DCA (Dichloroacetic acid) THERAPY

 

Dichloroacetic acid, often abbreviated DCA, is a chemical compound, an acid, and an analogue of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms, it has the chemical formulaCHCl2COOH.

Therapeutic use

Owing to the highly corrosive action of the acid, only the salts of dichloroacetic acid are used therapeutically, including its sodium and potassiu salts, sodium dichloroacetate and potassium dichloroacetate.

Lactic acidosis

The dichloroacetate ionstimulates the activity of the enzyme pyruvate dehydrogenase by inhibiting the enzyme p.d. kinase.Thus, it decreases lactate production by shifting the metabolism of pyruvate from glycolysis towards oxidationin the mitochondria.. This property has led to trials of DCA for the treatment of lactic acidosis humans, despite controversial issues anddresults with mainstream clinical trials. See (Stacpoole P, Kerr D, Barnes C, Bunch S, Carney P, Fennell E, Felitsyn N, Gilmore R, Greer M, Henderson G, Hutson A, Neiberger R, O'Brien R, Perkins L, Quisling R, Shroads A, Shuster J, Silverstein J, Theriaque D, Valenstein E (2006). "Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children". Pediatrics 117 (5): 1519–31. doi:10.1542/peds.2005-1226. PMID 16651305), Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano M, Shungu D, Millar W, Hong X, Gooch C, Mao X, Pascual J, Hirano M, Stacpoole P, DiMauro S, De Vivo D (2006). "Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial". Neurology 66 (3): 324–30. doi:10.1212/01.wnl.0000196641.05913.27. PMID 16476929. Stacpoole P, Wright E, Baumgartner T, Bersin R, Buchalter S, Curry S, Duncan C, Harman E, Henderson G, Jenkinson S (1992). "A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group". N Engl J Med 327 (22): 1564–9. PMID 1435883. 

Potential cancer applications

Cancer cells generally use glycolysis rather than respiration (oxidative phosphorylation) for energy (cf Warburg), as a result of hypoxiathat exists in tumorsand damaged mitochondria. (Source)

Usually dangerously damaged cells kill themselves via apoptosis, a mechanism of self-destruction that involves mitochondria, but this mechanism fails in cancer cells.

A study published in January 2007 by researchers at the University of Alberta testing DCA on in vitro cancer cell lines and a rat model, found that DCA restored mitochondrial function, thus restoring apoptosis, killing cancer cells in vitro, and shrinking the tumors in the rats. (Source).

These results received extensive media attention, beginning with an article in New Scientist titled "Cheap, ‘safe’ drug kills most cancers". ( Editorial: Gambling with your life", New Scientist, 31 March 2007). However the mainstream oncology system did little to promote clinical evidence in favor of dca.

Be that as it may, some doctors are treating cancer using DCA "off-label". The off label use of prescription drugs is common practice for cancer patients at the most prestigious medical institutions in the world, especially those diagnosed with cancers designated as orphan diseases, for which very few government-approved therapies are available.

Akbar and Humaira Khan have since March 2007 treated cancer patients using DCA off-label at their private clinic, Medicor Cancer Centres, in Toronto, Ca (cf. Researchers launch website on new cancer research, CTV.ca, 22 January 2007 ). They have treated several types of cancer and said on their web site that some patients "are showing varied positive responses to DCA including tumour shrinkage, reduction in tumour markers, symptom control, and improvement in lab tests". Although, they have not published their results nor reported it at medical conferences, they have uploaded details of patient responses and overall statistics on their web site. ( A Method of Treating Cancer Using Dichloroacetate, Application to the European Patent Office, 19 October 2006).

DCA has been used historically to treat patients with lactic acidosis, and therefore could arguably enter phase 2 trials in patients with cancer. DCA is non-patentable as a compound, though a patent has been filed for its use in cancer treatment. Research by Dr. Evangelos Michelakis has received no support from big pharma. Concerns have been raised that without strong intellectual property protection, the financial incentive for drug development is reduced, and therefore clinical trials of DCA may not be funded. Recognizing anticipated funding challenges, Dr Michelakis's lab took the unorthodox step of directly soliciting online donations to fund the research. After 6 months, his lab had raised over $800,000, enough to fund a small Clinical Phase 2 study. Dr. Michelakis and Dr. Archer have applied for a patent on the use of DCA in the treatment of cancer. (Source).

