http://clincancerres.aacrjournals.org/cgi/content/abstract/13/21/6359

After reading all this, I truly believe everyone taking DCA ought to also be taking B-6 and magnesium. Again, I welcome anyone's comments here.

Odd that Betaine is the salt of trimethylglycine. I read a bit about Pangamic acid's use in greyhounds. It lowers lactic acid, something DCA does as well.

http://jn.nutrition.org/cgi/content/full/128/12/2686S

Other additives. Several food additives, including dimethyl glycine (DMG), pangamic acid (vitamin B-15), arginine, tryptophan, aspartate, carnitine, creatine/ATP and bicarbonate have been suggested to improve the performance of racing dogs. To date, no controlled studies have shown any benefit. Gannon found that DMG and diisopropylammonium dichloroacetic acid (DIPA-DCA) reduced the race time of greyhounds (Gannon and Kendall 1982). Pangamic acid or vitamin B-15 is a substance of uncertain composition. It consists of an ester of DMG and gluconic acid but may include DIPA-DCA (Herbert 1988). The beneficial effects described by Gannon can probably be ascribed to dichloroacetic acid, a potent drug that activates pyruvate dehydrogenase and reduces lactic acidosis caused by exercise in dogs (Merrill et al. 1980). The appropriate dose is uncertain, and neurologic, hepatic, testicular, pulmonary and pancreatitic toxicities have been described in dogs (Cicmanec et al. 1991). Both DMG and DIPA-DCA are considered "unsafe food additives"; thus their use cannot be recommended (Herbert 1988).

Quote from the above paper, 'Different clinical approaches failed in neurotoxicity prevention, except calcium-magnesium infusions.

Conclusion: These data confirm the involvement of oxalate in oxaliplatin neurotoxicity and support the future use of AGXT genotyping as a pretherapeutic screening test to predict individual susceptibility to neurotoxicity.'

So perhaps supplementation with calcium and magnesium will lower PN - for people with the genetic predisposition to not metabolizing oxalate well.

There was (is) a company that used to be called Alteon (now Synvista), that makes a compound that used to be called ALT-711 (now Alagebrium) that is an Advanced Gycosylation End Product (AGE) crosslink *breaker*. In other words, it would break the protein/sugar crosslinks that contributed towards aging, etc.

Of course, the crosslinks would be re-established once Alagebrium was out of the system, so you would still need a crosslink *inhibitor* such as B6 etc. They also have an inhibitor compound called Aminoguanidine, if I remember correctly.

I watched their activities/clinical trials for years. They've always been on the cusp of a breakthrough, and the stock is down to pennies a share. I gave up on them after a while.

The company did get a big mention in Aubrey De Grey's book 'Ending Aging'. In that book, AGE's are listed as one the main engineering problems for Life Extension.

Fascinating that GcMAF works on this same basis of deglycosylation.

'INTRODUCTION
....A recent important observation was that cancer patients had de
creased capability of macrophage activation with their own serum
because of decreased precursor activity of the serum Gc protein (10).
Loss of the precursor activity of the Gc protein was found to be due
to the deglycosylation of Gc protein by serum NaGalase derived from
cancerous cells (Fig. lc; Refs. 10 and 22). Once Gc protein is
deglycosylated, lymphocyte glycosidases (i.e., j3-galactosidase and
sialidase of lymphocytes) can no longer convert the deglycosylated
Gc protein to the MAF (10). Thus, macrophages cannot be activated
under such a circumstance. However, GcMAF and DBPMAF can
bypass the decapitated macrophage activation cascade and efficiently
activate macrophages (10, 2 1).'

http://cancerres.aacrjournals.org/cgi/reprint/57/11/2187

Gc-MAF does NOT WORK because deglycosylation of Gc protein by serum NaGalase derived from cancerous cells

This is what I meant - as I understand it, macrophage cells are inactivated by the deglycosylation of Gc protein caused by nagalase (produced by cancer cells).

"Gc-MAF does NOT WORK because deglycosylation of Gc protein by serum NaGalase derived from cancerous cells"

Maybe you could clarify? Are you saying Gc-MAF lacks efficacy? Or that it "works" for a reason other than the mechanism you (sort of) describe?

Thanks,

Parachute

"Serum Gc protein (known as vitamin D(3)-binding protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of cancer patients was lost or reduced because Gc protein was deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Therefore, macrophages of cancer patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression."

Also view the video mentioned in the previous post

Have a good week-end

What I've been wondering though, is does DCA's efficacy (or lack thereof) relate more to genetics?

I'd certainly appreciate your thoughts on this.

Thanks,
Sandra

GSTZ1d: a new allele of glutathione transferase zeta and maleylacetoacetate isomerase.

