Dichloroacetic acid

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Dichloroacetic acid
File:Dichloroacetic-acid-2D-skeletal.png
File:Dichloroacetic-acid-3D-vdW.png
IUPAC name
Dichloroacetic acid
Other names
Dichloroethanoic acid
style="background: #F8EABA; text-align: center;" colspan="2" | Identifiers
CAS number 79-43-6 YesY
PubChem 6597
MeSH Dichloroacetate
RTECS number AG6125000
SMILES Script error: No such module "collapsible list".
style="background: #F8EABA; text-align: center;" colspan="2" | Properties
Molecular formula C2H2Cl2O2
Molar mass 128.94 g/mol
Appearance colorless liquid
Density 1.5634 g/cm3 (20 °C)
Melting point

9-11 °C

Boiling point

194 °C

Solubility in water miscible
Solubility miscible with ethanol, diethyl ether[1]
Acidity (pKa) 1.25[2]
style="background: #F8EABA; text-align: center;" colspan="2" | Thermochemistry
Std enthalpy of
formation ΔfHo298 		-496.3 kJ·mol-1[3]
style="background: #F8EABA; text-align: center;" colspan="2" | Hazards
MSDS MSDS (jtbaker)
R-phrases R35, R50
S-phrases (S1/2), S26, S45, S61
NFPA 704
1
3
0
style="background: #F8EABA; text-align: center;" colspan="2" | Related compounds
Related chloroacetic acids Chloroacetic acid
Trichloroacetic acid
Related compounds Acetic acid
Difluoroacetic acid
Dibromoacetic acid
 YesY (what is this?)  (verify)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Dichloroacetic acid, often abbreviated DCA, is the chemical compound with formula CHCl2COOH. It is an acid, an analogue of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms.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 are used as drugs since they inhibit the enzyme pyruvate dehydrogenase kinase.

Early reports of its activity against brain cancer cells led patients to treat themselves with DCA, which is commercially available in non-pharmaceutical grade. A phase 1 study in 5 patients concluded that DCA was safe, but wasn't designed to establish effectiveness.[4][5]

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 dissolved in water. As an acid with a pKa of 1.48,[6] pure dichloroacetic acid is very corrosive and extremely destructive to tissues of the mucous membranes and upper respiratory tract.[7]

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.[8] 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.[9] 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.[10][11][12][13]

A randomized controlled trial in children with congenital lactic acidosis found that while DCA was well tolerated, it was ineffective in improving clinical outcomes.[11] 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.[12] 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.[13]

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 glycolysis rather than respiration (oxidative phosphorylation) for energy (the Warburg effect), as a result of hypoxia that exists in tumors and damaged mitochondria.[14] Usually dangerously damaged cells kill themselves via apoptosis, a mechanism of self-destruction that involves mitochondria, but this mechanism fails in cancer cells.

A study published in January 2007 by researchers at the University of Alberta,[15] 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.[16]

These results received extensive media attention, beginning with an article in New Scientist titled "Cheap, ‘safe’ drug kills most cancers".[17] Subsequently, the American Cancer Society and other medical organizations have received a large volume of public interest and questions regarding DCA.[18] Reports have since pointed out that although the study results are promising, no formal clinical trials in humans with cancer have yet been conducted in the USA and are not yet final in Canada, emphasizing the need for caution in interpreting the preliminary results.[18][19]

Some doctors are treating cancer using DCA "off-label",[20][21] which generates controversy in some circles.[20] The off-label use of prescription drugs is common practice for cancer patients at the most prestigious medical institutions in the world, especially those diagnosed with cancers designated as orphan diseases, for which very few government-approved therapies are available.

Akbar and Humaira Khan have since March 2007 treated cancer patients using DCA off-label at their private clinic, Medicor Cancer Centres, in Toronto.[22] They have treated several types of cancer and said on their web site that some patients "are showing varied positive responses to DCA including tumour shrinkage, reduction in tumour markers, symptom control, and improvement in lab tests".[21] Although they have not published their results nor reported it at medical conferences, they have uploaded details of patient responses and overall statistics on their web site.[23] Significantly, by combining DCA with traditional chemotherapy, at least two patients have purportedly experienced complete remission of metastatic cancer[24], a response that is extremely atypical with chemotherapy alone.

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.[25] Dr. Polevoy himself is not an oncologist, but a medical doctor who runs an acne clinic in Kitchener, Ontario, as well as a web site devoted to exposing what he considers self-promotion and self-described "quack remedies" called Healthwatcher.net.[26]

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."[27]

Edit: The following sentence is broken. Recently it has been found in vitro that DCA during hypoxia (the goal of many anticancer drugs as cetuximab and bevacizumab (Avastin)) enhanced the growth of colorectal cancer tumors [28]. Thus, in some cancer types and in combination with other potential anticancer drugs, DCA treatment can induce tumor growth and thereby be fatal for cancer patients.

