Dichloroacetic acid 2997935 225520211 2008-07-14T03:13:58Z Rifleman 82 1255637 Reverted edits by [[Special:Contributions/200.53.42.75|200.53.42.75]] ([[User talk:200.53.42.75|talk]]) to last version by ClueBot {{chembox new | ImageFileL1 = Dichloroacetic-acid-2D-skeletal.svg | ImageFileR1 = Dichloroacetic-acid-3D-vdW.png | IUPACName = Dichloroacetic acid | OtherNames = Dichloroethanoic acid | Formula = CHCl<sub>2</sub>COOH | Section1 = {{Chembox Identifiers | Abbreviations = | CASNo = 79-43-6 | EINECS = | PubChem = 6597 | SMILES = ClC(Cl)C(=O)O | InChI = | RTECS = AG6125000 | MeSHName = Dichloroacetate | ChEBI = | KEGG = | ATCCode_prefix = | ATCCode_suffix = | ATC_Supplemental =}} | Section2 = {{Chembox Properties | MolarMass =128.9 g/mol | Appearance = colorless liquid | Density = 1.57 g/ml, liquid | MeltingPt = 9.5 °C | Melting_notes = | BoilingPt = 194 °C | Boiling_notes = | Solubility = miscible | SolubleOther = | Solvent = | pKa = 1.25<ref>[http://www.cem.msu.edu/~reusch/VirtTxtJml/acidity2.htm Ionization Constants of Heteroatom Organic Acids]</ref> | pKb = }} | Section3 = {{Chembox Structure | CrystalStruct = | Coordination = | MolShape = }} | Section4 = {{Chembox Thermochemistry | DeltaHf = | DeltaHc = | Entropy = | HeatCapacity = }} | Section5 = {{Chembox Pharmacology | AdminRoutes = | Bioavail = | Metabolism = | HalfLife = | ProteinBound = | Excretion = | Legal_status = | Legal_US = | Legal_UK = | Legal_AU = | Legal_CA = | PregCat = | PregCat_AU = | PregCat_US = }} | Section6 = {{Chembox Explosive | ShockSens = | FrictionSens = | ExplosiveV = | REFactor = }} | Section7 = {{Chembox Hazards | ExternalMSDS = [http://www.jtbaker.com/msds/englishhtml/d2144.htm MSDS (jtbaker)] | EUClass = | EUIndex = | MainHazards = | NFPA-H = 3 | NFPA-F = 1 | NFPA-R = 0 | NFPA-O = &nbsp; | RPhrases = {{R35}}, {{R50}} | SPhrases = {{S1/2}}, {{S26}}, {{S45}}, {{S61}} | RSPhrases = | FlashPt = | Autoignition = | ExploLimits = | PEL = }} | Section8 = {{Chembox Related | OtherAnions = | OtherCations = | OtherFunctn = [[Chloroacetic acid]]<br />[[Trichloroacetic acid]] | Function = [[chloroacetic acids]] | OtherCpds = [[Acetic acid]]<br />[[Difluoroacetic acid]]<br />[[Dibromoacetic acid]]}} }} '''Dichloroacetic acid''', often abbreviated '''DCA''', is a [[chemical compound]], an [[acid]], and an [[Analog (chemistry)|analogue]] of [[acetic acid]] in which two of the three [[hydrogen]] [[atom]]s of the [[methyl]] group have been replaced by [[chlorine]] atoms. The [[salt]]s and [[ester]]s of dichloroacetic acid are called '''dichloroacetates'''. The salts are under investigation as a possible treatment for [[cancer]]. == Chemistry and occurrence== The chemistry of dichloroacetic acid is typical for [[halogen]]ated [[organic acid]]s. It is a member of the [[chloroacetic acids]] family. The dichloroacetate ion is produced when dissolved in water. As an acid with a [[Acid dissociation constant|pK<sub>a</sub>]] of 1.48,<ref>Lide, D. R. (Ed.) (1990). CRC Handbook of Chemistry and Physics (70th Edn.). Boca Raton (FL):CRC Press.</ref> pure dichloroacetic acid is very corrosive and extremely destructive to tissues of the mucous membranes and upper respiratory tract.<ref name="MSDS">[http://www.jtbaker.com/msds/englishhtml/d2144.htm MSDS (jtbaker)]</ref> 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.<ref name=toxicology/> It is typically prepared by the [[reduction]] of [[trichloroacetic acid]]. == Therapeutic use == 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. === Lactic acidosis === The dichloroacetate [[ion]] stimulates the activity of the [[enzyme]] [[pyruvate dehydrogenase]] by inhibiting the enzyme [[pyruvate dehydrogenase kinase]].