|Jmol-3D images||Image 1|
|Molar mass||128.94 g mol−1|
|Density||1.5634 g/cm3 (20 °C)|
9-11 °C, 282-284 K, 48-52 °F
194 °C, 467 K, 381 °F
|Solubility in water||miscible|
|Solubility||miscible with ethanol, diethyl ether|
|Std enthalpy of
|S-phrases||(S1/2) S26 S45 S61|
|Related chloroacetic acids||Chloroacetic acid
|Related compounds||Acetic acid
| (what is: / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Dichloroacetic acid, often abbreviated DCA, is the chemical compound with formula CHCl
2COOH. It is an acid, an analogue of acetic acid, in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms. The salts and esters of dichloroacetic acid are called dichloroacetates. Salts of DCA have been studied as potential drugs because they inhibit the enzyme pyruvate dehydrogenase kinase.
Although preliminary studies have shown DCA can slow the growth of certain tumors in animal studies and in vitro studies, "Available evidence does not support the use of DCA for cancer treatment at this time."
Chemistry and occurrence
The chemistry of dichloroacetic acid is typical for halogenated organic acids. It is a member of the chloroacetic acids family. The dichloroacetate ion is produced when the acid is mixed with water. As an acid with a pKa of 1.35, pure dichloroacetic acid is very corrosive and extremely destructive to tissues of the mucous membranes and upper respiratory tract via inhalation.
DCA has been shown to occur in nature in at least one seaweed, Asparagopsis taxiformis.. It is a trace product of the chlorination of drinking water and is produced by the metabolism of various chlorine-containing drugs or chemicals. DCA is typically prepared by the reduction of trichloroacetic acid. DCA is prepared from chloral hydrate also by the reaction with calcium carbonate and sodium cyanide in water followed by acidifying with hydrochloric acid.
Owing to the highly corrosive action of the acid, only the salts of dichloroacetic acid are used therapeutically, including its sodium and potassium salts, sodium dichloroacetate and potassium dichloroacetate.
The dichloroacetate ion stimulates the activity of the enzyme pyruvate dehydrogenase by inhibiting the enzyme pyruvate dehydrogenase kinase. Thus, it decreases lactate production by shifting the metabolism of pyruvate from fermentation towards oxidation in the mitochondria. This property has led to trials of DCA for the treatment of lactic acidosis in humans.
A randomized controlled trial in children with congenital lactic acidosis found that while DCA was well tolerated, it was ineffective in improving clinical outcomes. A separate trial of DCA in children with MELAS (a syndrome of inadequate mitochondrial function, leading to lactic acidosis) was halted early, as all 15 of the children receiving DCA experienced significant nerve toxicity without any evidence of benefit from the medication. A randomized controlled trial of DCA in adults with lactic acidosis found that while DCA lowered blood lactate levels, it had no clinical benefit and did not improve hemodynamics or survival.
Thus, while early case reports and pre-clinical data suggested that DCA might be effective for lactic acidosis, subsequent controlled trials have found no clinical benefit of DCA in this setting. In addition, clinical trial subjects were incapable of continuing on DCA as a study medication owing to progressive toxicities.
Potential cancer applications
Cancer cells generally express increased glycolysis, because they rely on anaerobic respiration that occurs in the cytosol (lactic acid fermentation) rather than oxidative phosphorylation in the mitochondria for energy (the Warburg effect), as a result of hypoxia that exists in tumors and malfunctioning mitochondria. Usually dangerously damaged cells kill themselves via apoptosis, a mechanism of self-destruction that involves mitochondria, but this mechanism fails in cancer cells.
A phase I study published in January 2007 by researchers at the University of Alberta, who had tested DCA on human cancer cells grown in mice, found that DCA restored mitochondrial function, thus restoring apoptosis, allowing cancer cells to self-destruct and shrink the tumor.
These results received extensive media attention, beginning with an article in New Scientist titled "Cheap, ‘safe’ drug kills most cancers". Subsequently, the American Cancer Society and other medical organizations have received a large volume of public interest and questions regarding DCA. Clinical trials in humans with cancer have not been conducted in the USA and are not yet final in Canada, emphasizing the need for caution in interpreting the preliminary results.
Results of phase II clinical trials
In in vitro studies, Evangelos Michelakis of University of Alberta found that in tissue samples from 49 patients, DCA caused depolarization of mitochondria in GBM tissue but not in healthy brain tissue.
Five patients with primary GBM were entered into a phase II trial. Three had not responded to several chemotherapies and was considered appropriate for palliative care. Two were newly diagnosed and then went through surgical removal of tumour mass. All of them were treated with DCA and chemotherapy.