DCA has been used historically to treat patients with lactic acidosis, and therefore could arguably enter phase 2 trials in patients with cancer.[29]

DCA is non-patentable as a compound, though a patent has been filed for its use in cancer treatment.[30] 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 drug development is reduced, and therefore clinical trials of DCA may not be funded.[17][18][19][31] 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.[32] 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.[33][34]

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.[35] This initial trial is relatively small with enrollment of up to 50 patients.

When faced with the high costs of getting Food and Drug Administration approval, estimated by Tufts University to exceed one billion dollars [36], the chance of getting DCA approved for the treatment of cancer in the United States is extremely low. This problem is highlighted in the 2007 New York Times article by Ralph Moss titled "Patents over Patients" [37].

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",[38] but the limited scholarly literature suggests side effects of pain, numbness and gait disturbances in some patients.[38] 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.[39] Dichloroacetate can also have anxiolytic or sedative effects.[8]

DCA is generally well-tolerated, even in children.[40] However, at sustained, higher doses (generally 25 mg/kg/day taken orally, or greater), there is increased risk of several reversible toxicities, especially peripheral neuropathy,[41] neurotoxicity, and gait disturbance.

Doses of 5 mg/kg every three days limits effects from toxicity while maintaining adequate progress, according to a private cancer treatment clinic.[42]

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.[43] 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.[44][45] 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.[46]

Short-term, infused, bolus doses of DCA at 50 mg/kg/day have been well-tolerated[47]. Long term use (a year or more) of high doses of DCA has been shown to increase risk of liver cancer in mice, however the dosages required for carcinogenicity (> 77 mg/kg/day) are significantly higher than suggested therapeutic doses in humans.[48] 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 at dosages much higher than used for cancer therapy.[49]

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. ([1])

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.[50][51]

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.[52]

References

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External links

fr:Acide dichloroacétique it:Acido dicloroacetico nl:Dichloorazijnzuur ja:ジクロロ酢酸 pl:Kwas dichlorooctowy pt:Ácido dicloroacético ru:Дихлоруксусная кислота