<ref>{{cite journal |author=Stacpoole P |title=The pharmacology of dichloroacetate |journal=Metabolism |volume=38 |issue=11 |pages=1124–44 |year=1989 |pmid=2554095 |doi=10.1016/0026-0495(89)90051-6}}</ref> Thus, it decreases [[lactic acid|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.<ref name="stacpoole 1988">{{cite journal |author=Stacpoole P, Lorenz A, Thomas R, Harman E |title=Dichloroacetate in the treatment of lactic acidosis |journal=Ann Intern Med |volume=108 |issue=1 |pages=58–63 |year=1988 |pmid=3337517}}</ref><ref name="stacpoole2006">{{cite journal |author=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 |title=Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children |journal=Pediatrics |volume=117 |issue=5 |pages=1519–31 |year=2006 |pmid=16651305 |doi=10.1542/peds.2005-1226}}</ref><ref name="kaufmann2006">{{cite journal |author=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 |title=Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial |journal=Neurology |volume=66 |issue=3 |pages=324–30 |year=2006 |pmid=16476929 |doi=10.1212/01.wnl.0000196641.05913.27}}</ref><ref name="stacpoole1992">{{cite journal |author=Stacpoole P, Wright E, Baumgartner T, Bersin R, Buchalter S, Curry S, Duncan C, Harman E, Henderson G, Jenkinson S |title=A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group |journal=N Engl J Med |volume=327 |issue=22 |pages=1564–9 |year=1992 |pmid=1435883}}</ref> A [[randomized controlled trial]] in children with congenital [[lactic acidosis]] found that while DCA was well tolerated, it was ineffective in improving clinical outcomes.<ref name="stacpoole2006"/> A separate trial of DCA in children with [[MELAS]] (a syndrome of inadequate [[Mitochondrion|mitochondria]]l function, leading to lactic acidosis) was halted early, as all 15 of the children receiving DCA experienced significant [[peripheral neuropathy|nerve toxicity]] without any evidence of benefit from the medication.<ref name="kaufmann2006"/> 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 [[hemodynamic]]s or survival.<ref name="stacpoole1992"/> 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. {{Copyedit|date=February 2008}} === Potential cancer applications === Cancer cells generally use [[glycolysis]] rather than respiration ([[oxidative phosphorylation]]) for energy (the [[Warburg effect]]), as a result of [[Hypoxia (medical)|hypoxia]] that exists in [[tumor]]s and damaged mitochondria.<ref>{{cite journal |author=Xu R, Pelicano H, Zhou Y, Carew J, Feng L, Bhalla K, Keating M, Huang P |title=Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia |journal=Cancer Res |volume=65 |issue=2 |pages=613–21 |year=2005 |pmid=15695406}}</ref> Usually dangerously damaged cells kill themselves via [[apoptosis]], a mechanism of self-destruction that involves mitochondria, but this mechanism fails in [[cancer]] cells. According to the [[Warburg hypothesis]] of cancer growth, cancer is caused by the metabolic changes in mitochondria, although it is now known that cancer is caused by mutations in the genome of the cells. A study published in January 2007 by researchers at the [[University of Alberta]],<ref>[http://www.depmed.ualberta.ca/dca/ depmed.ualberta.ca]</ref> 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.<ref name="bonnet2007">{{cite journal |author=Bonnet S, Archer S, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee C, Lopaschuk G, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter C, Andrade M, Thebaud B, Michelakis E |title=A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth |journal=Cancer Cell |volume=11 |issue=1 |pages=37–51 |year=2007 |pmid=17222789 |doi=10.1016/j.ccr.2006.10.020}}</ref> These results received extensive media attention, beginning with an article in ''[[New Scientist]]'' titled "Cheap, ‘safe’ drug kills most cancers".