Dichloroacetic acid
Encyclopedia
Dichloroacetic acid, often abbreviated DCA, is the chemical compound
with formula
. 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have been replaced by chlorine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
.
Cancer cells change the way they metabolize oxygen in a way that promotes their survival. In laboratory studies of isolated cancer cells grown in tissue culture, DCA restores the original metabolism, and promotes their self-destruction. This has led to the use of DCA for treating cancer, by individuals experimenting with it themselves, by doctors administering it to patients as a non-approved drug, by scientists testing it in cancer tissue cultures in cell culture and in mice, and in human Phase II studies. DCA has improved certain biochemical parameters, but it has not demonstrated improved survival.
A study in mice at the University of Alberta
showed that "DCA induces apoptosis
, decreases proliferation, and inhibits tumor growth, without apparent toxicity." In 2010, a small human trial on 5 cancer patients and 49 samples of tissue was conducted. The results were encouraging, and DCA "appeared to extend the lives of four of the five study participants".
ated 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 1.48, pure dichloroacetic acid is very corrosive
and extremely destructive to tissues of the mucous membranes and upper respiratory tract.
DCA does not occur in nature. 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
.
and potassium
salts, sodium dichloroacetate and potassium dichloroacetate.
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 glycolysis
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 mitochondria
l 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.
rather than respiration (oxidative phosphorylation
) for energy (the Warburg effect
), as a result of hypoxia
that exists in tumor
s 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 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.
but not in normal brain tissue.
Five palliative patients with primary GBM were entered into a phase II trial. Three had not responded to several chemotherapies; two were newly diagnosed. After surgical removal of tumor mass, they were treated with DCA and chemotherapy.
Of the five patients tested, one 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.
. They have treated several types of cancer and said on their web site that some patients "are showing varied positive responses to DCA including tumor shrinkage, reduction in tumor markers, symptom control, and improvement in lab tests". Although they have not reported results at medical conferences, they have published one peer-reviewed paper in The Journal of Palliative Medicine and uploaded details of patient responses and overall statistics on their web site. They report that two patients who had DCA added to traditional chemotherapy had complete remission of metastatic cancer. Medicor states that the clinical results they have been getting are in agreement with clinical trials.
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.
able 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 clinical trials of DCA may not be funded. 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 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 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.
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. The Medicor Cancer Centre reports on its website the use of 20–25 mg/kg/day on a two-week on, one week off cycle. This cycling helps determine which side effects are due to DCA, which are due to cancer, and if treatment should be discontinued.
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 at high doses.
(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 potential
s 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.
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.
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.
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
with formula
Chemical formula
A chemical formula or molecular formula is a way of expressing information about the atoms that constitute a particular chemical compound....
. It is an acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
, an analogue
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
, in which two of the three hydrogen atoms of the methyl group
Methyl group
Methyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion...
have been replaced by chlorine
Chlorine
Chlorine is the chemical element with atomic number 17 and symbol Cl. It is the second lightest halogen, found in the periodic table in group 17. The element forms diatomic molecules under standard conditions, called dichlorine...
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
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
pyruvate dehydrogenase kinase
Pyruvate dehydrogenase kinase
Pyruvate dehydrogenase kinase is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP....
.
Cancer cells change the way they metabolize oxygen in a way that promotes their survival. In laboratory studies of isolated cancer cells grown in tissue culture, DCA restores the original metabolism, and promotes their self-destruction. This has led to the use of DCA for treating cancer, by individuals experimenting with it themselves, by doctors administering it to patients as a non-approved drug, by scientists testing it in cancer tissue cultures in cell culture and in mice, and in human Phase II studies. DCA has improved certain biochemical parameters, but it has not demonstrated improved survival.
A study in mice at the University of Alberta
University of Alberta
The University of Alberta is a public research university located in Edmonton, Alberta, Canada. Founded in 1908 by Alexander Cameron Rutherford, the first premier of Alberta and Henry Marshall Tory, its first president, it is widely recognized as one of the best universities in Canada...
showed that "DCA induces apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, decreases proliferation, and inhibits tumor growth, without apparent toxicity." In 2010, a small human trial on 5 cancer patients and 49 samples of tissue was conducted. The results were encouraging, and DCA "appeared to extend the lives of four of the five study participants".
Chemistry and occurrence
The chemistry of dichloroacetic acid is typical for halogenHalogen
The halogens or halogen elements are a series of nonmetal elements from Group 17 IUPAC Style of the periodic table, comprising fluorine , chlorine , bromine , iodine , and astatine...
ated organic acids. It is a member of the chloroacetic acids
Chloroacetic acids
In organic chemistry, the chloroacetic acids are three related chlorocarbon carboxylic acids:* Chloroacetic acid , CH2ClCOOH* Dichloroacetic acid , CHCl2COOH...
family. The dichloroacetate ion is produced when the acid is mixed with water. As an acid with a pKa
Acid dissociation constant
An acid dissociation constant, Ka, is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions...
of 1.48, pure dichloroacetic acid is very corrosive
Corrosive
A corrosive substance is one that will destroy or irreversibly damage another surface or substance with which it comes into contact. The main hazards to people include damage to the eyes, the skin, and the tissue under the skin; inhalation or ingestion of a corrosive substance can damage the...
and extremely destructive to tissues of the mucous membranes and upper respiratory tract.
