Cheap, safe cure for most cancers?

[Schneibster]

It's not dichloroethane. It's dichloroacetate.

 

[Ducky]

It's not dichloroethane. It's dichloroacetate.

Yes but is it as lethal as dihydrogen monoxide?


This to me is nice in vitro news. But let us remember vitamin C also showed promise in vitro in the 70's, but was useless in vivo.

I'll wait to see what happens when humans take it before getting my hopes up.

 

[Schneibster]

Does anyone know about the supposed mechanism of cancer that this is targeting? I had not heard about cancerous cells not using mitocondria, but the failures being in other areas.

It's actually called the Warburg Effect. It also interferes with apoptosis, the mechanism by which cancer cells are normally killed off before they can do too much damage; this mechanism is mediated by the mitochondria, which explains why the cell must both shift to this different metabolism, and does not die off.

So is this universal to cancers, common in cancers, or a subset of cancers? Given that cancer is a fairly diverse thing(I think, as they are any change in cells that causes them to grow out of control, why assume that they have that much in common)

I assume you meant to go on here and say that you were surprised that it should be so. I suspect but do not know for certain that this metabolism shift happens in all malignant cancer; the fact that the chemical is touted as a cheap cure for many if not most cancers argues that it very likely is a feature of many if not most of them.

As for why this isn't being used, well look at when they tried mega-dose betacaratine to prevent lung cancer, it increased the rates. so care is something that it is wise to take.

And there are some risks associated with this stuff too- there is a peripheral nervous system damage risk, and in case you're not familiar with what that means, it can lead to the symptoms of leprosy. So it looks like there is still some work to be done.

I'll point out however that the Warburg Effect apparently is, or leads directly to, a known point of attack against cancer that some chemotherapy drugs already in use are directed against. I think that it might be possible that this stuff would be a bit less nasty than some or other of the current spectrum of chemo; IIRC, the ones that attack that particular point were reputed in some literature I was reading a few years back to be rather nasty, since interfering with anything to do with sugar metabolism has the direst imaginable effects on your well-being and how you feel. But I don't swear to it.

 

[Darat]

...snip...

The problem I guess is if it isn't patentable and the drug will be cheap to make, everyone could do it so no one will make any money, so who would put in the hundreds of millions required to go through all the clinical trials?

Governments, large charities and so on.

 

[Schneibster]

Yes but is it as lethal as dihydrogen monoxide?

I think dichloroethane is a better solvent, at least for hydrocarbons and fats, but I doubt dichloroacetate is; OTOH, I would put the LD50 for either of them much lower than the LD50 for dihydrogen monoxide; I would guess you'd need at least a gallon of that. And a bucket. And strong hands.

This to me is nice in vitro news. But let us remember vitamin C also showed promise in vitro in the 70's, but was useless in vivo.

I'll wait to see what happens when humans take it before getting my hopes up.

Yeah, I hear you- it's a complicated system and there's no telling how something will get caught up in things.

 

[JJM]

It's not dichloroethane. It's dichloroacetate.

The cited article on harmful effects (J Clin Pharmacol. 2006 Dec;46(12):1449-59) pertains to dichloroethane but sometimes calls it "dichloroacetate;" I have no idea why. The article is not relevant to the antitumor compound.

 

[SteveGrenard]

One “other” condition at least for which dichloroacetate has been studied does not appear to be all that rare although it may be rarely used for this:

Bersin, et al., Dichloroacetate as metabolic therapy for myocardial ischemia and failure, American Heart Journal, 134(5)(Part 1):841-855 (1997).

There also seems to be a patent on the molecule, found at:

http://www.patentstorm.us/patents/7084173-claims.html

There are more citations including the above one at the end of this page.