<ref name="newscientist">{{cite web | url=http://www.newscientist.com/article.ns?id=dn10971 | title=Cheap, ‘safe’ drug kills most cancers | date=2007-01-17 | accessdate=2007-01-17 | publisher=New Scientist}}</ref> Subsequently, the [[American Cancer Society]] and other medical organizations have received a large volume of public interest and questions regarding DCA.<ref name="abcnews">[http://abcnews.go.com/Health/CancerPreventionAndTreatment/story?id=2848454&page=1 "DCA: Cancer Breakthrough or Urban Legend?"]. From [[ABC News]], [[5 February]] [[2007]]. Accessed 15 February 2007.</ref> Reports have since pointed out that although the study results are promising, no formal [[clinical trial]]s in humans with cancer have yet been conducted, emphasizing the need for caution in interpreting the preliminary results,<ref name="abcnews"/><ref name="nowonderdrug">[http://www.newscientist.com/article/mg19325890.200-no-wonder-drug.html "No Wonder Drug"], letter to ''[[New Scientist]]'' from Ralph Moss Lemont. Published [[February 3]] [[2007]]. Accessed 16 February 2007.</ref> though some doctors are treating patients with DCA "off-label",<ref> http://www.nationalreviewofmedicine.com/issue/poll/featured_article.html</ref><ref name="medicor">[http://www.medicorcancer.com/DCAtherapy.html Medicor Cancer Centres – DCA Therapy<!-- Bot generated title -->]</ref> and under a cloud of controversy.<ref> http://www.nationalreviewofmedicine.com/issue/poll/featured_article.html</ref> Medicor Cancer Centres, a private clinic in [[Toronto]], run by the husband-and-wife team of Drs. Humaira and Akbar Khan, is since March 2007<ref name="medicor2">http://www.medicorcancer.com/NatPost-may28_2007.pdf</ref> using DCA off-label for the treatment of several cancers 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".<ref name="medicor"/> However, they have not published their results nor reported it at medical conferences. Dr. Terry Polevoy, of Kitchener, Ontario, called on the College of Physicians and Surgeons of Ontario to take away the Khans' licences for offering a compound that hasn't been proven to shrink tumours in humans. "They are not oncologists. They should not be making these decisions. I think they should be disciplined for using this stuff. That, to me, is unethical, to use something that has never been proved to do anything." But the College said that it was not their role to say which therapies a doctor can use.<ref>{{cite web |url=http://www.canada.com/edmontonjournal/news/story.html?id=68943c8e-6838-4376-8add-2e3e4198453b |title=Doctors prescribe DCA to cancer patients |accessdate=2007-10-08 |format= |work=}}</ref> ''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."<ref>[http://www.newscientist.com/channel/health/mg19325972.900-editorial-gambling-with-your-life.html "Editorial: Gambling with your life"], New Scientist, [[31 March]] [[2007]]</ref> More than 90% of drugs entering phase I trials are found unacceptable.<ref>[http://ctj.sagepub.com/cgi/reprint/3/2/154?ijkey=64ce64b350cea076a54234e8cfc67700403a8885&keytype2=tf_ipsecsha Society for Clinical Trials Board of Directors.] The Society for Clinical Trials opposes US legislation to permit marketing of unproven medical therapies for seriously ill patients. Clin Trials 2006;3:154. [Free Full Text]</ref> The [[FDA]] approves 8-11% of drugs entering Phase I testing.<ref>Food&Drug Packaging, August, 2004</ref><ref>Nature Reviews Drug Development, August 2004</ref> DCA has been used historically to treat patients with lactic acidosis, and therefore could arguably enter phase 2 trials in patients with cancer.<ref>[http://www.depmed.ualberta.ca/dca/ A Letter from Dr. Evangelos Michelakis]</ref> DCA is non-[[patent]]able as a compound, though a patent has been filed for its use in cancer treatment.