DiChloroAcetate ( DCA ) vs Cancer )
New Scientist ( Wednesday, January 17, 2007 ) ---
New Scientist has received an unprecedented amount of interest in this story from readers. If you would like up-to-date information on any plans for clinical trials of DCA in patients with cancer, or would like to donate towards a fund for such trials, please visit the site set up by the University of Alberta and the Alberta Cancer Board ( http://www.depmed.ualberta.ca/dca ). We will also follow events closely and will report any progress as it happens.It is rare to find a drug that sweeps away decades of assumptions and reveals a radical approach to treating all forms of a disease. But a simple, small molecule called dichloroacetate (DCA) has done just that - and to that most dreaded of diseases: cancer.
The new findings might also force a rethink on what actually causes cells to turn cancerous in the first place.
In 1930, biochemist Otto Warburg, proposed that cells turn cancerous through a fundamental change in the way they generate their energy. Normally, cells use specialised organelles called mitochondria to supply their energy. Cancer cells shift to a process called glycolysis which takes place in the main body of the cell. Glycolysis is an inefficient system of making energy which normal cells employ only when oxygen is in short supply, switching to mitochondrial energy production when oxygen levels increase.
Curiously, Warburg discovered that cancer cells continue to use glycolysis even when oxygen is plentiful. He called this the “Warburg effect”, and claimed it was common to all cancer cells.
His ideas were dismissed and buried long ago, not least when another famous biochemist, Hans Krebs, said the Warburg effect was a symptom of cancer, not the primary cause. This scepticism was reinforced by the belief that cancer cells switch to glycolysis because their mitochondria are damaged and don’t work any more.
Enter DCA, which has been used for years to treat people with mitochondrial disease. The drug boosts the ability of mitochondria to generate energy. When given to cancer cells it did the same: the cells switched from glycolysis to mitochondrial energy production. What's more, functional mitochondria help cells recognise functional abnormalities and trigger cell death.
In tests, the DCA caused cancer cells to lose their “immortality” and die. When the drug was given to rats with human tumours, the tumours shrank. Warburg may have been right after all - glycolysis may be more than just a symptom of cancer.
So why not rush straight into clinical trials with this drug? It is cheap, does not appear to affect normal cells, we know its side effects, and it should work on all cancers.
There's a hitch: dichloroacetate is an old drug and so cannot be patented. The upshot is that pharmaceutical companies can’t stop rivals making and selling it more cheaply, so it’s not worth their while to go to the huge expense of testing it in clinical trials.
This is not a new problem. Many drugs are left on the shelf because companies cannot make lots of money from them. It has happened for diseases that affect mainly poor people, such as TB, although there are now an increasing number of initiatives to help deal with these cases. But cancer is historically a disease that chiefly afflicts the rich, and testing DCA will need a one-off effort.
Drugs companies will be falling over themselves to find a patentable drug with similar action to DCA. Any of these that reach the market will be hugely expensive. It would be a scandal if a cheap alternative with such astonishing potential were not given a chance simply because it won't turn a big enough profit.
http://www.futurepundit.com/archives/004028.html (January 21, 2007)
Mitochondria Activation Reduces Cancer
A small molecule activates suppressed mitochondria in cancer cells and the cells start acting normal.
January 16, 2007 - Edmonton - DCA is an odourless, colourless, inexpensive, relatively non-toxic, small molecule. And researchers at the University of Alberta believe it may soon be used as an effective treatment for many forms of cancer.
One qualifier to the above statement: Whether dichloroacetate (DCA) would really be non-toxic when used in therapeutic doses against cancer remains to be seen. When used to treat a genetic disorder involving high lactic acid DCA caused peripheral neuropathy. DCA inhibits a kinase enzyme that deactivates an enzyme called pyruvate dehydrogenase (PDH) which is involved in mitochondrial metabolism (i.e, it is involved in sugar breakdown to make energy).
Dr. Evangelos Michelakis, a professor at the U of A Department of Medicine, has shown that dichloroacetate (DCA) causes regression in several cancers, including lung, breast and brain tumors.
Michelakis and his colleagues, including post-doctoral fellow Dr. Sebastian Bonnet, have published the results of their research in the journal Cancer Cell.
Many cancer cells do not break sugar down completely. They just do a step called glycolysis. They do not do a step called the Krebs cycle (aka the citric acid cycle or tricarboxylic acid cycle or TCA cycle) which extracts all the energy out of sugar molecules to make energy carrier molecules called NADH and ATP. This was first observed about cancer all the way back in the 1930s. Up until now the assumption to explain this was that cancer cells lost that ability. But this result suggests that not only do cancer cells suppress that ability but that suppression helps them grow uncontrollably.
Pyruvate dehydrogenase (PDH) synthesizes acetyl-CoA which is used in the first step of the TCA cycle in mitochondria. If DCA has either toxicity problems or problems with achieving sufficient doses that does not defeat this approach to anti-cancer drug development. The kinase that DCA blocks could become a target for drug development. A drug that would disable that kinase would likely activate mitochondria in cancer cells just like DCA does.
