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Dichloroacetic acidFrom Wikipedia, the free encyclopedia

Dichloroacetic acid

IUPAC name[hide]

Dichloroacetic acid

Other names[hide]

Dichloroethanoic acid

Identifiers

CAS number  79-43-6 

PubChem 6597

ChemSpider  1771!17 

"#$$ 9%S&5!S3%' 

Dru()an*  D)++9

,.. C11149 

/eS& Dichloroacetate

Ch)$ C&)$0363+6 

Ch/)% C&/)%1396 

2CS number  A.61!5

mol-3D ima(e $ma(e 1

SMILES

[ho]

InChI

[ho]

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Diluoroacetic acid

Dibromoacetic acid

Fcept here noted otherieB data are (iGen or material in their tandard

tate =at !5 >C =77 >@?B 1 *Pa?

  =Geri;? =hat i0  < H?

$noboF reerence

Dichloroacetic acid, often abbreviated DCA, is the chemical compound with formula CHCl2CH! "t is an acid, ananalo#ue of acetic acid, in which two of the three hydro#en atoms ofthe methyl #roup have been replaced by chlorineatoms! $he salts and esters of dichloroacetic acid arecalled dichloroacetates! %alts of &C' have been studied as potential dru#s because they inhibitthe en(yme pyruvate dehydro#enase kinase!)2*

 'lthou#h preliminary studies have shown &C' can slow the #rowth of certain tumors in animal

studies and in vitrostudies, +'vailable evidence does not support the use of &C' for cancer treatmentat this time!+)3*

Contents

  )hide*

• 1 Chemistry and occurrence

• 2 $herapeutic uses

o 2!1 actic acidosis

• 3 -otential cancer applications

o 3!1 .esults of phase "" clinical trials

o 3!2 Concerns about pre/trial use

o

3!3 -lanned and on#oin# clinical trials• %ide effects

o !1 europathy

o !2 Carcino#enicity

• %elf/medication

• .eferences

• 4 56ternal links

Chemistry and occurrence[edit]

$he chemistry of dichloroacetic acid is typical for  halo#enated or#anic acids! "t is a member ofthe chloroacetic acidsf amily! $he dichloroacetate ion is produced when the acid is mi6ed with water! 'san acid with a p7a of 1!3,)1* pure dichloroacetic acid is very corrosive and e6tremely destructive to

tissues of the mucous membranes and upper respiratory tract via inhalation!)*

&C' has been shown to occur in nature in at least one seaweed, Asparagopsis taxiformis!)* "t is atrace product of thechlorination of drinkin# water and is produced by the metabolism ofvarious chlorine/containin# dru#s or chemicals!)*&C' is typically prepared bythe reduction of  trichloroacetic acid! &C' is prepared from chloral hydrate also by the reactionwith calcium carbonate and sodium cyanide in water followed by acidifyin# with hydrochloric acid!

Therapeutic uses[edit]

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win# to the hi#hly corrosive action of the acid, only the salts of dichloroacetic acid are usedtherapeutically, includin# its sodium and potassium salts, sodium dichloroacetate and potassiumdichloroacetate!

Lactic acidosis[edit]

$he dichloroacetate ion stimulates the activity of the en(yme pyruvate dehydro#enase by inhibitin# theen(yme pyruvate dehydro#enase kinase!)4* $hus, it decreases lactate production by shiftin# themetabolism of pyruvate fromfermentation towards o6idation in the mitochondria! $his property has ledto trials of &C' for the treatment of lactic acidosis in humans!)8*)9*)10*)11*

 ' randomi(ed controlled trial in children with con#enital lactic acidosis found that while &C' was welltolerated, it was ineffective in improvin# clinical outcomes! )9*  ' separate trial of &C' in childrenwith :5'% ;a syndrome of inade<uatemitochondrial function, leadin# to lactic acidosis= was haltedearly, as all 1 of the children receivin# &C' e6perienced si#nificant nerve to6icity without anyevidence of benefit from the medication!)10* ' randomi(ed controlled trial of &C' in adults with lacticacidosis found that while &C' lowered blood lactate levels, it had no clinical benefit and did notimprove hemodynamics or survival!)11*

$hus, while early case reports and pre/clinical data su##ested that &C' mi#ht be effective for lacticacidosis, subse<uent controlled trials have found no clinical benefit of &C' in this settin#! "n addition,clinical trial sub>ects were incapable of continuin# on &C' as a study medication owin# to pro#ressive

to6icities!