<ref>{{cite web |url=http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20070120/DCA_feature_070121/20070122?hub=Health |title=CTV.ca | Researchers launch website on new cancer research |accessdate=2007-10-08 |format= |work=}}</ref> Research by Dr. Evangelos Michelakis has received no support from the [[pharmaceutical industry]]. Concerns have been raised that without strong intellectual property protection, the financial incentive for pharmaceutical industry interest is reduced, and therefore clinical trials of DCA may not be funded.<ref name="abcnews"/><ref name="newscientist"/><ref name="nowonderdrug"/><ref name="express">[http://www.expressnews.ualberta.ca/article.cfm?id=8153 "Small molecule offers big hope against cancer"], by Ryan Smith. From ExpressNews, a University of Alberta publication. Published [[January 16]] [[2007]]. Accessed 15 February 2007.</ref> 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, Dr Michelakis's lab took the unorthodox step of directly soliciting online donations to fund the research.<ref>[http://www.depmed.ualberta.ca/dca/ Official University of Alberta DCA Site<!-- Bot generated title -->]</ref> 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.<ref>[http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20070120/DCA_feature_070121/20070122?hub=Health Researchers launch website on new cancer research], CTV.ca, [[22 January]] [[2007]]</ref><ref>[http://v3.espacenet.com/textdes?DB=EPODOC&IDX=WO2006108276&F=0&QPN=WO2006108276 A Method of Treating Cancer Using Dichloroacetate], Application to the European Patent Office, [[19 October]] [[2006]]</ref> 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 in Cancer.<ref>http://www.depmed.ualberta.ca/dca/letter_092407.pdf DCA Update: Health Canada Approves First DCA Clinical Trial in Cancer, [[24 September]] [[2007]]</ref> This initial trial will be relatively small (enrollment- up to 50 patients in the following 18 months). The patients will originate from the Edmonton area and be available for scheduled assessments for the duration of the trial. == Side effects == Reports in the lay press after the 2007 [[University of Alberta]] announcement claim that dichloroacetate "has actually been used safely in humans for decades",<ref name="DCA Cancer 2">{{cite news | url=http://www.theglobeandmail.com/servlet/story/RTGAM.20070117.wxhcancer17/BNStory/specialScienceandHealth/home | title=Long-used drug shows new promise for cancer | date=2007-01-17 | accessdate=2007-01-17 | publisher=[[The Globe and Mail]]}}</ref> but the limited scholarly literature suggests side effects of pain, numbness and [[Gait (human)|gait]] disturbances in some patients.<ref name="DCA Cancer 2"/> 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.<ref>{{cite journal |author=Kaufmann P, Engelstad K, Wei Y ''et al.'' |title=Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial |journal=Neurology |volume=66 |issue=3 |pages=324–30 |year=2006 |pmid=16476929 |doi=10.1212/01.wnl.0000196641.05913.27}}</ref> Dichloroacetate can also have [[anxiolytic]] or [[sedation|sedative]] effects.<ref name=toxicology>{{cite journal |author=Stacpoole P, Henderson G, Yan Z, James M |title=Clinical pharmacology and toxicology of dichloroacetate |journal=Environ Health Perspect |volume=106 Suppl 4 |issue= |pages=989–94 |year=1998 |pmid=9703483 |doi=10.2307/3434142}} [http://www.ehponline.org/members/1998/Suppl-4/989-994stacpoole/stacpoole-full.html Free full text]</ref> 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.<ref>{{cite journal |author=Stacpoole P, Harwood H, Cameron D, Curry S, Samuelson D, Cornwell P, Sauberlich H |title=Chronic toxicity of dichloroacetate: possible relation to thiamine deficiency in rats |journal=Fundam Appl Toxicol |volume=14 |issue=2 |pages=327&ndash;37 |year=1990 |pmid=2318357 |doi=10.1016/0272-0590(90)90212-3}}</ref> 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.