Blackburn AC, Coggan M, Tzeng HF, Lantum H, Polekhina G, Parker MW, Anders MW, Board PG.
Molecular Genetics Group, Division of Molecular Medicine, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
The zeta class glutathione transferases (GSTs) are known to catalyse the isomerization of maleylacetoacetate (MAA) to fumarylacetoacetate (FAA), and the biotransformation of dichloroacetic acid to glyoxylate. A new allele of human GSTZ1, characterized by a Thr82Met substitution and termed GSTZ1d, has been identified by analysis of the expressed sequence tag (EST) database. In European Australians, GSTZ1d occurs with a frequency of 0.16. Like GSTZ1b-1b and GSTZ1c-1c, the new isoform has low activity with dichloroacetic acid compared with GSTZ1a-1a. The low activity appears to be due to a high sensitivity to substrate inhibition. The maleylacetoacetate isomerase (MAAI) activity of all known variants was compared using maleylacetone as a substrate. Significant differences in activity were noted, with GSTZ1a-1a having a notably lower catalytic efficiency. The unusual catalytic properties of GSTZ1a-1a in both reactions suggest that its characteristic arginine at position 42 plays a significant role in the regulation of substrate access and/or product release. The different amino acid substitutions have been mapped on to the recently determined crystal structure of GSTZ1-1 to evaluate and explain their influence on function.
http://www.ncbi.nlm.nih.gov/pubmed/11692075?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Human glutathione transferase zeta.

Board PG, Anders MW.
Molecular Genetics Group, John Curtin School of Medical Research, Australian National University, CAnaberra, Australia.
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.
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

Role of dichloroacetate in the treatment of genetic mitochondrial diseases.

Stacpoole PW, Kurtz TL, Han Z, Langaee T.
Department of Medicine, Division of Endocrinology and Metabolism, College of Medicine, University of Florida, Gainesville, FL 32610-0226, USA. peter.stacpoole@medicine.ufl.edu
Dichloroacetate (DCA) is an investigational drug for the treatment of genetic mitochondrial diseases. Its primary site of action is the pyruvate dehydrogenase (PDH) complex, which it stimulates by altering its phosphorylation state and stability. DCA is metabolized by and inhibits the bifunctional zeta-1 family isoform of glutathione transferase/maleylacetoacetate isomerase. Polymorphic variants of this enzyme differ in their kinetic properties toward DCA, thereby influencing its biotransformation and toxicity, both of which are also influenced by subject age. Results from open label studies and controlled clinical trials suggest chronic oral DCA is generally well-tolerated by young children and may be particularly effective in patients with PDH deficiency. Recent in vitro data indicate that a combined DCA and gene therapy approach may also hold promise for the treatment of this devastating condition.
http://www.ncbi.nlm.nih.gov/pubmed/18647626?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedreviews&logdbfrom=pubmed

The other factor is about the environment. For instance, among others, the lipid intake type and the kind of inflammatory micro-environment.

a) We know now that the lipid composition of cardiolipin is dose dependent. And so is the composition of immune system cells different membranes (outer cell, outer mitochondria, ER, etc...) (3). If somebody intake mainly vegetable oil (omega 6) the composition will be totally different in behavior than if that person consume omega 3 and very little omega 6. Even though, if that person is a man and if that person follow a Budwig diet, There is a high probability that this person won't metabolize enough DHA. So, even if DCA opened the channel, the cardiolipin composition may or may not help the proper reaction. Think of the lipid composition of cardiolipins as a kind of amplifier. Add to that other signal amplifiers like acteyl-L-carnitine and lipoid acid (but the issue of ROS version capsase is not yet resolved).
b) the inflammation environment is quite important too. So important that the Nature journal in January 2009 made the suggestion to add a new property to the Hannahan and weinberg Hallmark of cancer model (4): Inflammation (5). Speaking of inflammation, there is a good chance that what is thought that cafeine is the active ingredient helping DCA may be in fact Theaflavins found in black tea and which is a very potent anti-inflammatory agent. By downregulating the local inflammation it also reduces the cytokine and chemokine levels which in turn do not activate some gene expression pathways that may potentially counteract the effect of DCA. I am writing a text about this (see: http://www.nutritionaloncology.org/cancerCells&Inflammation.html). This is a work in progress but with enough material to give you a good idea of the importance of the tumoral inflammation micro-environment.

So the fcator that could influence the DCA response are:
a) oncogenes
b) transcription factor and environmental elements
c) environmental elements composition and concentration
d) immune system modulation and cell membrane composition.
e) other factors that I forget for the moment.

Cheers
Didier PH Martin, PhD.

References:
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(1) http://www.atcc.org/ATCCAdvancedCatalogSearch/ProductDetails/tabid/452/Default.aspx?ATCCNum=HTB-38&Template=cellBiology
(2) http://www.atcc.org/ATCCAdvancedCatalogSearch/ProductDetails/tabid/452/Default.aspx?ATCCNum=HTB-37&Template=cellBiology
(3) Philip C. Calder. The relationship between the fatty acid composition of immune system cells and their function. Prostaglandin, Leukotrienes and essential fatty acids. (2008) 101-108
(4) http://www.weizmann.ac.il/home/fedomany/Bioinfo05/lecture6_Hanahan.pdf
(5) http://www.nature.com/nature/journal/v457/n7225/full/457036b.html