Sigma-Aldrich lists the following from its search page at:

http://www.sigmaaldrich.com/catalog/search/AdvancedSearchPage

Ethyl dichloroacetate (1)
Methyl dichloroacetate (2)
Methyl dichloroacetate solution (1)
Methyl dichloroacetate-1-13C (1)
Potassium dichloroacetate (1)
Sodium dichloroacetate (1)
5-ALPHA-CHOLESTAN-3-BETA-YL DICHLOROACETATE (1)
ANDROST-5-EN-3-BETA-YL DICHLOROACETATE (1)
CHOLEST-5-EN-3-BETA-YL DICHLOROACETATE (1)
ETHYL DICHLOROACETATE (1)

 

[SteveGrenard]

Another condition for which this substance has recently been studied is probably MELAS which is an acronym for a combination of effects:
mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).

According to this study, cited below, any benefit according to these authors was overshadowed by its side effect which was to cause (no doubt painful)
peripheral toxicity/neuropathy. They say they were unable to detect any potential benefit due to side effects causing the trial drug to be discontinued. I have not looked at the comments or responses which may agree or disagree or equivocate. Such side effects can sometimes be ameliorated with changes in dosages and timing of dosages or using other
forms of the molecule so there is sure to be more to come:

Neurology. 2006 Feb 14;66(3):324-30.

Comment in:
Neurology. 2006 Feb 14;66(3):302-3.
Neurology. 2006 Jul 11;67(1):184; author reply 184.
Neurology. 2006 Oct 10;67(7):1313; author reply 1313.

Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial.
· Kaufmann P,
· Engelstad K,
· Wei Y,
· Jhung S,
· Sano MC,
· Shungu DC,
· Millar WS,
· Hong X,
· Gooch CL,
· Mao X,
· Pascual JM,
· Hirano M,
· Stacpoole PW,
· DiMauro S,
· De Vivo DC.

Department of Neurology, Columbia University, New York 10032, USA. pk88@columbia.edu

OBJECTIVE: To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). BACKGROUND: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS. METHODS: The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety.

RESULTS: During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms. CONCLUSION: DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.

 

[SteveGrenard]

The cited article on harmful effects (J Clin Pharmacol. 2006 Dec;46(12):1449-59) pertains to dichloroethane but sometimes calls it "dichloroacetate;" I have no idea why. The article is not relevant to the antitumor compound.

It appears on reading this cite that it pertains to 1,2-(13)C-Dichloroacetate and I don't see anywhere where dichloroethane is mentioned including in its title and throughout its abstract. Where exactly do you find DCA being cross defined as dichloroethane? Why do you feel this is not relevant to the antitumor compound which is called dichloroacetate?

The toxicity of dichloroacetate has also been observed in human trials. It produced peripheral nerve toxicity and neuropathy which can be extremely painful. That study, which was terminated before completion due to this, is cited above.

 

[robinson]

Testing this on cancer patients should be a breeze.

This to me is nice in vitro news. But let us remember vitamin C also showed promise in vitro in the 70's, but was useless in vivo.

Hmmm... not to sidetrack this discussion, but that is simply not true. OK maybe that isn't a sidetrack.

 

[JJM]

It appears on reading this cite that it pertains to 1,2-(13)C-Dichloroacetate and I don't see anywhere where dichloroethane is mentioned including in its title and throughout its abstract. Where exactly do you find DCA being cross defined as dichloroethane? Why do you feel this is not relevant to the antitumor compound which is called dichloroacetate?

The toxicity of dichloroacetate has also been observed in human trials. It produced peripheral nerve toxicity and neuropathy which can be extremely painful. That study, which was terminated before completion due to this, is cited above.

As I said, there seems to be confusion over the term.
http://cat.inist.fr/?aModele=afficheN&cpsidt=15512315
“The suspected carcinogenic solvent 1,2-dichloroethane (1,2-DCA) is the most abundant chlorinated C[2] groundwater pollutant on earth.”

J Clin Pharmacol. 2006 Dec;46(12):1449-59.
“Dichloroacetate (DCA) is a putative environmental hazard, owing to its ubiquitous presence in the biosphere and its association with animal and human toxicity. We sought to determine the kinetics of environmentally relevant concentrations of 1,2-(13)C-DCA administered to healthy adults.”[Bold added]

One could vaguely imagine a name of "1,2 dichloroacetic" acid; but it would be an acetyl chloride* (CH2ClCOCl), not an acetate.

