Dichloroacetic acid

From Wikipedia, the free encyclopedia
  (Redirected from Dichloroacetate)
Jump to: navigation, search
Dichloroacetic acid
Dichloroacetic-acid-2D-skeletal.png Dichloroacetic-acid-3D-vdW.png
Identifiers
CAS number 79-43-6 YesY
PubChem 6597
ChemSpider 10771217 YesY
UNII 9LSH52S3LQ YesY
DrugBank DB08809
KEGG C11149 YesY
MeSH Dichloroacetate
ChEBI CHEBI:36386 YesY
ChEMBL CHEMBL13960 YesY
RTECS number AG6125000
Jmol-3D images Image 1
Properties
Molecular formula C2H2Cl2O2
Molar mass 128.94 g mol−1
Appearance Colorless liquid
Density 1.5634 g/cm3 (20 °C)
Melting point 9 to 11 °C (48 to 52 °F; 282 to 284 K)
Boiling point 194 °C (381 °F; 467 K)
Solubility in water miscible
Solubility miscible with ethanol, diethyl ether[1]
Acidity (pKa) 1.35[1]
Thermochemistry
Std enthalpy of
formation
ΔfHo298
-496.3 kJ·mol-1[1]
Hazards
MSDS MSDS (jtbaker)
R-phrases R35 R50
S-phrases (S1/2) S26 S45 S61
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oil Health code 3: Short exposure could cause serious temporary or residual injury. E.g., chlorine gas Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
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 (77 °F), 100 kPa)
 YesY (verify) (what is: YesY/N?)
Infobox references

Dichloroacetic acid, often abbreviated DCA, is the chemical compound with formula CHCl
2
COOH
. It is an acid, an analogue of acetic acid, in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms.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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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 and antacid and and estrogen blocker. [25]

Concerns about pre-trial use[edit]

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]

Planned and ongoing clinical trials[edit]

DCA is not a novel substance so a composition of matter patent cannot be granted. However, several method of use patent applications have been filed for its use in cancer treatment.[28][29] Some of these applications were never prosecuted, but at least one has been granted.[30] Research by Evangelos Michelakis has received no support from the pharmaceutical industry.[31] Concerns have been raised that without strong intellectual property protection, the financial incentive for drug development is reduced, and therefore obtaining sufficient funds to conduct clinical trials presents difficulty.[15][17][18][32] 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, Michelakis's lab took the unorthodox step of directly soliciting online donations to fund the research.[33] After 6 months, his lab had raised over $800,000, enough to fund a small Clinical Phase 2 study.

On 24 September 2007, the University of Alberta's Department of Medicine 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.[34] This initial trial was relatively small with enrollment of up to 50 patients. The trial was completed in August 2009.[35] In May 2010 the team published a press release[36] stating no conclusions could be drawn as a result of the trial. A paper describing the results was published[19] but not linked from the press release. Only five patients had been treated with the drug during the trial.

In May 2011, online reports[37] suggested that the Alberta group had released new data which the media "had not reported". However, this appeared to be caused by confusion between dates (the previous update was May 2010[38]) and cancer charities moved quickly to counter these rumours,[39][40] which were subsequently covered in New Scientist magazine.[41]

Side effects[edit]

Reports in the lay press after the 2007 University of Alberta announcement claim that dichloroacetate "has actually been used safely in humans for decades",[42] DCA is generally well tolerated, even in children.[43] Short-term, infused, bolus doses of DCA at 50 mg/kg/day have been well tolerated.[44]

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][42]

Studies have also shown that it can be carcinogenic in male B6C3F1 mice at high doses.[45]

Neuropathy[edit]

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.[46]

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.[47] 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.[48][49] 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.[50]

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.[51]

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

Carcinogenicity[edit]

The Environmental Protection Agency has listed DCA as likely to be a cancer-causing agent in humans.[52] 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.[52][53] The International Agency for Research on Cancer classifies DCA as a Group 2B carcinogen ("possibly carcinogenic to humans").[54]

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.[45] 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.[55]

Self-medication[edit]

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.[56][57]

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.[58]

References[edit]