Potential cancer applications[edit]

Cancer cells #enerally e6press increased #lycolysis, because they rely on anaerobic respiration thatoccurs in the cytosol ;lactic acid fermentation= rather than o6idative phosphorylation in themitochondria for ener#y ;the Warbur# effect=, as a result of hypo6ia that e6ists in tumors andmalfunctionin# mitochondria!)12*)13* ?sually dan#erously dama#ed cells kill themselves via apoptosis, amechanism of self/destruction that involves mitochondria, but this mechanism fails in cancer cells!

$he potential use of &C' in vivo is complicated by its poor bioavailability and limited ability topenetrate to its tar#et in the mitochondria!)1*

 ' phase " study published in @anuary 2004 by researchers at the ?niversity of 'lberta, who had tested&C' on human cancer cells #rown in mice,)1* found that &C' restored mitochondrial function, thus

restorin# apoptosis, allowin# cancer cells to self/destruct and shrink the tumor!)1*

$hese results received e6tensive media attention, be#innin# with an article in New Scientist  titled+Cheap, AsafeA dru# kills most cancers+!)1* %ubse<uently, the 'merican Cancer %ociety and othermedical or#ani(ations have received a lar#e volume of public interest and <uestions re#ardin# &C'!)14* Clinical trials in humans with cancer have not been conducted in the ?%' and are not yet final inCanada, emphasi(in# the need for caution in interpretin# the preliminary results! )14*)18*

Results of phase II clinical trials[edit]

"n in vitro studies, 5van#elos :ichelakis of ?niversity of 'lberta found that in tissue samples from 9patients, &C' caused depolari(ation of mitochondria in B: tissue but not in healthy brain tissue!)19*

Five patients with primary B: were entered into a phase "" trial! $hree had not responded to severalchemotherapies and were considered appropriate for  palliative care! $wo were newly dia#nosed andthen went throu#h sur#ical removal of tumour mass! 'll of them were treated with &C' andchemotherapy!)19*

f the five patients tested, one of the first three died after three months! $he survivin# four werefollowed for 1 months! $heir 7arnofsky scores were unchan#ed in two cases, and decreased by 10points in two patients!)19*

&C' was associated with tumor re#ression and had a #ood safety profile! &C' side effects wereminimal!)19*

:ichelakis is proceedin# with phase three human studies with private fundin# from philanthropic#roups and individuals! &C'As le#al status as a discovery is public domain because it was made or

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discovered as far back as 18)20* and has been used in the treatment of canine and human lacticacidosis, some who presented at the be#innin# of treatment with cancer!

Concerns about pre-trial use[edit]

Followin# its initial publication, The New Scientist  later editoriali(ed, +$he dru# may yet live up to itspromise as an anti/cancer a#ent D clinical trials are e6pected to start soon! "t may even spawn anentirely new class of anti/cancer dru#s! For now, however, it remains e6perimental, never yet properlytested in a person with cancer! -eople who self/administer the dru# are takin# a very lon# shot and,unlikely as it may sound, could even make their health worse!+)21*

"n 2010, it was found that for human colorectal tumours #rown in mice, under hypo6ic conditions, &C'decreased rather than increased apoptosis, resultin# in enhanced #rowth of the tumours!)22* $hesefindin#s su##est that at least in some cancer types &C' treatment could be detrimental to patienthealth, hi#hli#htin# the need for further testin# before it can be considered a safe and effective cancertreatment!)22*

Planned and ongoing clinical trials[edit]

&C' is not a novel substance so a composition of matter  patent cannot be #ranted! However,several method of use patent applications have been filed for its use in cancer treatment!)23*)2* %ome ofthese applications were never  prosecuted, but at least one has been #ranted!)2* .esearchby 5van#elos :ichelakis has received no support from the pharmaceutical industry!)2* Concerns havebeen raised that without stron# intellectual property protection, the financial incentive for dru#development is reduced, and therefore obtainin# sufficient funds to conduct clinical trials presentsdifficulty!)1*)14*)18*)24* However, other sources of fundin# e6istE previous studies of &C' have been fundedby #overnment or#ani(ations such as the ational "nstitutes of Health, the Food and &ru#