The putative antitumor compound, dichloroacetate, has the formula CHCl2CO2- (either the anion or an ester; in this case it is pretty clearly the anion) which is 2,2-dichloroacetate, not 1,2.

I am a retired chemistry professor, and I have no idea why the literature is so confusing over this term. As I said- I understand your confusion.

Your last post inre the literature on the toxicology of (the real) DCA seems hopeful to me. While DCA may be unsuitable for chronic use, one could hope it could serve well in acute treatment of cancer.


*No matter how it is administered, anything more than a trace amount of an acetyl chloride would be highly corrosive at the site of application. And it would have a very short lifetime (seconds) in physiological fluids.

 

[JamesM]

The cited article on harmful effects (J Clin Pharmacol. 2006 Dec;46(12):1449-59) pertains to dichloroethane but sometimes calls it "dichloroacetate;" I have no idea why. The article is not relevant to the antitumor compound.

Notwithstanding the oddity of the nomenclature as you state in your last post, the figures in the quoted paper clearly show an acetate with two chlorines on the sp3 carbon. 1,2-dichloroethane doesn't seem to be in the paper at all.

 

[SteveGrenard]

The Belgian paper you quote involves the detoxificiation of dichloroethane in the environment, not the administration and kinetics of dichloroacetate to humans which was the subject of the first paper cited.

Perhaps the abstract of the Belgian paper would shed further light on this confusion:

Complete lab-scale detoxification of groundwater containing 1,2-dichloroethane
Auteur(s) / Author(s)
DE WILDEMAN S. (1) ; LINTHOUT G. (1) ; VAN LANGENHOVE H. (1) ; VERSTRAETE W. (1) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Laboratory of Microbial Ecology and Technology (LabMET), Ghent University, Faculty of Agricultural and Applied Biological Sciences, Coupure Links 653, 9000 Ghent, BELGIQUE

"The suspected carcinogenic solvent 1,2-dichloroethane (1,2-DCA) is the most abundant chlorinated C[2] groundwater pollutant on earth.

However, an efficient reductive in situ detoxification technology for this compound is not known.

Detoxification results of 1,2-DCA with the recently isolated anaerobic bacterium Desulfitobacterium dichloroeliminans strain DCA1 are presented. First, it was verified that strain DCA1 could compete for nutrients in the presence of fast-growing Enterococcus faecalis; the latter was observed in the enrichment culture from which strain DCAI was isolated. Subsequently, lab-scale bioaugmentation of the strain to groundwater containing 40 mg 1,2-DCA/1 indicated that the bacterium has strong metabolic activity under prevailing environmental conditions, converting the pollutant into ethene. During exponential growth, the maximum 1,2-DCA dechlorination rate exceeded 350 nmol chloride released per min per mg total bacterial protein. Growth and dechlorination within the community with autochthonous bacteria indicated a high competitive strength of strain DCA1. Interestingly this dechlorination process does not produce any toxic byproducts, such as vinyl chloride. Furthermore, complete groundwater detoxification happens within a short time-frame (days) and is robust in terms of bacterial competition, oxygen tolerance, high ionic strength, and pH range.
Revue / Journal Title

Applied microbiology and biotechnology (Appl. microbiol. biotechnol.) ISSN 0175-7598 CODEN AMBIDG

Source / Source
2004, vol. 63, no5, pp. 609-612 [4 page(s) (article)] (15 ref.)

 

[JJM]

Notwithstanding the oddity of the nomenclature as you state in your last post, the figures in the quoted paper clearly show an acetate with two chlorines on the sp3 carbon. 1,2-dichloroethane doesn't seem to be in the paper at all.

Well, as I said, there is confusion. I don't have immediate access to the J Clin Pharm paper which says “Dichloroacetate (DCA) is a putative environmental hazard."