<ref>{{cite journal |author=Kurlemann G, Paetzke I, Moller H, Masur H, Schuierer G, Weglage J, Koch HG |title=Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy |journal=Eur J Pediatr |volume=154 |issue=11 |pages=928&ndash;32 |year= 1995 |pmid=8582409 |doi=10.1007/BF01957508}}</ref><ref>{{cite journal |author=Spruijt L, Naviaux RK, McGowan KA, Nyhan WL, Sheean G, Haas RH, Barshop BA |title=Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate |journal=Muscle Nerve |volume=24 |issue=7 |pages=916&ndash;24 |year=2001 |pmid=11410919 |doi=10.1002/mus.1089}}</ref> 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.<ref>{{cite journal |author=Oishi K, Yoshioka M, Ozawa R, Yamamoto T, Oya Y, Ogawa M, Kawai M |title=Dichloroacetate treatment for adult patients with mitochondrial disease |journal=Rinsho Shinkeigaku |volume=43 |issue=4 |pages=154&ndash;61 |year=2003 |pmid=12892050}}</ref> 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 [[Hepatocellular carcinoma|liver cancer]] in humans.<ref name="">Environ Health Perspect. 2006 Sep;114(9):1457-63 PMID 16966105 ([http://www.ehponline.org/members/2006/8692/8692.html free full text])</ref> == Self-medication == <!-- Anonymous self-reports are not a reliable source and should not be included in Wikipedia articles, please read [[Wikipedia:No_original_research]], [[Wikipedia:Verifiability]], and [[Wikipedia:Reliable sources]]. Please do not add them. --> 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.<ref>{{cite news | url = http://www.canada.com/topics/news/national/story.html?id=80b15f9d-cb4a-46a0-a4bc-f1a4ddea60d3&k=56245 | title = Experts caution against patients compiling own data on unapproved cancer drug | author = Andrea Sands | publisher = Edmonton Journal | date = [[March 18]], [[2007]]}}</ref> == References == {{Reflist|2}} == External links == * {{ICSC|0868|08}} * {{cite news |author = CTV.ca News Staff |title = Small molecule offers hope for cancer treatment | url = http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20070116/cancer_dca_070116/20070116 | work = CTV.ca Website |publisher = [[CTV television network]] | date = [[16 January]] [[2007]] |accessdate = 2007-01-31 |language = English}} * {{cite news |author = Evangelos Michelakis and Stephen Archer |title = Researchers launch website on new cancer research | url = http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20070120/DCA_feature_070121/20070122?hub=Health | work = CTV.ca Website |publisher = [[CTV television network]] | date = [[22 January]] [[2007]] |accessdate = 2007-01-31 |language = English}} * [http://www.depmed.ualberta.ca/dca/ DCA Research Information Website] ([[University of Alberta]] and the Alberta Cancer Board) * [http://www.depmed.ualberta.ca/dca/stke.pdf Metabolic Targeting as an Anticancer Strategy: Dawn of a New Era?] PDF of a scientific paper by researchers from the University of Toronto, Canada * [http://www.newscientisttech.com/article/mg19325920.400-wait-for-clinical-trials.html Wait for Clinical Trials], New Scientist, [[24 February]] [[2007]] * [http://info.cancerresearchuk.org/news/behindtheheadlines/dca/ Questions over DCA 'cancer drug'], by Cancer Research UK * [http://www.stanford.edu/group/hopes/treatmts/ebuffer/j4.html Dichloroacetate, Huntington's disease, and metabolic disorders] * [http://www.economist.com/science/displaystory.cfm?story_id=8548706 Cancer Biology – Cramping Tumors] Economist, [[January 18]], [[2007]] * [http://www.medicorcancer.com/DCAtherapyData.html Medicor Cancer Centre's Observational DCA Treatment Data], updated March 2008 [[Category:Carboxylic acids]] [[Category:Chemotherapeutic agents]] [[Category:Organochlorides]] [[de:Dichloressigsäure]] [[fr:Acide dichloroacétique]] [[it:Acido dicloroacetico]] [[nl:Dichloorazijnzuur]] [[pl:Kwas dichlorooctowy]] [[pt:Ácido dicloroacético]]