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Dichloroacetic acid

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This is an old revision of this page, as edited by 70.50.194.14 (talk) at 18:42, 22 December 2014 (Formerly 98 removing valid peer reviewed published DCA research, why suppress? drug co puppet?). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Dichloroacetic acid
Names
IUPAC name
Dichloroacetic acid
Other names
Dichloroethanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.001.098 Edit this at Wikidata
KEGG
MeSH Dichloroacetate
RTECS number
  • AG6125000
UNII
  • InChI=1S/C2H2Cl2O2/c3-1(4)2(5)6/h1H,(H,5,6) checkY
    Key: JXTHNDFMNIQAHM-UHFFFAOYSA-N checkY
  • InChI=1/C2H2Cl2O2/c3-1(4)2(5)6/h1H,(H,5,6)
    Key: JXTHNDFMNIQAHM-UHFFFAOYAK
  • ClC(Cl)C(O)=O
Properties
C2H2Cl2O2
Molar mass 128.94 g·mol−1
Appearance Colorless liquid
Density 1.5634 g/cm3 (20 °C)
Melting point 9 °C (48 °F; 282 K)
Boiling point 194 °C (381 °F; 467 K)
miscible
Solubility miscible with ethanol, diethyl ether[1]
Acidity (pKa) 1.35[1]
Thermochemistry
-496.3 kJ·mol-1[1]
Hazards
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 3: Short exposure could cause serious temporary or residual injury. E.g. chlorine gasFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
3
1
0
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

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 It is an acid, an analogue of acetic acid, in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms.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.[2]

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."[3]

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,[1] pure dichloroacetic acid is very corrosive and extremely destructive to tissues of the mucous membranes and upper respiratory tract via inhalation.[4]

DCA has been shown to occur in nature in at least one seaweed, Asparagopsis taxiformis.[5] It is a trace product of the chlorination of drinking water and is produced by the metabolism of various chlorine-containing drugs or chemicals.[6] 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.

Therapeutic uses

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.[7] 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.[8][9][10][11]

A randomized controlled trial in children with congenital lactic acidosis found that while DCA was well tolerated, it was ineffective in improving clinical outcomes.[9] 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.[10] 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.[11]

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.[12][13] Usually dangerously damaged cells kill themselves via apoptosis, a mechanism of self-destruction that involves mitochondria, but this mechanism fails in cancer cells.

The potential use of DCA in vivo is complicated by its poor bioavailability and limited ability to penetrate to its target in the mitochondria.[14]

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,[15] found that DCA restored mitochondrial function, thus restoring apoptosis, allowing cancer cells to self-destruct and shrink the tumor.[16]

These results received extensive media attention, beginning with an article in New Scientist titled "Cheap, 'safe' drug kills most cancers".[15] Subsequently, the American Cancer Society and other medical organizations have received a large volume of public interest and questions regarding DCA.[17] 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.[17][18]

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.[19]

Five patients with primary GBM were entered into a phase II trial. Three had not responded to several chemotherapies and were 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.[19]

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.[19]

DCA was associated with tumor regression and had a good safety profile. DCA side effects were minimal.[19]

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[20] and has been used in the treatment of canine and human lactic acidosis, some who presented at the beginning of treatment with cancer.

Published Evidence for Human Efficacy

Several publications demonstrate the effectiveness of DCA as an anti-cancer therapy: A case report of a patient with a leg tumour and liver metastases (possible sarcoma, officially classified as unknown primary tumour)[21] A case report of complete remission of a rare kidney cancer with DCA therapy following palliative radiation[22] A case series of 3 patients with various cancers who responded to intravenous DCA[23] A case report of a patient with lymphoma who had complete remission of the cancer with DCA [24] A case report of a patient with cholangiocarcinoma who responded to DCA with an antacid and an estrogen blocker. [25]

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."[26]

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.[27] 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.[27]

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",[28] DCA is generally well tolerated, even in children.[29] Short-term, infused, bolus doses of DCA at 50 mg/kg/day have been well tolerated.[30]

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.[7][28]

Studies have also shown that it can be carcinogenic in male B6C3F1 mice at high doses.[31]

Neuropathy

A clinical trial where DCA was given to patients with MELAS syndrome (a form of genetically inherited lactic acidosis) at 25 mg/kg/day was ended prematurely due to excessive peripheral nerve toxicity.[32]

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.[33] 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.[34][35] 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.[36]

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.[37]

Dichloroacetate can also have anxiolytic or sedative effects.[6]

Carcinogenicity

The Environmental Protection Agency has listed DCA as likely to be a cancer-causing agent in humans.[38] DCA is on the California Environmental Protection Agency's list of known cancer-causing agents and is listed as a cause of reproductive harm in men.[38][39] The International Agency for Research on Cancer classifies DCA as a Group 2B carcinogen ("possibly carcinogenic to humans").[40]

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.[31] 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.[41]

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.[42][43]

Physicians 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.[44]