I remember a scientist telling me decades ago that classic intermediary metabolism doesn't get the attention it deserves because everyone was rushing into genetics. Many scientists decided that there was little of interest left to learn from studying the main pathways of energy metabolism. This result argues for his view. How can we get all the way to the year 2007 without noticing sooner the powerful results from a simple long known molecule?
Michelakis decided the conventional wisdom on cancer and mitochondria might be wrong and decided to test it.
Until recently, researchers believed that cancer-affected mitochondria are permanently damaged and that this damage is the result, not the cause, of the cancer. But Michelakis, a cardiologist, questioned this belief and began testing DCA, which activates a critical mitochondrial enzyme, as a way to "revive" cancer-affected mitochondria.
The results astounded him.
Michelakis and his colleagues found that DCA normalized the mitochondrial function in many cancers, showing that their function was actively suppressed by the cancer but was not permanently damaged by it.
More importantly, they found that the normalization of mitochondrial function resulted in a significant decrease in tumor growth both in test tubes and in animal models. Also, they noted that DCA, unlike most currently used chemotherapies, did not have any effects on normal, non-cancerous tissues.
No one single molecule is going to cure all cancers by itself. But combinations of compounds that each toxicity highly specific to cancer cells will certainly end up curing a great many cancers. Monoclonal antibodies targetted at cancers, anti-angiogenesis compounds that block blood vessel growth in cancers, gene therapies that activate in cancer cells and assorted other compounds such as DCA are going to cure many cancers when used in combination.
"I think DCA can be selective for cancer because it attacks a fundamental process in cancer development that is unique to cancer cells," Michelakis said. "Cancer cells actively suppress their mitochondria, which alters their metabolism, and this appears to offer cancer cells a significant advantage in growth compared to normal cells, as well as protection from many standard chemotherapies. Because mitochondria regulate cell death - or apoptosis - cancer cells can thus achieve resistance to apoptosis, and this appears to be reversed by DCA."
The suppression of mitochondria might be a way for cancer cells to divide in low oxygen environments found deep in tumors lacking in sufficient vasculature. By turning on mitochondria in these cells their need for oygen is probably increased and that likely contributes to their death. This suggests that DCA might work well in combination with anti-angiogenesis drugs since the ability of anti-angiogenesis drugs to block blood vessel growth will decrease the amount of oxygen available to tumors and therefore make more cells in tumors susceptible to the effects of DCA.
DCA (aka Ceresine) has a big problem: It is not patentable and hence provides little incentive for commercial companies to raise money to fund clinical studies to develop it as an anti-cancer drug. People who are philosophically opposed to patents ought to take note of this.
Furthermore, the DCA compound is not patented or owned by any pharmaceutical company, and, therefore, would likely be an inexpensive drug to administer, Michelakis added.
However, as DCA is not patented, Michelakis is concerned that it may be difficult to find funding from private investors to test DCA in clinical trials. He is grateful for the support he has already received from publicly funded agencies, such as the Canadian Institutes for Health Research (CIHR), and he is hopeful such support will continue and allow him to conduct clinical trials of DCA on cancer patients.
If DCA is on the market in less regulated countries then maybe it'll get tried out in human cancer patients under less restrictive regulatory regimes.
DCA hasn't been tried yet in humans against cancer.
Evangelos Michelakis of the University of Alberta in Edmonton, Canada, and his colleagues tested DCA on human cells cultured outside the body and found that it killed lung, breast and brain cancer cells, but not healthy cells. Tumours in rats deliberately infected with human cancer also shrank drastically when they were fed DCA-laced water for several weeks.
People who have fatal diseases should be allowed to try anything as a treatment.
WO 2006108276
A METHOD OF TREATING CANCER USING DICHLOROACETATE
( 10-19-2006 )
[ PDF ]
MICHELAKIS EVANGELOS (CA); ARCHER STEPHEN (CA)
Applicant: UNIV ALBERTA (CA); MICHELAKIS EVANGELOS (CA); ARCHER STEPHEN (CA)
Classification: - international: A61K31/19; A61P35/00; C12Q1/00; A61K31/185; A61P35/00; C12Q1/00; - European: G01N33/50D2B
Application number: WO2006CA00548 20060411
Priority number(s): US20050669884P 20050411
Environmental Health Perspectives 106 (Suppl. 4): 989-994 (August 1998)
Peter Stackpoole, et al.: Clinical Pharmacology and Toxicology of Dichloroacetate
www.newscientist.com/channel/health/mg19325874.700-cheap-safe-drug-kills-most-cancers.html - 40k [ PDF ]
DCA v CANCER
(Google Search)Cheap, safe drug kills most cancers... However, Michelakis's experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died ...
FuturePundit: Mitochondria Activation Reduces Cancer
The kinase that DCA blocks could become a target for drug development. A drug that would disable that kinase would likely activate mitochondria in cancer.
www.futurepundit.com/archives/004028.html - 17kmitochondria | Science Buzz
When cells switch mitochondria off, they become “immortal”, outliving other cells in the tumour and so becoming dominant. Once reawakened by DCA, ...
buzz.smm.org/buzz/buzz_tags/mitochondria - 15kScience Buzz - mitochondria
Once reawakened by DCA, mitochondria reactivate apoptosis and order the abnormal cells to die. But perhaps the best thing about this ...
buzz.smm.org/buzz/taxonomy/term/2019/0/feed - 4kDCA: A cheap, safe, effective “cure” for cancer? at Fresh. Healthy ...
