, 07:04 AM (PST)
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20. "RE: DCA and the MAAI pathway"
In response to message #12
 
   >Interference with the tyrosine degradation pathway may be
>just one way that dca can lose its effect and the cause may
>be quite subtle. For instance if not broken down, the
>tyrosine catabolite succinylacetone inhibits aminolevulinic
>acid dehydratase, which increases delta aminolevlinic acid
>(also known as 5-ALA) which induces iron release from
>ferritin via free radical production. High levels of iron
>are drivers of tumour growth and oxidative damage.
>
>Most of us are aware that mainstream chemo also loses
>effectiveness and in some cases drives metastasis by
>upregulating the NF-KB pathway (which can hopefully be
>inhibited by taking alpha lipoic acid/curcumin. And of
>course individual responses may reflect subtles differences
>in our genes, ages, the food we eat. The amount we take...
>
>So hard to know what to do, there is so much trial and
>error. But a first step should be to ask any long term good
>responders exactly what they are on in terms of as complete
>list of pharmaceuticals, supplements (incl brands), diet,
>their age, type of cancer if known. Something they are
>taking may be acting in concert to make dca more effective
>or it may be preventing a downstream pathway that ultimately
>leads to resistance in some people. Include the time of day
>drugs/supplements are taken.
>
>If we compare the long terms responders to the resistant or
>non-responders something might just stand out. Also include
>side effects if any. For instance aminolevulinic acid
>accumulation might mimic the symptoms of Acute Intermittent
>Prophyria - constipation, abdominal pain, vomiting,
>hypertension, PN, seizures, delirium, coma, depression and
>it may give us the clue that dca has exhausted the MAAI/GSTZ
>pathway in these persons resulting in apoptosis inhibition
>via tyrosinemia triggered chronic stress via Akt, BAD & Bcl.
>
>For dca to work there also needs to be an intact
>mitochondrian apoptopic pathway. One of the earlier
>discussion I had here was considering the use of acetyl l
>carnitine to boost cellular cardiolipin levels and also
>taking high dose DHA to load up the cardiolipin so that when
>dca restarts the mitochondria the free radicals generated
>within the cell by both energy pathways triggers apoptosis.
>The older you get the lower your cellular cardiolipin
>levels. If you also have diabetes you will have lower
>cardiolipin levels through a hypothesized upregulation of a
>cardiolipin digesting enzyme. But we don't have any data on
>whether this will work for cancer, although ALC has been
>trialled separately in chemo patients to reduce neuropathy.
>
>Could you give us more data on your father? Please be aware
>I don't have any medical training but I hope we can make a
>difference and figure out why he stopped responding which
>would help us all. For example if he was on statins for
>chloresterol which can be cancer protective because of their
>anti inflammatory effects they also prevent production of
>coenzyme q10 a required co-enzyme for cellular energy
>production and which in breast cancer patients at least, has
>been shown to be at lower levels.
>
>I'm assuming he was on alpha lipoic acid? Originally I was
>against its use as a potent anti-oxidant as I thought it
>would prevent ROS mediated apoptosis in the cell but Sandra
>has changed my mind and the studies seem to support its
>action as an anti cancer agent. Curcumin also has good NF-KB
>and apoptosis inducing effects. However it may have trouble
>being absorbed into the body.
>
>http://www.febsletters.org/article/S0014-5793(08)00339-6/abstract
>Abstract
>We report here that alpha-lipoic acid (α-LA), a
>naturally-occurring antioxidant, scavenges reactive oxygen
>species (ROS) followed by an increase in apoptosis of human
>hepatoma cells. Apoptosis induced by α-LA was dependent
>upon the activation of the caspase cascade and the
>mitochondrial death pathway. α-LA induced increases in
>caspase-9 and caspase-3 but had no significant effect on
>caspase-8 activity. Apoptosis induced by α-LA was found
>to be mediated through the tensin homologue deleted on
>chromosome 10 (PTEN)/Akt pathway. Prior to cell apoptosis,
>PTEN was activated and its downstream target Akt was
>inhibited. Our findings indicate that increasing ROS
>scavenging could be a therapeutic strategy to treat cancer.
>
>Also see this on chloroquine. Unfortunately the dose of its
>less effective counterpart quinine from Tonic Water probably
>wouldn't be effective (although if it doesn't hurt...)
>
>http://www.ncbi.nlm.nih.gov/pubmed/19194831?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
>
>The present study was to investigate the anticancer effect
>of chloroquine on proliferation of mouse colon cancer cell
>line CT26 in vivo and in vitro and the possible mechanism.
>We found that chloroquine inhibited CT26 proliferation by
>concentration- and time-dependent manner. This effect was
>associated with apoptosis induction and decreased level of
>phosphorylated p42/44 mitogen-activated protein kinase and
>phosphorylated Akt. The in vivo study showed
>chloroquine-reduced tumor volume and prolonged survival time
>in CT26-bearing mice. These observations indicated
>chloroquine could inhibit CT26 proliferation by inducing
>apoptosis both in vitro and in vivo, providing its
>chemotherapeutic potential of human cancers.
>
>Mack