On 24 September 2007, the Department of Medicine of Alberta University reported that after the trial funding was secured, both the Alberta local ethics committee and Health Canada approved the first DCA clinical trial for cancer.This initial trial is relatively small with enrollment of up to 50 patients. ( Kurlemann G, Paetzke I, Moller H, Masur H, Schuierer G, Weglage J, Koch HG (1995). "Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy". Eur J Pediatr 154 (11): 928–32. doi:10.1007/BF01957508. PMID 8582409.)

The promise of DCA as a cheap, effective and safe treatment for cancer generated a great deal of public interest. Many people turned to self-medication. (Spruijt L, Naviaux RK, McGowan KA, Nyhan WL, Sheean G, Haas RH, Barshop BA (2001). "Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate". Muscle Nerve 24 (7): 916–24. doi:10.1002/mus.1089. PMID 11410919.) 

When faced with the high costs of getting FDA approval, estimated by Tufts University to exceed one billion dollars [34], the chance of getting DCA approved for the treatment of cancer in the United States is extremely low. (cf. Environ Health Perspect. 2006 Sep;114(9):1457-63 PMID 16966105 (free full text) This problem is highlighted in the 2007 New York TImesarticle by Ralph Moss titled "Patents over Patients" (Andrea Sands (March 18, 2007). "Experts caution against patients compiling own data on unapproved cancer drug". Edmonton Journal. http://www.canada.com/topics/news/national/story.html?id=80b15f9d-cb4a-46a0-a4bc-f1a4ddea60d3&k=56245.).

Side effects

Reports in the lay press after the 2007 Univ of Albertaannouncement claim that dichloroacetate "has actually been used safely in humans for decades", but the limited scholarly literature suggests side effects of pain, numbness and gait disturbances in some patients.Dichloroacetate can also have anxiolytic or sedative effects. (Cheap, ‘safe’ drug kills most cancers". New Scientist. 2007-01-17. http://www.newscientist.com/article.ns?id=dn10971. ).

DOSAGE

 

Doses of 5 mg/kg every three days limits effects from toxicity while maintaining adequate progress. (Source).

Animal studies suggest that the neuropathy and neurotoxicity during chronic dichloroacetate treatment may be partly due to depletion of thiamine, and thiamine supplementation in rats reduced these effects. ( Stacpoole P, Harwood H, Cameron D, Curry S, Samuelson D, Cornwell P, Sauberlich H (1990). "Chronic toxicity of dichloroacetate: possible relation to thiamine deficiency in rats". Fundam Appl Toxicol 14 (2): 327–37. doi:10.1016/0272-0590(90)90212-3. PMID 2318357). However, more recent studies in humans suggest that peripheral neuropathy is a common side effect during chronic DCA treatment, even with coadministration of oral thiamine.(cf Kurlemann G, Paetzke I, Moller H, Masur H, Schuierer G, Weglage J, Koch HG (1995). "Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy". Eur J Pediatr 154 (11): 928–32. doi:10.1007/BF01957508. PMID 8582409).

 

ARTICLE WHEN DCA AS A CANCER THERAPY WAS INVOKED IN THE MEDIA

Cancer finding hailed

Causes disease to regress: Molecule could treat lung, breast, brain cancers

Melissa Leong, National Post

Published: Wednesday, January 17, 2007

A simple molecule, used for decades to treat children with rare metabolic diseases, commits "immortal" cancer cells to a natural death and could soon be used to treat many forms of cancer, according to a new study. University of Alberta researchers were excited to discover that dichloroacetate (DCA) causes regression in several cancers, including lung, breast and brain tumours."It's important for the future of cancer," said Dr. Evangelos Michelakis, a professor at the University of Alberta's department of medicine and an author of the study.