DCA does not occur in nature. It is a trace product of the chlorination
Chlorination
Chlorination is the process of adding the element chlorine to water as a method of water purification to make it fit for human consumption as drinking water...
of drinking water and is produced by the metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of various chlorine
Chlorine
Chlorine is the chemical element with atomic number 17 and symbol Cl. It is the second lightest halogen, found in the periodic table in group 17. The element forms diatomic molecules under standard conditions, called dichlorine...
-containing drugs or chemicals. DCA is typically prepared by the reduction
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
of trichloroacetic acid
Trichloroacetic acid
Trichloroacetic acid is an analogue of acetic acid in which the three hydrogen atoms of the methyl group have all been replaced by chlorine atoms....
.
Therapeutic use
Owing to the highly corrosive action of the acid, only the salts of dichloroacetic acid are used therapeutically, including its sodiumSodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
salts, sodium dichloroacetate and potassium dichloroacetate.
Lactic acidosis
The dichloroacetate ionIon
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
stimulates the activity of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
pyruvate dehydrogenase
Pyruvate dehydrogenase
Pyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the...
by inhibiting the enzyme pyruvate dehydrogenase kinase
Pyruvate dehydrogenase kinase
Pyruvate dehydrogenase kinase is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP....
. Thus, it decreases lactate
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
production by shifting the metabolism of pyruvate from glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
towards oxidation in the mitochondria. This property has led to trials of DCA for the treatment of lactic acidosis
Lactic acidosis
Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...
in humans.
A randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
in children with congenital lactic acidosis
Lactic acidosis
Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...
found that while DCA was well tolerated, it was ineffective in improving clinical outcomes. A separate trial of DCA in children with MELAS
MELAS
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes – abbreviated to MELAS – is one of the family of mitochondrial cytopathies, which also include MERRF, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984...
(a syndrome of inadequate mitochondria
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
l function, leading to lactic acidosis) was halted early, as all 15 of the children receiving DCA experienced significant nerve toxicity
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
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 use glycolysisGlycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
rather than respiration (oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
) for energy (the Warburg effect
Warburg effect
The phrase "Warburg effect" is used for two unrelated observations in biochemistry, one in plant physiology and the other in oncology, both due to Nobel laureate Otto Heinrich Warburg.-Plant physiology:...
), as a result of hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
that exists in tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s and malfunctioning mitochondria. Usually dangerously damaged cells kill themselves via apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, 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 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
New Scientist
New Scientist is a weekly non-peer-reviewed English-language international science magazine, which since 1996 has also run a website, covering recent developments in science and technology for a general audience. Founded in 1956, it is published by Reed Business Information Ltd, a subsidiary of...
titled "Cheap, ‘safe’ drug kills most cancers". Subsequently, the American Cancer Society
American Cancer Society
The American Cancer Society is the "nationwide community-based voluntary health organization" dedicated, in their own words, "to eliminating cancer as a major health problem by preventing cancer, saving lives, and diminishing suffering from cancer, through research, education, advocacy, and...
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 tissueGlioblastoma multiforme
Glioblastoma multiforme is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells and accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBMs...
but not in normal brain tissue.
Five palliative patients with primary GBM were entered into a phase II trial. Three had not responded to several chemotherapies; two were newly diagnosed. After surgical removal of tumor mass, they were treated with DCA and chemotherapy.
Of the five patients tested, one died after three months. The surviving four were followed for 15 months. Their Karnofsky scores
Performance status
In medicine , performance status is an attempt to quantify cancer patients' general well-being and activities of daily life. This measure is used to determine whether they can receive chemotherapy, whether dose adjustment is necessary, and as a measure for the required intensity of palliative care...
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.
Off-label use
Akbar and Humaira Khan have since March 2007 treated cancer patients using DCA off-label at their private clinic, Medicor Cancer Centres, in TorontoToronto
Toronto is the provincial capital of Ontario and the largest city in Canada. It is located in Southern Ontario on the northwestern shore of Lake Ontario. A relatively modern city, Toronto's history dates back to the late-18th century, when its land was first purchased by the British monarchy from...
. They have treated several types of cancer and said on their web site that some patients "are showing varied positive responses to DCA including tumor shrinkage, reduction in tumor markers, symptom control, and improvement in lab tests". Although they have not reported results at medical conferences, they have published one peer-reviewed paper in The Journal of Palliative Medicine and uploaded details of patient responses and overall statistics on their web site. They report that two patients who had DCA added to traditional chemotherapy had complete remission of metastatic cancer. Medicor states that the clinical results they have been getting are in agreement with clinical trials.