 'dministration, the Canadian "nstitutes of Health .esearch and by private charities ;e.g. the :uscular&ystrophy 'ssociation=! .eco#ni(in# anticipated fundin# challen#es, :ichelakisAs lab took theunorthodo6 step of directly solicitin# online donations to fund the research! )28*  'fter months, his labhad raised over 800,000, enou#h to fund a small Clinical -hase 2 study!

n 2 %eptember 2004, the ?niversity of 'lbertaAs &epartment of :edicine reported that after the trialfundin# was secured, both the 'lberta local ethics committee and Health Canada approved the first&C' clinical trial for cancer !)29* $his initial trial was relatively small with enrollment of up to 0 patients!$he trial was completed in 'u#ust 2009!)30* "n :ay 2010 the team published a press release)31* statin#no conclusions could be drawn as a result of the trial! ' paper describin# the results was

published)19* but not linked from the press release! nly five patients had been treated with the dru#durin# the trial!

"n :ay 2011, online reports)32* su##ested that the 'lberta #roup had released new data which themedia +had not reported+! However, this appeared to be caused by confusion between dates ;theprevious update was :ay 2010 )33*= and cancer charities moved <uickly to counter these rumours,)3*

)3* which were subse<uently covered in ew %cientist ma#a(ine! )3*

Side effects[edit]

.eports in the lay press after the 2004 ?niversity of 'lberta announcement claim that dichloroacetate+has actually been used safely in humans for decades+, )34*&C' is #enerally well tolerated, even inchildren!)38* %hort/term, infused, bolus doses of &C' at 0 m#Gk#Gday have been well tolerated!)39*

 't sustained, hi#her doses ;#enerally 2 m#Gk#Gday taken orally, or #reater=, there is increased risk ofseveral reversible to6icities, especially peripheral neuropathy,neuroto6icity, and #ait disturbance!)4*)34*

%tudies have also shown that it can be carcino#enic in male C3F1 mice at hi#h doses! )0*

Neuropathy[edit]

 ' clinical trial where &C' was #iven to patients with :5'% syndrome ;a form of #eneticallyinherited lactic acidosis= at 2 m#Gk#Gday was ended prematurely due to e6cessive peripheral nerveto6icity!)1*

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 'nimal studies su##est that the neuropathy and neuroto6icity durin# chronic dichloroacetate treatmentmay be partly due to depletion of  thiamine, and thiamine supplementation in rats reduced theseeffects!)2* However, more recent studies in humans su##est that peripheral neuropathy is a commonside effect durin# chronic &C' treatment, even with coadministration of oral thiamine!)3*)* 'nadditional study reported that 0 m#Gk#Gday &C' treatment resulted in unsteady #ait and lethar#y intwo patients, with symptoms occurrin# after one month for one patient and two months for the second!Bait disturbance and consciousness were recovered with cessation of &C', however sensory

nerve action potentials did not recover in one month!)*

 'nimals and patients treated with &C' have elevated levels of delta/aminolevulinic acid ;delta/''= inthe urine! ' study published in 2008 su##ests that this product may be the cause of the neuroto6ic sideeffect of &C' by blockin# peripheral myelin formation!)*

&ichloroacetate can also have an6iolytic or sedative effects!)*

Carcinogenicity[edit]

$he 5nvironmental -rotection '#ency has listed &C' as likely to be a cancer/causin# a#ent inhumans!)4* &C' is on the California 5nvironmental -rotection '#encyAs list of known cancer/causin#a#ents and is listed as a cause of reproductive harm in men!)4*)8* $he "nternational '#ency for.esearch on Cancer classifies &C' as a Broup 2 carcino#en ;+possibly carcino#enic to humans+=!)9*

on# term use ;three years or more= of hi#h doses ; 44 m#Gk#Gday= of &C' has been shown to

increase risk of liver cancer in mice!)0* %tudies of thetrichloroethylene ;$C5= metabolites dichloroaceticacid ;&C'=, trichloroacetic acid ;$C'=, and chloral hydrate su##est that both &C' and $C' areinvolved in $C5/induced liver  tumori#enesis and that many &C' effects are consistent with conditionsthat increase the risk of liver cancer  in humans!)0*

Self-medication[edit]

$he promise of &C' as a cheap, effective and safe treatment for cancer #enerated a #reat deal ofpublic interest! :any people turned to self/medication!)1*)2*

-hysicians warned of potential problems if people attempt to try &C' outside a controlled clinical trial!+"f it starts #oin# badly, who is followin# you before it #ets out of controlI y the time you reali(e yourliver is failin#, youAre in bi# trouble+, said aura %hanner, 'ssociate -rofessor of Health 5thics at the?niversity of 'lberta!)3*

References[edit]

1! J @ump up toKa b c  d  Haynes, William :!, ed! ;2011=! CRC Handbook of Chemistry andPhysics ;92nd ed!=! oca .aton, FK C.C -ress! "% 1398110!