It is also clear that the other paper, with a web-link, refers to 1,2-dichloroethane as 1,2-DCA, and calls it a pollutant. And another post on this thread claims we don't make enough (true)dichloroacetate to be of environmental concern.

So, I remain confused.

 

[ChristineR]

Anyone else old enough to remember when interferon was going to cure all cancers?

Now interferon was not, and is not, nonsense science, but it has not cured all cancers.

 

[casebro]

Aw, nuts!

I hadn't read about the cancellation of the Mito disease trial, only of it's start a couple years ago. Publication bias?

It sure sounded good to read here about how DCA works in the cancer cells, changing the energy system to oxidizing glucose. My metabolic problem (probably MIDD, genetically speaking MT a3243g) is that my mitochndria don't burn fats, so my muscles fatigue in minutes. Getting the mitos to change to oxidizing sugar would be near to a cure.

One study showed mito disease genes in 17% of diabetics, and that if you have those genes, you WILL become diabetic. Not such rare disease, if you ask me.

Sorry about the confusion I caused of DCA/DCA. But I didn't write the artical, I only posted it's link. But so far as environmental pollution goes, it does look to me like a distinction without a difference. Both occur as a result of chlorination pollution, both are harmfull to humans, depending on dose?

 

[Schneibster]

I think that the confusion arose because the Europeans use "DCA" to describe what the US calls "DCE:" 1,2-dichloroethane, which is a pollutant and not the subject either of the article or of any clinical trials.

What the US calls "DCA" is 1,2-dichloroacetate, which is NOT a pollutant, and which is the potential drug cited in both the article in the OP, and the articles SteveGrenard posted clinical trials for other conditions on (and thanks, Steve- those might come in handy later).

IOW, I think the "DCA" acronym is what caused the confusion.

 

[SteveGrenard]

I think that the confusion arose because the Europeans use "DCA" to describe what the US calls "DCE:" 1,2-dichloroethane, which is a pollutant and not the subject either of the article or of any clinical trials.

What the US calls "DCA" is 1,2-dichloroacetate, which is NOT a pollutant, and which is the potential drug cited in both the article in the OP, and the articles SteveGrenard posted clinical trials for other conditions on (and thanks, Steve- those might come in handy later).

IOW, I think the "DCA" acronym is what caused the confusion.

I agree the confusion was caused by a translation difference.

 

[Schneibster]

Anyone else old enough to remember when interferon was going to cure all cancers?

Yep.

Now interferon was not, and is not, nonsense science, but it has not cured all cancers.

Nope. It has, however, ameliorated at least some of them; and is used today in chemotherapy for cancer. And it helps. But of course, your point is the hype, and I agree with that point.

 

[JJM]

I think that the confusion arose because the Europeans use "DCA" to describe what the US calls "DCE:" 1,2-dichloroethane, which is a pollutant and not the subject either of the article or of any clinical trials.

What the US calls "DCA" is 1,2-dichloroacetate, which is NOT a pollutant, and which is the potential drug cited in both the article in the OP, and the articles SteveGrenard posted clinical trials for other conditions on (and thanks, Steve- those might come in handy later).

IOW, I think the "DCA" acronym is what caused the confusion.

[Bold added] What the US calls DCA is still not 1,2-dichloroacetate; as I wrote previously, that is a misnomer for CH2ClCOCl. In acetate (CH3CO2-) the methyl group (CH3) is numbered 2, and anything substituted there is numbered 2. The putative drug is 2,2-dichloroacetate, or CHCl2CO2-. If the chlorine were on the #1 carbon, it would not be called acetate, it would be an acetyl chloride. In fact, unless editorial policies have recently changed, I can't imagine a chemist referring to 2,2-dichloroacetate; it would simply be "dichloroacetate" since there is nowhere else to put chlorine on acetate.

The J Clin Pharm paper, cited by SG, that concerns a pollutant is pretty clearly not relevant to the discussion of the drug. I, too, appreciate the other articles cited by SG, and the explanation of the Warburg effect by Schneib.