Cancer cells, such as these breast cancer cells, have been killed in test tubes and rats by a molecule called dichloroacetate (DCA).

The findings were published yesterday in the journal Cancer Cell.
DCA, a non-toxic compound comprised of "a couple of oxygens, a couple of chlorides and a couple of carbons," appears to repair the damage that cancer cells cause to mitochondria -- the energy- producing units in cells.
Mitochondria regulate cell death and because cancer cells suppress their mitochondria, they achieve "immortality," Dr. Michelakis said. This appears to offer cancer cells a significant advantage in growth compared to normal cells as well as protection from many standard chemotherapies, he said.
DCA "puts life into the mitochondria," making cancer cells more susceptible to apoptosis -- a natural cell suicide mechanism that enables a person to control cell numbers and kill off cells that threaten his or her survival, he said.
DCA, being so small, is easily absorbed into the body, and after oral intake, it can reach areas in the body that other drugs cannot -- making it possible to treat brain cancers. It could one day be used in conjunction with traditional chemotherapies, Dr. Michelakis said.

"The DCA will enable the cell death mechanisms and then chemotherapy would have a much easier job; you could use lower doses and [the chemotherapy would be] less toxic," he said.

DCA affects cancer cells without affecting normal ones, he added.
Because the inexpensive drug has been used on both healthy and ill patients for 30 years, it can be immediately tested on people suffering from cancer, Dr. Michelakis said. But because DCA is not patented and is not owned by a pharmaceutical company, it will be a challenge to find funding to begin clinical trials, he said. Until the past few years, researchers believed damage to mitochondria in cancer cells was permanent. But Dr. Michelakis, a cardiologist, wanted to test this belief. "When you see what DCA can do in other mitochondria, we said, 'Why don't we try it in cancer?' "

Researchers used human tumours and studied them in test tubes and in rats.
"This preliminary research ... offers hope to thousands of Canadians and all others around the world who are afflicted by cancer," Dr. Philip Branton of the CIHR Institute of Cancer said in a statement. 

What are Mitochondria?

Mitochondria are the power source for your cells. They use enzymes to convert organic materials into energy. It has been a generally accepted theory that a cell's mitochondria are damaged when cancer cells form. When the mitochondria are 'disabled', the cancerous cells use a very inefficient method called glycolysis to produce their energy.

Mitochondria are also essential for apoptosis. This function is very effective in killing off cancer cells.

What is Apoptosis?

The simplest way to define apoptosis is to say that it is something built into the cells in your body that effectively tell them to kill themselves. Basically it's a built-in cell suicide mechanism! It's a type of cell death where your body uses this built-in function to allow it to control the number of cells and eliminate cells that threaten its survival.

Cancer cells turn off your body's self destruct mechanism. That's part of the reason why they are so hard to eliminate. DCA reactivates the mitochondria in the cancerous cells, which in turn allows apoptosis to take place in the cell.

DCA has been used to treat mitochondrial diseases for over 30 years with relatively few side effects. It can cause pain, numbness and gait disturbances in some patients. Dichloroacetate has been used for many years to treat children with mitochondrial related diseases. When weighed against the inherent pain and other side effects of most typical modern cancer treatments, DCA wins 'hands down'. It can be taken by mouth and it is easily absorbed by the body.

What is DCA?

Dichloroacetate (DCA) is an inexpensive, non-patented compound that has been used for over 30 years to treat mitochondrial diseases with relatively few side effects. It is a relatively non-toxic molecule, and because it is such a small molecule, it can easily be absorbed by the body. DCA can be taken orally. As a result, clinical trials on patients with cancer could begin almost immediately. Dichloroacetate 'turns on' dormant mitochondria in the cancerous cells permitting apoptosis to occur,

The fact that DCA is not patented or owned by any pharmaceutical company is a double edged sword. On one hand it can be manufactured and distributed for a fraction of what newly developed drugs cost. Unfortunately, for the same reason, funding research into its use as an aid in curing cancer will be difficult to find. Pharmaceutical companies usually provide the money needed for this type of research.

REFERENCES AND RESEARCH AVENUES

 

 

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