sv:Diklorättiksyra
  1. ↑ Lide, David R. (1998). Handbook of Chemistry and Physics (87 ed.). Boca Raton, FL: CRC Press. pp. 3–164. ISBN 0849305942. 
  2. ↑ Lide, David R. (1998). Handbook of Chemistry and Physics (87 ed.). Boca Raton, FL: CRC Press. p. 1278. ISBN 0849305942. 
  3. ↑ Lide, David R. (1998). Handbook of Chemistry and Physics (87 ed.). Boca Raton, FL: CRC Press. pp. 5–30. ISBN 0849305942. 
  4. ↑ Matthew G. Vander Heiden, Editorial:Brain Cancer Targeting Cell Metabolism in Cancer Patients, Sci Transl Med 12 May 2010 2:31ed1
  5. ↑ Metabolic Modulation of Glioblastoma with Dichloroacetate E. D. Michelakis et al., Sci Transl Med 12 May 2010: Vol. 2, Issue 31, p. 31ra34 DOI: 10.1126/scitranslmed.3000677
  6. ↑ Lide, D. R. (Ed.) (1990). CRC Handbook of Chemistry and Physics (70th Edn.). Boca Raton (FL):CRC Press.
  7. ↑ MSDS (jtbaker)
  8. ↑ 8.0 8.1 Stacpoole P, Henderson G, Yan Z, James M (1998). "Clinical pharmacology and toxicology of dichloroacetate". Environ Health Perspect. Environmental Health Perspectives, Vol. 106. 106 Suppl 4: 989–94. doi:10.2307/3434142. PMC 1533324 Freely accessible. PMID 9703483.  Free full text
  9. ↑ Stacpoole P (1989). "The pharmacology of dichloroacetate". Metabolism. 38 (11): 1124–44. doi:10.1016/0026-0495(89)90051-6. PMID 2554095. 
  10. ↑ Stacpoole P, Lorenz A, Thomas R, Harman E (1988). "Dichloroacetate in the treatment of lactic acidosis". Ann Intern Med. 108 (1): 58–63. PMID 3337517. 
  11. ↑ 11.0 11.1 Stacpoole P, Kerr D, Barnes C, Bunch S, Carney P, Fennell E, Felitsyn N, Gilmore R, Greer M, Henderson G, Hutson A, Neiberger R, O'Brien R, Perkins L, Quisling R, Shroads A, Shuster J, Silverstein J, Theriaque D, Valenstein E (2006). "Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children". Pediatrics. 117 (5): 1519–31. doi:10.1542/peds.2005-1226. PMID 16651305. 
  12. ↑ 12.0 12.1 Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano M, Shungu D, Millar W, Hong X, Gooch C, Mao X, Pascual J, Hirano M, Stacpoole P, DiMauro S, De Vivo D (2006). "Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial". Neurology. 66 (3): 324–30. doi:10.1212/01.wnl.0000196641.05913.27. PMID 16476929. 
  13. ↑ 13.0 13.1 Stacpoole P, Wright E, Baumgartner T, Bersin R, Buchalter S, Curry S, Duncan C, Harman E, Henderson G, Jenkinson S (1992). "A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group". N Engl J Med. 327 (22): 1564–9. doi:10.1056/NEJM199211263272204. PMID 1435883. 
  14. ↑ Xu R, Pelicano H, Zhou Y, Carew J, Feng L, Bhalla K, Keating M, Huang P (2005). "Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia". Cancer Res. 65 (2): 613–21. PMID 15695406. 
  15. ↑ depmed.ualberta.ca
  16. ↑ 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 (2007). "A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth". Cancer Cell. 11 (1): 37–51. doi:10.1016/j.ccr.2006.10.020. PMID 17222789. 
  17. ↑ 17.0 17.1 "Cheap, 'safe' drug kills most cancers". New Scientist. 2007-01-17. Retrieved 2007-01-17. 
  18. ↑ 18.0 18.1 18.2 "DCA: Cancer Breakthrough or Urban Legend?". From ABC News, 5 February 2007. Accessed 15 February 2007.
  19. ↑ 19.0 19.1 "No Wonder Drug", letter to New Scientist from Ralph Moss Lemont. Published February 3, 2007. Accessed 16 February 2007.
  20. ↑ 20.0 20.1 http://www.nationalreviewofmedicine.com/issue/poll/featured_article.html
  21. ↑ 21.0 21.1 Medicor Cancer Centres – DCA Therapy
  22. ↑ http://www.medicorcancer.com/NatPost-may28_2007.pdf
  23. ↑ http://www.medicorcancer.com/DCAtherapy.html
  24. ↑ http://www.medicorcancer.com/dca-data.html
  25. ↑ "Doctors prescribe DCA to cancer patients". Retrieved 2007-10-08. 
  26. ↑ http://www.healthwatcher.net
  27. ↑ "Editorial: Gambling with your life", New Scientist, 31 March 2007
  28. ↑ http://www.cancerletters.info/article/S0304-3835(10)00251-X/fulltext
  29. ↑ A Letter from Dr. Evangelos Michelakis
  30. ↑ "CTV.ca: Researchers launch website on new cancer research". Retrieved 2007-10-08. 
  31. ↑ "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.
  32. ↑ Official University of Alberta DCA Site
  33. ↑ Researchers launch website on new cancer research, CTV.ca, 22 January 2007
  34. ↑ A Method of Treating Cancer Using Dichloroacetate, Application to the European Patent Office, 19 October 2006
  35. ↑ http://www.depmed.ualberta.ca/dca/letter_092407.pdf DCA Update: Health Canada Approves First DCA Clinical Trial in Cancer, 24 September 2007
  36. ↑ http://csdd.tufts.edu/InfoServices/OutlookPDFs/Outlook2008.pdf
  37. ↑ Moss, Ralph W. (1 April 2007). "Patents Over Patients". The New York Times. Retrieved 1 May 2010. 
  38. ↑ 38.0 38.1 "Long-used drug shows new promise for cancer". The Globe and Mail. 2007-01-17. Retrieved 2007-01-17. 
  39. ↑ Kaufmann P, Engelstad K, Wei Y; et al. (2006). "Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial". Neurology. 66 (3): 324–30. doi:10.1212/01.wnl.0000196641.05913.27. PMID 16476929. 
  40. ↑ 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. PMID 18647626. 
  41. ↑ Stacpoole PW (1989). "The pharmacology of dichloroacetate". Metabolism. 38 (11): 1124–44. doi:10.1016/0026-0495(89)90051-6. PMID 2554095. 
  42. ↑ http://www.medicorcancer.com/dca-data.html
  43. ↑ 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. 
  44. ↑ Kurlemann G, Paetzke I, Moller H, Masur H, Schuierer G, Weglage J, Koch HG (1995). "Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy". Eur J Pediatr. 154 (11): 928–32. doi:10.1007/BF01957508. PMID 8582409. 
  45. ↑ Spruijt L, Naviaux RK, McGowan KA, Nyhan WL, Sheean G, Haas RH, Barshop BA (2001). "Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate". Muscle Nerve. 24 (7): 916–24. doi:10.1002/mus.1089. PMID 11410919. 
  46. ↑ Oishi K, Yoshioka M, Ozawa R, Yamamoto T, Oya Y, Ogawa M, Kawai M (2003). "Dichloroacetate treatment for adult patients with mitochondrial disease". Rinsho Shinkeigaku. 43 (4): 154–61. PMID 12892050. 
  47. ↑ 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. 
  48. ↑ 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. 
  49. ↑ Environ Health Perspect. 2006 Sep;114(9):1457-63 PMID 16966105 (free full text)
  50. ↑ http://www.nature.com/nature/journal/v446/n7135/full/446474a.html
  51. ↑ http://www.newscientist.com/article/mg19526171.600
  52. ↑ Andrea Sands (March 18, 2007). "Experts caution against patients compiling own data on unapproved cancer drug". Edmonton Journal. 
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