References

  1. ^ a b c d Haynes, William M., ed. (2011). CRC Handbook of Chemistry and Physics (92nd ed.). Boca Raton, Florida: CRC Press. ISBN 1-4398-5511-0.
  2. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016.2Fj.str.2007.07.001, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016.2Fj.str.2007.07.001 instead.
  3. ^ "Dichloracetate (DCA)". American Cancer Society. Retrieved 1 December 2012.
  4. ^ J.T. Baker MSDS
  5. ^ http://paradigmslip.ca/references/uhm_phd_7810263_r.pdf
  6. ^ a b Stacpoole P, Henderson G, Yan Z, James M (1998). "Clinical pharmacology and toxicology of dichloroacetate". Environ Health Perspect. 106 Suppl 4: 989–994. doi:10.2307/3434142. JSTOR 3434142. PMC 1533324. PMID 9703483.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ a b Stacpoole PW (1989). "The pharmacology of dichloroacetate". Metabolism. 38 (11): 1124–1144. doi:10.1016/0026-0495(89)90051-6. PMID 2554095.
  8. ^ Stacpoole P, Lorenz A, Thomas R, Harman E (1988). "Dichloroacetate in the treatment of lactic acidosis". Ann Intern Med. 108 (1): 58–63. doi:10.7326/0003-4819-108-1-58. PMID 3337517.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  20. ^ T. E. (Thomas Edward) Thorpe. A Dictionary of Applied Chemistry. Vol. 3. Page 9 of 189 at www.ebooksread.com/authors-eng/t-e-thomas-edward-thorpe/a-dictionary-of-applied-chemistry-volume-3-hci/page-9-a-dictionary-of-applied-chemistry-volume-3-hci.shtml
  21. ^ “Use of Oral Dichloroacetate for Palliation of Leg Pain Arising from Metastatic Poorly Differentiated Carcinoma: A Case Report.” Khan A, J Palliat Med. 2011 Apr 12
  22. ^ “Case Report of Long Term Complete Remission of Metastatic Renal Squamous Cell Carcinoma After Palliative Radiotherapy and Adjuvant Dichloroacetate”, Khan A, Advances in Cancer Research and Treatment, Vol 2012 (2012)
  23. ^ A Novel Form of Dichloroacetate Therapy for Patients With Advanced Cancer: A Report of 3 Cases. Khan A, Marier D, Marsden E, Andrews D, Eliaz I., Altern Ther Health Med. 2014 Oct;20(S2):21-28.
  24. ^ Non-Hodgkin's Lymphoma Reversal with Dichloroacetate. Flavin DF. J Oncol. 2010;2010. pii: 414726. doi: 10.1155/2010/414726. Epub 2010 Sep 16.
  25. ^ Co-treatment of dichloroacetate, omeprazole and tamoxifen exhibited synergistically antiproliferative effect on malignant tumors: in vivo experiments and a case report. Ishiguro T1, Ishiguro R, Ishiguro M, Iwai S. Hepatogastroenterology. 2012 Jun;59(116):994-6.
  26. ^ "Editorial: Gambling with your life", New Scientist, 31 March 2007
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  28. ^ a b Picard, André (2007-01-17). "Long-used drug shows new promise for cancer". Toronto: The Globe and Mail. Retrieved 2007-01-17.
  29. ^ Pearson H; Kurtz, TL; Han, Z; Langaee, T (2008). "Role of dichloroacetate in the treatment of genetic mitochondrial diseases". Adv Drug Deliv Rev. 60 (13, 14): 1478–1487. doi:10.1016/j.addr.2008.02.014. PMC 3746325. PMID 18647626.
  30. ^ Agbenyega T, Planche T, Bedu-Addo G, Ansong D, Owusu-Ofori A, Bhattaram VA, Nagaraja NV, Shroads AL, Henderson GN, Hutson AD, Derendorf H, Krishna S, Stacpoole PW (2003). "Population kinetics, efficacy, and safety of dichloroacetate for lactic acidosis due to severe malaria in children". J Clin Pharmacol. 43 (4): 386–396. doi:10.1177/0091270003251392. PMID 12723459.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ^ a b DeAngelo AB, Daniel FB, Stober JA, Olson GR (1991). "The carcinogenicity of dichloroacetic acid in the male B6C3F1 mouse". Fundam Appl Toxicol. 16 (2): 337–347. doi:10.1016/0272-0590(91)90118-N. PMID 2055364.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  32. ^ Kaufmann P; Engelstad K; Wei Y; et al. (2006). "Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial". Neurology. 66 (3): 324–330. doi:10.1212/01.wnl.0000196641.05913.27. PMID 16476929. {{cite journal}}: Unknown parameter |author-separator= ignored (help)
  33. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  37. ^ Felitsyn, N; McLeod, C; Shroads, AL; Stacpoole, PW; Notterpek, L (2008). "The heme precursor delta-aminolevulinate blocks peripheral myelin formation". Journal of Neurochemistry. 106 (5): 2068–2079. doi:10.1111/j.1471-4159.2008.05552.x. PMC 2574579. PMID 18665889.
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  40. ^ Agents Classified by the IARC Monographs, International Agency for Research on Cancer
  41. ^ Caldwell JC, Keshava N (September 2006). "Key issues in the modes of action and effects of trichloroethylene metabolites for liver and kidney tumorigenesis". Environ. Health Perspect. 114 (9): 1457–63. doi:10.1289/ehp.8692. PMC 1570066. PMID 16966105.
  42. ^ Pearson, Helen (2007). "Cancer patients opt for unapproved drug". Nature. 446 (7135): 474–475. doi:10.1038/446474a. PMID 17392750.
  43. ^ Interview: Would you try an untested cancer drug?, New Scientist, August 15, 2007
  44. ^ Andrea Sands (March 18, 2007). "Experts caution against patients compiling own data on unapproved cancer drug". Edmonton Journal.
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