2! Jup up! 7ato, :!E i, @!E Chuan#, @! !E Chuan#, &! $! ;2004=! +&istinct %tructural:echanisms for "nhibition of -yruvate &ehydro#enase 7inase "soforms by 'L&4,&ichloroacetate, and .adicicol+! Strctre "# ;8=K 992D100!doiK10!101G>!str!2004!04!001! -:C 284138! -:"& 148392! edit

3! Jup up! +&ichloracetate ;&C'=+! 'merican Cancer %ociety! .etrieved 1 &ecember2012!

! Jup up! @!$! aker :%&%! Jup up! httpKGGparadi#mslip!caGreferencesGuhmMphdM481023Mr!pdf ! J @ump up toKa b %tacpoole -, Henderson B, Nan L, @ames : ;1998=! +Clinical

pharmacolo#y and to6icolo#y of dichloroacetate+! !nviron Hea"th Perspect ! 10 %uppl K 989D99! doiK10!2304G3312! @%$. 3312! -:C 13332!-:"& 940383!

4! J @ump up toKa b %tacpoole -W ;1989=! +$he pharmacolo#y ofdichloroacetate+! #etabo"ism$% ;11=K 112D11! doiK10!101G002/09;89=9001/! -:"& 209!

8! Jup up! %tacpoole -, oren( ', $homas ., Harman 5 ;1988=! +&ichloroacetate in thetreatment of lactic acidosis+! Ann $ntern #ed  "&% ;1=K 8D3! doiK10!432G0003/819/108/1/8! -:"& 333414!

9! J @ump up toKa b %tacpoole -, 7err &, arnes C, unch %, Carney -, Fennell 5, Felitsyn ,Bilmore ., Breer :, Henderson B, Hutson ', eiber#er ., Arien ., -erkins , Ouislin# .,

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32! Jup up! $he Cure for Cancer Has een Found and is -urposely ein# "#nored /$echnorati blo# ;accessed 1G0G2011=

33! Jup up! &C' .esearch $eam publishes results of Clinical $rials / ?niversity of 'lbertawebsite

3! Jup up! -otential cancer dru# &C' tested in early trials / Cancer .esearch ?7 scienceblo#

3! Jup up! C.M?7 tweet / tweeted 1G0G11

3! Jup up! Cancer dru# resurfaces and threatens false optimism / ew %cientist, 1 :ay201134! J @ump up toKa b -icard, 'ndrT ;2004/01/14=! +on#/used dru# shows new promise for

cancer+! $orontoK $he Blobe and :ail! .etrieved 2004/01/14!38! Jup up! -earson HE 7urt(, $E Han, LE an#aee, $ ;2008=! +.ole of dichloroacetate in

the treatment of #enetic mitochondrial diseases+!  Adv 'rg 'e"iv Rev. (&;13,1=K 148D184! doiK10!101G>!addr!2008!02!01! -:C 3432!-:"& 1842!

39! Jup up! '#benye#a $, -lanche $, edu/'ddo B, 'nson# &, wusu/fori ', hattaramP', a#ara>a P, %hroads ', Henderson B, Hutson '&, &erendorf H, 7rishna %, %tacpoole -W;2003=! +-opulation kinetics, efficacy, and safety of dichloroacetate for lactic acidosis due to severemalaria in children+! % C"in Pharmaco". +$ ;=K 38D39! doiK10!1144G009124000321392!-:"& 124239!

0! J @ump up toKa b &e'n#elo ', &aniel F, %tober @', lson B. ;1991=! +$hecarcino#enicity of dichloroacetic acid in the male C3F1 mouse+! )ndam App" Toxico". "( ;2=K334D34! doiK10!101G0242/090;91=90118/! -:"& 203!