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-patentPatent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
able 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 clinical trials of DCA may not be funded. However, other sources of funding exist; previous studies of DCA have been funded by government organizations such as the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
, the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
, the Canadian Institutes of Health Research
Canadian Institutes of Health Research
Canadian Institutes of Health Research is the major federal agency responsible for funding health research in Canada. It is the successor to the Medical Research Council of Canada. It aims to create new health knowledge, and to translate that knowledge from the research setting into real world...
and by private charities (e.g. the Muscular Dystrophy Association
Muscular Dystrophy Association
The Muscular Dystrophy Association is an American organization which combats muscular dystrophy and diseases of the nervous system and muscular system in general by funding research, providing medical and community services, and educating health professionals and the general public...
). 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 Department of Medicine of Alberta University reported that after the trial funding was secured, both the Alberta local ethics committee and Health Canada
Health Canada
Health Canada is the department of the government of Canada with responsibility for national public health.The current Minister of Health is Leona Aglukkaq, a Conservative Member of Parliament appointed to the position by Prime Minister Stephen Harper.-Branches, regions and agencies: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.
Side effects
Reports in the lay press after the 2007 University of AlbertaUniversity of Alberta
The University of Alberta is a public research university located in Edmonton, Alberta, Canada. Founded in 1908 by Alexander Cameron Rutherford, the first premier of Alberta and Henry Marshall Tory, its first president, it is widely recognized as one of the best universities in Canada...
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. The Medicor Cancer Centre reports on its website the use of 20–25 mg/kg/day on a two-week on, one week off cycle. This cycling helps determine which side effects are due to DCA, which are due to cancer, and if treatment should be discontinued.
At sustained, higher doses(generally 25 mg/kg/day taken orally, or greater), there is increased risk of several reversible toxicities, especially peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
, neurotoxicity
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
, and gait disturbance. Studies have also shown that it can be carcinogenic at high doses.
Neuropathy
A clinical trial where DCA was given to patients of MELASMELAS
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes – abbreviated to MELAS – is one of the family of mitochondrial cytopathies, which also include MERRF, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984...
(a form of genetically inherited lactic acidosis
Lactic acidosis
Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...
) at 25 mg/kg/day was ended prematurely due to excessive peripheral nerve toxicity. Dichloroacetate can also have anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
or sedative
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
effects.
Animal studies suggest that the neuropathy and neurotoxicity
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
during chronic dichloroacetate treatment may be partly due to depletion of thiamine
Thiamine
Thiamine or thiamin or vitamin B1 , named as the "thio-vitamine" is a water-soluble vitamin of the B complex. First named aneurin for the detrimental neurological effects if not present in the diet, it was eventually assigned the generic descriptor name vitamin B1. Its phosphate derivatives are...
, 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
Sensory nerve
Sensory nerves are nerves that receive sensory stimuli, such as how something feels and if it is painful, smooth, rough, etc.They are made up of nerve fibers, called sensory fibers .Sensory neurons are neurons that are activated by sensory input Sensory nerves are nerves that receive sensory...
action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
s 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
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
formation.
Carcinogenicity
Long term use (a year 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
Trichloroethylene
The chemical compound trichloroethylene is a chlorinated hydrocarbon commonly used as an industrial solvent. It is a clear non-flammable liquid with a sweet smell. It should not be confused with the similar 1,1,1-trichloroethane, which is commonly known as chlorothene.The IUPAC name is...
(TCE) metabolites dichloroacetic acid (DCA), trichloroacetic acid
Trichloroacetic acid
Trichloroacetic acid is an analogue of acetic acid in which the three hydrogen atoms of the methyl group have all been replaced by chlorine atoms....
(TCA), and chloral hydrate
Chloral hydrate
Chloral hydrate is a sedative and hypnotic drug as well as a chemical reagent and precursor. The name chloral hydrate indicates that it is formed from chloral by the addition of one molecule of water. Its chemical formula is C2H3Cl3O2....
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
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
in humans.
Self-medication
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.Doctors warned of potential problems if people attempt to try DCA outside a controlled clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
. "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.
External links
- DCA Research Information Website (University of AlbertaUniversity of AlbertaThe University of Alberta is a public research university located in Edmonton, Alberta, Canada. Founded in 1908 by Alexander Cameron Rutherford, the first premier of Alberta and Henry Marshall Tory, its first president, it is widely recognized as one of the best universities in Canada...
) - Wait for Clinical Trials, New Scientist, 24 February 2007
- Potential cancer drug DCA tested in early trials, by Cancer Research UK
- Interviewing Drs. Akbar and Humaira Khan about DCA
- Cancer Biology – Cramping Tumors Economist, January 18, 2007
- Official University of Alberta DCA (dichloroacetate) Website, The University of Alberta Discovery. March 15, 2007