Dichloroacetic acid
Overview
Dichloroacetic acid, often abbreviated DCA, is a chemical compound, an acid, and an analogue of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms.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. The salts are under investigation as a possible treatment for cancer.
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,[1] pure dichloroacetic acid is very corrosive and extremely destructive to tissues of the mucous membranes and upper respiratory tract.[2]
DCA does not occur in nature. It is a product of the chlorination of water and is produced by the metabolism of various chlorine-containing drugs or chemicals.[3] 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.[4] 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.[5][6][7][8]
A randomized controlled trial in children with congenital lactic acidosis found that while DCA was well tolerated, it was ineffective in improving clinical outcomes.[6] 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.[7] 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.[8]
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 oxidation for energy (the Warburg effect), as a result of hypoxia that exists in tumors and damaged mitochondria.[9] The body often kills damaged cells by 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,[10] 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.[11]
These results received extensive media attention, beginning with an article in New Scientist titled "Cheap, Safe Drug Kills Most Cancers".[12] Subsequently, the American Cancer Society and other medical organizations have received a large volume of public interest and questions regarding DCA.[13] Reports have since pointed out that although the study results are promising, no formal clinical trials in humans with cancer have yet been conducted, emphasizing the need for caution in interpreting the preliminary results,[13][14] though some doctors are treating patients with DCA "off-label," [15][16] and under a cloud of controversy.[17] 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[18] 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."[16] 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.[19]
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."[20]
More than 90% of drugs entering phase I trials are found unacceptable.[21] The FDA approves 8-11% of drugs entering Phase I testing.[22][23] DCA has been used historically to treat patients with lactic acidosis, and therefore could arguably enter phase 2 trials in patients with cancer.[24]
DCA is non-patentable as a compound, though a patent has been filed for its use in cancer treatment.[25] 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.[13][12][14][26] 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.[27]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.[28][29]
On 24th 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.[30] 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",[31] but the limited scholarly literature suggests side effects of pain, numbness and gait disturbances in some patients.[31] 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.[32] Dichloroacetate can also have anxiolytic or sedative effects.[3]
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]
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.[37]
Self-medication
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.[38]
Two websites founded by Jim Tassano, an operator at a pest-control company in Sonora, California, claim to promote information about DCA and its potential benefits for pets and humans. TheDCASite.com aims “to be the meeting place, for the world, where all important information on DCA is gathered and shared". The second website, BuyDCA.com, manufactured and sold DCA to the public until the FDA ordered the site to cease production and sales of the compound.[39] According to Phil Walsky, an FDA special agent who investigated the two websites, it is illegal to sell DCA online for human or animal consumption in the US because it has not been approved for such uses.[40]
References
- ↑ Lide, D. R. (Ed.) (1990). CRC Handbook of Chemistry and Physics (70th Edn.). Boca Raton (FL):CRC Press.
- ↑ MSDS (jtbaker)
- ↑ 3.0 3.1 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
- ↑ Stacpoole P (1989). "The pharmacology of dichloroacetate". Metabolism. 38 (11): 1124–44. PMID 2554095.
- ↑ 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.
- ↑ 6.0 6.1 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. PMID 16651305.
- ↑ 7.0 7.1 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. PMID 16476929.
- ↑ 8.0 8.1 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. PMID 1435883.
- ↑ 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.
- ↑ depmed.ualberta.ca
- ↑ 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.
- ↑ 12.0 12.1 "Cheap, safe drug kills most cancers". New Scientist. 2007-01-17. Retrieved 2007-01-17.
- ↑ 13.0 13.1 13.2 "DCA: Cancer Breakthrough or Urban Legend?". From ABC News, 5 February 2007. Accessed 15 Feb 2007.
- ↑ 14.0 14.1 "No Wonder Drug", letter to New Scientist from Ralph Moss Lemont. Published February 3 2007. Accessed 16 Feb 2007.
- ↑ http://www.nationalreviewofmedicine.com/issue/poll/featured_article.html
- ↑ 16.0 16.1 http://www.medicorcancer.com/DCAtherapy.html
- ↑ http://www.nationalreviewofmedicine.com/issue/poll/featured_article.html
- ↑ http://www.medicorcancer.com/NatPost-may28_2007.pdf
- ↑ "Doctors prescribe DCA to cancer patients". Retrieved 2007-10-08.
- ↑ "Editorial: Gambling with your life", New Scientist, 31 March 2007
- ↑ 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]
- ↑ Food&Drug Packaging, August, 2004
- ↑ Nature Reviews Drug Development, August 2004
- ↑ A Letter from Dr. Evangelos Michelakis
- ↑ "CTV.ca". Retrieved 2007-10-08. Text " Researchers launch website on new cancer research " ignored (help)
- ↑ "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.
- ↑ http://www.depmed.ualberta.ca/dca/
- ↑ Researchers launch website on new cancer research, CTV.ca, 22 January 2007
- ↑ A Method of Treating Cancer Using Dichloroacetate, Application to the European Patent Office, 19 October 2006
- ↑ http://www.depmed.ualberta.ca/dca/letter_092407.pdf DCA Update: Health Canada Approves First DCA Clinical Trial in Cancer, 24th September 2007
- ↑ 31.0 31.1 "Long-used drug shows new promise for cancer". The Globe and Mail. 2007-01-17. Retrieved 2007-01-17.
- ↑ 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.
- ↑ 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&ndash, 37. PMID 2318357.
- ↑ 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&ndash, 32. PMID 8582409.
- ↑ 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&ndash, 24. PMID 11410919.
- ↑ 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&ndash, 61. PMID 12892050.
- ↑ Environ Health Perspect. 2006 Sep;114(9):1457-63 PMID 16966105 (free full text)
- ↑ Andrea Sands (March 18, 2007). "Experts caution against patients compiling own data on unapproved cancer drug". Edmonton Journal.
- ↑ "Illegal 'cancer drug' website shut down, Linda Geddes". New Scientist. 27 July 2007.
- ↑ "Cancer therapy: When all else fails, Linda Geddes". New Scientist. 28 March 2007.
External links
- Template:ICSC
- CTV.ca News Staff (16 January 2007). "Small molecule offers hope for cancer treatment". CTV.ca Website. CTV television network. Retrieved 2007-01-31. Check date values in:
|date=(help) - Evangelos Michelakis and Stephen Archer (22 January 2007). "Researchers launch website on new cancer research". CTV.ca Website. CTV television network. Retrieved 2007-01-31. Check date values in:
|date=(help) - DCA Reseach Information Website (University of Alberta and the Alberta Cancer Board)
- Metabolic Targeting as an Anticancer Strategy: Dawn of a New Era? PDF of a scientific paper by researchers from the University of Toronto, Canada
- Wait for Clinical Trials, New Scientist, 24 February 2007
- Questions over DCA 'cancer drug', by Cancer Research UK
- Dichloroacetate, Huntington's disease, and metabolic disorders
- Cancer Biology - Cramping Tumors Economist, January 18, 2007
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