Dear Mack,
The first round (45 days) my dad was taking very minimum supplements, because I was not able to get everything for him at the time. The result was so good, that I hardly believe it is true. For the second round ( 2 months) I did got many supplements, like flaxseed oil, Lecithin, alpha Lipoid acid, Potassium, Magnesium, etc, but the result was very negative, so I suspected that something in this round may have worked up to stop the effectiveness of DCA to cause this. So I ask him to go back to what he took during the first round. But the result of the third round (exactly as the first round) is alarmingly worse, which convinced me that DCA has stopped working for him. He has been always taking DCA, without on and off schedule like others did. I realize that this could be one of the reasons why DCA stopped working for him. FYI, he never exceeded the dosage of 26mg/kg/day during his entire usage of DCA.
I am thinking to add artesimin/artesunate, because it can combine with free iron and this may work in synergy with DCA, but until today, I still can not find them now for my dad.
Best regards,
David


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parachute
Member since Mar-20-07
50 posts
Feb-16-09, 10:43 PM (PST)
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21. "Artemisinin (was: RE: DCA and the MAAI pathway)"
In response to message #20
 
   David,

Artemisinin is available in various formulations, best summary may be this one:

http://www.allergyresearchgroup.com/_search.php?page=1&q=Super+Artemisinin

It is not easy to purchase directly from Allergy Research. The same products are packaged for sale to consumers by NutriCology. For example:

http://www.herbspro.com/38743/ARTEMISININ.htm

http://www.iherb.com/productdetails.aspx?c=1&pid=3484&utm_source=gb&utm_medium=f3

http://www.herbalremedies.com/artemisinin-gel.html

Artesunate for IV administration can be purchased here:

http://www.alldaychemist.com

Best wishes,

Randy



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parachute
Member since Mar-20-07
50 posts
Feb-18-09, 06:34 AM (PST)
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24. "More RE: Artemisinin (was: RE: DCA and the MAAI pathway"
In response to message #21
 
   Better yet:

http://www.arrowheadhealthworks.com/artprods.htm

"ß-Artemether Plus™ is a pharmaceutical grade timed-release blend of both water soluable and fat soluable compounds (ß-Artemether, Artemesinin, Artusenate) from Dihydroartemesinin.

"ß-Artemether Plus™ is manufactured by the same pharmacist and was the original formula used for the study" by Dr Lai and Dr. Singh at the University of Washington.

Randy


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davidportia
Member since Jul-23-08
66 posts
Feb-18-09, 07:01 AM (PST)
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25. "RE: More RE: Artemisinin (was: RE: DCA and the MAAI pat"
In response to message #24
 
   >Better yet:
>
>http://www.arrowheadhealthworks.com/artprods.htm
>
>"ß-Artemether Plus™ is a pharmaceutical grade timed-release
>blend of both water soluable and fat soluable compounds
>(ß-Artemether, Artemesinin, Artusenate) from
>Dihydroartemesinin.
>
>"ß-Artemether Plus™ is manufactured by the same pharmacist
>and was the original formula used for the study" by Dr Lai
>and Dr. Singh at the University of Washington.
>
>Randy

Randy,
Thank you for this great update. I will take time to read it.


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Sandra
Member since Feb-27-07
687 posts
Mar-13-09, 02:46 AM (PST)
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28. "RE: More RE: Artemisinin (was: RE: DCA and the MAAI pat"
In response to message #25
 
Googled around - there is a MUCH better supplier.

http://www.hepalin.com/artemix.htm


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Sandra
Member since Feb-27-07
687 posts
Mar-13-09, 02:43 AM (PST)
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27. "RE: Lipoic Acid as a prooxidant"
In response to message #12
 
Found an article suggesting lipoic acid can also act as a prooxidant.

http://www.ncbi.nlm.nih.gov/pubmed/12127266?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedreviews&logdbfrom=pubmed
Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid.

