Dichloroacetic acid

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Dichloroacetic acid
IUPAC name Dichloroacetic acid
Other names Dichloroethanoic acid
Dichloroacetate
Molecular formula CHCl2COOH
Identifiers
CAS number [79-43-6]
PubChem 6597
MeSH Dichloroacetate
RTECS number AG6125000
SMILES ClC(Cl)C(=O)O
Properties
Molar mass 128.9 g/mol
Appearance colorless liquid
Density 1.57 g/ml, liquid
Melting point

13.5 °C
Boiling point

194 °C
Solubility in water miscible
Acidity (pKa) 1.25
Hazards
MSDS MSDS (jtbaker)
NFPA 704

1
3
0
 
R-phrases R35, R50
S-phrases S1/2, S26, S45, S61
Related Compounds
Related chloroacetic acids Chloroacetic acid
Trichloroacetic acid
Related compounds Acetic acid
Difluoroacetic acid
Dibromoacetic acid
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)
Infobox disclaimer and references

Dichloroacetic acid (systematic name dichloroethanoic acid) is an analogue of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms. It is prepared by the reduction of trichloroacetic acid.

Dichloroacetic acid (DCA) shares the same acronym as its conjugate base, dichloroacetate. The conjugate base is the form used for therapy.

Contents

[edit] Chemistry

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 a strong acid with a pKa of 1.3,[1] pure dichloroacetic acid is very corrosive and extremely destructive to tissues of the mucous membranes and upper respiratory tract.[2]

[edit] Therapeutic use

[edit] Lactic acidosis

The dichloroacetate ion stimulates the activity of the enzyme pyruvate dehydrogenase by inhibiting the enzyme pyruvate dehydrogenase kinase.[3] 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.[4][5][6][7]

A randomized controlled trial in children with congenital lactic acidosis found that while DCA was well-tolerated, it was ineffective in improving clinical outcomes.[5] A separate trial of DCA in children with MELAS (a syndrome of inadequate mitochondrial function, leading to lactic acidosis) was halted early as 15 out of 15 of the children receiving DCA experienced significant nerve toxicity without any evidence of benefit from the medication.[6] 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.[7]

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 due to progressive toxicities.

[edit] Potential cancer applications

Cancer cells generally use glycolysis rather than oxidation for energy (the Warburg effect) as a result of hypoxia in tumors and damaged mitochondria.[8] The body often kills damaged cells by 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,[9] 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.[10]

These results received extensive media attention, beginning with an article in New Scientist entitled "Cheap, Safe Drug Kills Most Cancers".[11] Subsequently, the American Cancer Society and other medical organizations have received a large volume of public interest and questions regarding DCA.[12] Reports have since pointed out that although the study results are promising, no clinical trials in humans with cancer have yet been conducted, emphasizing the need for caution in interpreting the preliminary results.[12][13]

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."[14]

The historical likelihood that a promising agent in pre-clinical (i.e., cell-line killing) trials will become an effective human cancer drug is 5%, and the likelihood of an FDA approval for any given drug entering Phase I testing is reportedly 8-11%.[15][16] Dichloroacetic acid had not entered Phase I testing for use as a cancer agent as of February, 2007.

DCA is a non-patentable molecule. Concerns have therefore been raised that without pharmaceutical industry interest, trials of DCA may not be funded.[12][11][13][17] 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).

[edit] Adverse 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",[18] but the limited scholarly literature suggests side effects of pain, numbness and gait disturbances in some patients.[18] 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.[19] Dichloroacetate can also have anxiolytic or sedative effects.[20]

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.[21] 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.[22][23] 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.[24]

[edit] Self-medication

Doctors warned of potential problems if people attempts 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.[25]

The most prominent web site promoting self-medication with DCA is thedcasite.com, according to the New Scientist.[26] At least eight contributors to the chatroom claimed to be taking DCA or giving it to a close relative, including an anonymous 48-year-old physician with an undisclosed cancer that was spreading from his thigh to his lungs. The physician started taking DCA on 27 February, but was disappointed after the lung tumors grew larger and more active. On 21 March he stopped taking DCA because of adverse effects, but the adverse effects continued to develop, and on 24 March he developed numbness in his hands, which he believed were a sign of neuropathy, and a hypoglycemic attack. He advises people not to medicate except under medical supervision.

The chat participants were swapping tips on how to get DCA, how to prepare it for human consumption, and what supplements they should be taking to minimise side effects, according to the New Scientist. The site was founded by Jim Tassano, who operates a pest-control company in Sonora, California, and also founded another site, buydca.com, which offers to sell DCA for treatment of cancer "in animals." Because DCA has not been approved for human use, it is illegal for a web site to sell it for human or animal consumption in the US, said special agent Phil Walsky of the US Food and Drug Administration's Office of Criminal Investigations, which is investigating the two sites. DCA has never been approved for veterinary use either. Sigma-Aldrich recently restricted sales of DCA. However, DCA is a widely used laboratory chemical that can be ordered from thousands of companies.

[edit] References

  1. ^ U.S. Patent 6011173 
  2. ^ MSDS (jtbaker)
  3. ^ Stacpoole P (1989). "The pharmacology of dichloroacetate". Metabolism 38 (11): 1124-44. PMID 2554095. 
  4. ^ 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. 
  5. ^ a b 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. PMID 16651305. 
  6. ^ a b 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. PMID 16476929. 
  7. ^ a b 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. PMID 1435883. 
  8. ^ 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. 
  9. ^ depmed.ualberta.ca
  10. ^ 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. PMID 17222789. 
  11. ^ a b Cheap, safe drug kills most cancers. New Scientist (2007-01-17). Retrieved on January 17, 2007.
  12. ^ a b c "DCA: Cancer Breakthrough or Urban Legend?". From ABC News, 5 February 2007. Accessed 15 Feb 2007.
  13. ^ a b "No Wonder Drug", letter to New Scientist from Ralph Moss Lemont. Published February 3, 2007. Accessed 16 Feb 2007.
  14. ^ "Editorial: Gambling with your life", New Scientist, 31 March 2007
  15. ^ Food&Drug Packaging, August, 2004
  16. ^ Nature Reviews Drug Development, August 2004
  17. ^ "Small molecule offers big hope against cancer", by Ryan Smith. From ExpressNews, a University of Alberta publication. Published January 16, 2007. Accessed 15 Feb 2007.
  18. ^ a b "Long-used drug shows new promise for cancer", The Globe and Mail, 2007-01-17. Retrieved on January 17, 2007.
  19. ^ 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. PMID 16476929. 
  20. ^ Stacpoole P, Henderson G, Yan Z, James M (1998). "Clinical pharmacology and toxicology of dichloroacetate". Environ Health Perspect 106 Suppl 4: 989–94. PMID 9703483.  Free full text
  21. ^ 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. PMID 2318357. 
  22. ^ 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. PMID 8582409. 
  23. ^ 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. PMID 11410919. 
  24. ^ 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. 
  25. ^ Andrea Sands. "Experts caution against patients compiling own data on unapproved cancer drug", Edmonton Journal, March 18, 2007.
  26. ^ Cancer therapy: When all else fails, Linda Geddes. New Scientist (28 March 2007).

[edit] External links

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