1! Jup up! 7aufmann -, 5n#elstad 7, Wei N et al! ;200=! +&ichloroacetate causes to6icneuropathy in :5'%K a randomi(ed, controlled clinical trial+! Nero"ogy  (( ;3=K 32D330! doiK10!1212G01!wnl!0000191!0913!24! -:"& 14929!

2! Jup up! %tacpoole -, Harwood H, Cameron &, Curry %, %amuelson &, Cornwell -,%auberlich H ;1990=! +Chronic to6icity of dichloroacetateK possible relation to thiamine deficiency inrats+! )ndam App" Toxico"  "+ ;2=K 324D34!doiK10!101G0242/090;90=90212/3! -:"& 231834!

3! Jup up! 7urlemann B, -aet(ke ", :oller H, :asur H, %chuierer B, We#la#e @, 7ochHB ;199=! +$herapy of comple6 " deficiencyK peripheral neuropathy durin# dichloroacetatetherapy+! !r % Pediatr  "#+ ;11=K 928D32!doiK10!1004GF019408! -:"& 88209!

! Jup up! %prui>t , aviau6 .7, :cBowan 7', yhan W, %heean B, Haas .H,arshop ' ;2001=! +erve conduction chan#es in patients with mitochondrial diseases treatedwith dichloroacetate+! #sc"e Nerve )+ ;4=K 91D2!doiK10!1002Gmus!1089! -:"& 1110919!

! Jup up! ishi 7, Noshioka :, (awa ., Namamoto $, ya N, #awa :, 7awai :;2003=! +&ichloroacetate treatment for adult patients with mitochondrial disease+!RinshoShinkeigak +$ ;=K 1D1! -:"& 1289200!

! Jup up! Felitsyn, E :ceod, CE %hroads, 'E %tacpoole, -WE otterpek, ;2008=!+$heheme precursor delta/aminolevulinate blocks peripheral myelin formation+!%orna" ofNerochemistry  "&( ;=K 208D2049! doiK10!1111G>!141/19!2008!02!6! -:C 2449! -:"& 18889!

4! J @ump up toKa b +&ichloroacetate ;&C'=+!  'merican Cancer %ociety!8! Jup up! Chemica"s *nown to the State to Case Cancer or Reprodctive

Toxicity !California 5nvironmental -rotection '#ency! @anuary 31, 201!9! Jup up!  '#ents Classified by the "'.C :ono#raphs, "nternational '#ency for .esearch

on Cancer 0! Jup up! Caldwell @C, 7eshava ;%eptember 200=! +7ey issues in the modes of action

and effects of trichloroethylene metabolites for liver and kidney tumori#enesis+!!nviron. Hea"thPerspect. ""+ ;9=K 14D3! doiK10!1289Gehp!892!-:C 1400! -:"& 1910!

1! Jup up! -earson, Helen ;2004=! +Cancer patients opt for unapproveddru#+! Natre ++(;413=K 4D4! doiK10!1038G4a! -:"& 1439240!

2! Jup up! "nterviewK Would you try an untested cancer dru#I, ew %cientist, 'u#ust 1,2004

3! Jup up! 'ndrea %ands ;:arch 18, 2004=! +56perts caution a#ainst patients compilin#own data on unapproved cancer dru#+! 5dmonton @ournal!

External links[edit]

• "nternational Chemical %afety Card 088

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• C$P!ca ews %taff ;1 @anuary 2004=! +%mall molecule offers hope for cancertreatment+! CT+.ca ,ebsite ;C$P television network=! .etrieved 2004/01/31!

• &C' .esearch "nformation Website ;?niversity of 'lberta=

• Wait for Clinical $rials, ew %cientist, 2 February 2004

• -otential cancer dru# &C' tested in early trials, by Cancer .esearch ?7

• "nterviewin# &rs! 'kbar and Humaira 7han about &C'

• Cancer iolo#y D Crampin# $umors 5conomist, @anuary 18, 2004• fficial ?niversity of 'lberta &C' ;dichloroacetate= Website, $he ?niversity of 'lberta

&iscovery! :arch 1, 2004

Cate#oriesK

• r#anochlorides

• "'.C Broup 2 carcino#ens

•  'cetic acids

•  'lternative cancer treatments

• 56perimental cancer dru#s

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