Moini H, Packer L, Saris NE.
Department of Applied Chemistry and Microbiology, PB 56 Viikki Biocenter, FIN-00014, University of Helsinki, Helsinki, Finland. hmoini@usc.edu
Reactive oxygen (ROS) and nitrogen oxide (RNOS) species are produced as by-products of oxidative metabolism. A major function for ROS and RNOS is immunological host defense. Recent evidence indicate that ROS and RNOS may also function as signaling molecules. However, high levels of ROS and RNOS have been considered to potentially damage cellular macromolecules and have been implicated in the pathogenesis and progression of various chronic diseases. alpha-Lipoic acid and dihydrolipoic acid exhibit direct free radical scavenging properties and as a redox couple, with a low redox potential of -0.32 V, is a strong reductant. Several studies provided evidence that alpha-lipoic acid supplementation decreases oxidative stress and restores reduced levels of other antioxidants in vivo. However, there is also evidence indicating that alpha-lipoic acid and dihydrolipoic acid may exert prooxidant properties in vitro. alpha-Lipoic acid and dihydrolipoic acid were shown to promote the mitochondrial permeability transition in permeabilized hepatocytes and isolated rat liver mitochondria. Dihydrolipoic acid also stimulated superoxide anion production in rat liver mitochondria and submitochondrial particles. alpha-Lipoic acid was recently shown to stimulate glucose uptake into 3T3-L1 adipocytes by increasing intracellular oxidant levels and/or facilitating insulin receptor autophosphorylation presumably by oxidation of critical thiol groups present in the insulin receptor beta-subunit. Whether alpha-lipoic acid and/or dihydrolipoic acid-induced oxidative protein modifications contribute to their versatile effects observed in vivo warrants further investigation.


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rtshinn
Member since Mar-7-07
102 posts
Mar-13-09, 02:08 PM (PST)
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29. "RE: Lipoic Acid as a prooxidant"
In response to message #27
 
   I think I've fallen way behind in the anti-oxidant pro-oxidant discussion. Can anyone explain what/when you want either?

If I rememebr right, I think that some of the supplements you take, Sandra, are also considered antioxidants.

Would you want anti-oxidants to prevent cancer, but once you have it, take pro-oxdants to speed up apoptosis, or??


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Sandra
Member since Feb-27-07
687 posts
Mar-14-09, 00:33 AM (PST)
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30. "RE: Lipoic Acid as a prooxidant"
In response to message #29
 
Yeah, I'm revamping my list now... learning more about half-life and mechanism of action of various supplements. With Artemisinin (and I believe DCA) we want to cause ROS, so yes free radicals are good. But some antioxidants (like vitamin C and quercetin) have such a short half-life that they can be taken away from Artemisinin (which also has a short half-life). This allows healthy cells to be strengthened, within impeding the pro-oxidant action of Artemisinin. DCA's long half-life is still confusing me as to what to keep or toss, and many supplements are needed with DCA to reduce PN, so I'm not taking it right now.


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Sandra
Member since Feb-27-07
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Mar-14-09, 00:36 AM (PST)
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31. "RE: Lipoic Acid as a prooxidant"
In response to message #30
 
>Yeah, I'm revamping my list now... learning more about
>half-life and mechanism of action of various supplements.
>With Artemisinin (and I believe DCA) we want to cause ROS,
>so yes free radicals are good. But some antioxidants (like
>vitamin C and quercetin) have such a short half-life that
>they can be taken away from Artemisinin (which also has a
>short half-life). This allows healthy cells to be
>strengthened, within impeding the pro-oxidant action of
>Artemisinin. DCA's long half-life is still confusing me as
>to what to keep or toss, and many supplements are needed
>with DCA to reduce PN, so I'm not taking it right now.

Darn - I hate that you can't edit. Typo 'within impeding' should be 'without impeding'


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Sandra
Member since Feb-27-07
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Feb-09-09, 05:31 AM (PST)
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13. "RE: DCA and the MAAI pathway"
In response to message #9
 
David,

A couple other things you may want to investigate, Verapamil or I-3-C:

http://www.thedcasite.com/Resistance/Resistance.html
(incidentally, magnesium is also a calcium channel blocker)

or a proton pump inhibitor, like Tagamet

http://www.thedcasite.com/dcaforum/DCForumID10/349.html

Take care,
Sandra


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