Of the five patients tested, one of the first three died after three months. The surviving four were followed for 15 months. Their Karnofsky scores were unchanged in two cases, and decreased by 10 points in two patients.
DCA was associated with tumor regression and had a good safety profile. DCA side effects were minimal.
Michelakis is proceeding with phase three human studies with private funding from philanthropic groups and individuals. DCA's legal status as a discovery is public domain because it was made or discovered as far back as 1864 and has been used in the treatment of canine and human lactic acidosis, some who presented at the beginning of treatment with cancer.
Concerns about pre-trial use
Following its initial publication, The New Scientist later editorialized, "The drug may yet live up to its promise as an anti-cancer agent – clinical trials are expected to start soon. It may even spawn an entirely new class of anti-cancer drugs. For now, however, it remains experimental, never yet properly tested in a person with cancer. People who self-administer the drug are taking a very long shot and, unlikely as it may sound, could even make their health worse."
In 2010, it was found that for human colorectal tumours grown in mice, under hypoxic conditions, DCA decreased rather than increased apoptosis, resulting in enhanced growth of the tumours. These findings suggest that at least in some cancer types DCA treatment could be detrimental to patient health, highlighting the need for further testing before it can be considered a safe and effective cancer treatment.
Planned and ongoing clinical trials
DCA is non-patentable as a compound, though a patent has been filed for its use in cancer treatment. Research by Evangelos Michelakis has received no support from the pharmaceutical industry. Concerns have been raised that without strong intellectual property protection, the financial incentive for drug development is reduced, and therefore obtaining sufficient funds to conduct clinical trials presents difficulty. However, other sources of funding exist; previous studies of DCA have been funded by government organizations such as the National Institutes of Health, the Food and Drug Administration, the Canadian Institutes of Health Research and by private charities (e.g. the Muscular Dystrophy Association). Recognizing anticipated funding challenges, 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. Michelakis and Archer have applied for a patent on the use of DCA in the treatment of cancer.
On 24 September 2007, the University of Alberta's Department of Medicine 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 was relatively small with enrollment of up to 50 patients. The trial was completed in August 2009. In May 2010 the team published a press release stating no conclusions could be drawn as a result of the trial. A paper describing the results was published but not linked from the press release. Only five patients had been treated with the drug during the trial.
In May 2011, online reports suggested that the Alberta group had released new data which the media "had not reported". However, this appeared to be caused by confusion between dates (the previous update was May 2010) and cancer charities moved quickly to counter these rumours, which were subsequently covered in New Scientist magazine.
The use of this compound as an anti-cancer agent has been patented.
Reports in the lay press after the 2007 University of Alberta announcement claim that dichloroacetate "has actually been used safely in humans for decades", DCA is generally well tolerated, even in children. Short-term, infused, bolus doses of DCA at 50 mg/kg/day have been well tolerated.
At sustained, higher doses (generally 25 mg/kg/day taken orally, or greater), there is increased risk of several reversible toxicities, especially peripheral neuropathy, neurotoxicity, and gait disturbance.
Studies have also shown that it can be carcinogenic in male B6C3F1 mice at high doses.
A clinical trial where DCA was given to patients of MELAS (a form of genetically inherited lactic acidosis) at 25 mg/kg/day was ended prematurely due to excessive peripheral nerve toxicity. Dichloroacetate can also have anxiolytic or sedative effects.
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. 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. An additional study reported that 50 mg/kg/day DCA treatment resulted in unsteady gait and lethargy in two patients, with symptoms occurring after one month for one patient and two months for the second. Gait disturbance and consciousness were recovered with cessation of DCA, however sensory nerve action potentials did not recover in one month.
It has been reported that animals and patients treated with DCA have elevated levels of delta-aminolevulinic acid (delta-ALA) in the urine. A study published in 2008 suggests that this product may be the cause of the neurotoxic side effect of DCA by blocking peripheral myelin formation.
Long term use (three years or more) of high doses (> 77 mg/kg/day) of DCA has been shown to increase risk of liver cancer in mice. Studies of the trichloroethylene (TCE) metabolites dichloroacetic acid (DCA), trichloroacetic acid (TCA), and chloral hydrate suggest that both DCA and TCA are involved in TCE-induced liver tumorigenesis and that many DCA effects are consistent with conditions that increase the risk of liver cancer in humans. It should be noted here that the maximum recommended dose for cancer treatment is 20mg/kg/day (less than 1/3rd of the 77mg/kg/day shown to increase liver cancer risk in mice).
Doctors warned of potential problems if people attempt to try DCA outside a controlled clinical trial. "If it starts going badly, who is following you before it gets out of control? By the time you realize your liver is failing, you're in big trouble", said Laura Shanner, Associate Professor of Health Ethics at the University of Alberta.
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