  1. ^ a b c d Haynes, William M., ed. (2011). CRC Handbook of Chemistry and Physics (92nd ed.). Boca Raton, FL: CRC Press. ISBN 1439855110. 
  2. ^ Kato, M.; Li, J.; Chuang, J. L.; Chuang, D. T. (2007). "Distinct Structural Mechanisms for Inhibition of Pyruvate Dehydrogenase Kinase Isoforms by AZD7545, Dichloroacetate, and Radicicol". Structure 15 (8): 992–1004. doi:10.1016/j.str.2007.07.001. PMC 2871385. PMID 17683942.  edit
  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. 
  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. 
  9. ^ 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): 1519–1531. doi:10.1542/peds.2005-1226. PMID 16651305. 
  10. ^ 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): 324–330. doi:10.1212/01.wnl.0000196641.05913.27. PMID 16476929. 
  11. ^ 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): 1564–1569. doi:10.1056/NEJM199211263272204. PMID 1435883. 
  12. ^ 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. 
  13. ^ Kim JW, Dang CV (2006). "Cancer's molecular sweet tooth and the Warburg effect". Cancer Res. 66 (18): 8927–8930. doi:10.1158/0008-5472.CAN-06-1501. PMID 16982728. 
  14. ^ Rakesh K. Pathak, Sean Marrache, Donald A. Harn, and Shanta Dhar. "Mito-DCA: A Mitochondria Targeted Molecular Scaffold for Efficacious Delivery of Metabolic Modulator Dichloroacetate". ACS Chem. Biol. doi:10.1021/cb400944y. 
  15. ^ a b c "Cheap, ‘safe’ drug kills most cancers". New Scientist. 2007-01-17. Retrieved 2007-01-17. 
  16. ^ Bonnet, Sébastien; Archer, Stephen L.; Allalunis-Turner, Joan; Haromy, Alois; Beaulieu, Christian; Thompson, Richard; Lee, Christopher T.; Lopaschuk, Gary D. et al. (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. ^ a b c "DCA: Cancer Breakthrough or Urban Legend?" From ABC News, 5 February 2007. Accessed 15 February 2007.
  18. ^ a b "No Wonder Drug", letter to New Scientist from Ralph Moss Lemont. Published February 3, 2007. Accessed 16 February 2007.
  19. ^ a b c d e Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC. (2010). "Metabolic Modulation of Glioblastoma with Dichloroacetate". Sci Transl Med 2 (31): 31ra34–31ra34. doi:10.1126/scitranslmed.3000677. PMID 20463368. 
  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
  27. ^ a b Shahrzad, Siranoush; Lacombe, Kristen; Adamcic, Una; Minhas, Kanwal; Coomber, Brenda L. (November 2010). "Sodium dichloroacetate (DCA) reduces apoptosis in colorectal tumor hypoxia". Cancer Letters 297 (1): 75–83. doi:10.1016/j.canlet.2010.04.027. PMID 20537792. 
  28. ^ "CTV.ca: Researchers launch website on new cancer research". CTV News. 
  29. ^ A Method of Treating Cancer Using Dichloroacetate, Application to the European Patent Office, 19 October 2006
  30. ^ US 8071645, Newell, M. Karen; Newell, Evan & Villalobos-Menuey, Elizabeth, "Systems and methods for treating human inflammatory and proliferative diseases and wounds, with fatty acid metabolism inhibitors and/or glycolytic inhibitors" 
  31. ^ "CTV.ca: Small molecule offers hope for cancer treatment". CTV News. Retrieved 21 April 2012. 
  32. ^ "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.
  33. ^ Official University of Alberta DCA Site
  34. ^ http://www.dca.med.ualberta.ca/Home/Updates/letter_092407.pdf, 24 September 2007
  35. ^ The Safety and Efficacy of DCA for the Treatment of Brain Cancer, ClinicalTrials.gov identifier: NCT00540176
  36. ^ Outlook 2008, Tufts Center for the Study of Drug Development
  37. ^ The Cure for Cancer Has Been Found and is Purposely Being Ignored - Technorati blog (accessed 16/05/2011)
  38. ^ DCA Research Team publishes results of Clinical Trials - University of Alberta website
  39. ^ Potential cancer drug DCA tested in early trials - Cancer Research UK science blog
  40. ^ @CR_UK tweet - tweeted 16/05/11
  41. ^ Cancer drug resurfaces and threatens false optimism - New Scientist, 16 May 2011
  42. ^ a b Picard, André (2007-01-17). "Long-used drug shows new promise for cancer". Toronto: The Globe and Mail. Retrieved 2007-01-17. 
  43. ^ 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. 
  44. ^ 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. 
  45. ^ 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. 
  46. ^ 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. 
  47. ^ 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. 
  48. ^ 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. 
  49. ^ 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. 
  50. ^ 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. 
  51. ^ 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. 
  52. ^ a b "Dichloroacetate (DCA)". American Cancer Society. 
  53. ^ "Chemicals Known to the State to Cause Cancer or Reproductive Toxicity". California Environmental Protection Agency. January 31, 2014. 
  54. ^ Agents Classified by the IARC Monographs, International Agency for Research on Cancer
  55. ^ 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. 
  56. ^ Pearson, Helen (2007). "Cancer patients opt for unapproved drug". Nature 446 (7135): 474–475. doi:10.1038/446474a. PMID 17392750. 
  57. ^ Interview: Would you try an untested cancer drug?, New Scientist, August 15, 2007
  58. ^ Andrea Sands (March 18, 2007). "Experts caution against patients compiling own data on unapproved cancer drug". Edmonton Journal. 

External links[edit]