Because mitochondria regulate cell death–or apoptosis–cancer cells can thus achieve resistance to apoptosis, and this appears to be reversed by DCA.” ...
freshhealthyuseful.com/2007/01/dca-a-cheap-safe-effective-cure-for-cancer/ - 23kSmall molecule offers big hope against cancer - ExpressNews ...
Scientists and doctors have used DCA for decades to treat children with inborn errors of metabolism due to mitochondrial diseases. Mitochondria, the energy ...
www.expressnews.ualberta.ca/article.cfm?id=8153 - 22kThe Why Files | Small molecule could be big cancer fighter
Biochemical tests showed that mitochondria in the DCA-treated cancer cells were releasing compounds that stimulate apoptosis -- cellular suicide. ...
whyfiles.org/shorties/225cancer_drug/ - 17kBittertizer’s Blog
However, Michelakis’s experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died ...
bittertizer.wordpress.com/ - 24kScienceDaily: Small Molecule Offers Big Hope Against Cancer
Because mitochondria regulate cell death--or apoptosis--cancer cells can thus achieve resistance to apoptosis, and this appears to be reversed by DCA." ...
www.sciencedaily.com/releases/2007/01/070116134001.htm - 99kOnce reawakened by DCA, mitochondria reactivate apoptosis and order the abnormal cells to die. “The results are intriguing because they point to a critical ...
www.tedkarol.com/blog/index.xml - 10
http://www.newscientist.com/data/images/ns/blog/shortsharp/hd_sss.gif
Thursday, March 29, 2007Cancer Pharmacy for the Desperate and Vulnerable
by
Linda Geddes, Biomedical editor
Almost two years ago my aunt died from ovarian cancer. At age 53, she was younger than my mother and, the last time I saw her, I remember her producing a pile of computer print-outs of alternative cancer therapies she had read about on the internet. She was desperate, and she wanted my advice on whether the science behind their claims was robust or not. After examining the literature, it was with great sadness that I told her that, in my opinion, their claims were unfounded.
Pouring cold water on someone’s hopes is a terrible thing. In the case of DCA, I have to say there are at least some grounds for excitement. Lab studies have shown that it can kill cancer cells by reactivating mitochondria, which will then recognise a cell as cancerous and destroy it. But until we see whether this mechanism applies to cells in the human body it is impossible to know whether it will work in human cancer.
We also have no idea of the doses that could produce this effect; of their side effects in cancer patients, or about whether DCA interacts with existing cancer medications. DCA is not a harmless drug – as Lawrence Burgh’s example illustrates, it can have side effects. Fortunately, Burgh is a physician whose oncologist was aware that he was taking DCA. He was taking supplements to try and reduce side effects, and at the first sign of trouble, he stopped taking it.
Not everyone who is experimenting with DCA is so cautious. Self-medicating with DCA could cause nerve or liver damage, and perhaps even death. People with terminal cancer may feel that they have nothing to lose – but there may be a different option.
Statistically speaking, if a cancer drug has passed initial safety tests in phase 1 clinical trials, it has a one in 20 chance of being approved. If it has passed phase 2 trials (the stage before large scale trials in patients with the disease) it has a one in 5 chance of being approved. Yet doctors are struggling to recruit patients into these trials. In the US, fewer than 5% of adult cancer patients are enrolled. True, not everyone can take part in clinical trials because they have other physical ailments, their insurance companies won’t cover them, or because they live too far away from trial centres. But it seems at least worth trying, before opting for the ultra-gamble of DCA.
Sadly, many of the posts I came across while researching the DCA site, expressed a feeling that their doctors didn’t care – that they were made to feel like “dead men walking”. I’m sure that most doctors do their utmost to listen to their patients concerns, but for those who fall through the net, it should be noted that website communities seem to be filling a gap in providing at least some of the comfort, support, and hope that impersonal hospital visits may lack.
When this drives people to campaign for a drug like DCA to be put through clinical trials, or to push doctors to try the latest approved drugs, this can be a great thing. But people should treat what they read on the internet with care. There is a risk that these forums could push an already vulnerable person to make their shortened life even more painful.
So what is the answer in a situation like this? Should patients have the ultimate say in how they choose to treat their own bodies; or should these most vulnerable of people be protected from the exploitative promises of untried therapies?
http://www.newscientist.com/article/dn12369-illegal-cancer-drug-website-shut-down.html
27 July 2007 Illegal 'cancer drug' website shut down
NewScientist.com news service
by Linda Geddesdca"Is DCA worth trying? We absolutely think so," proclaimed a website promoting the laboratory chemical sodium dichloroacetate (DCA) as a treatment for cancer earlier this year.
The US Food and Drug Administration (FDA) clearly did not agree. Last week it visited the site's owners and told them to stop making and selling DCA from a sister website, or face criminal prosecution.
Jim Tassano of Sonora, California, claims to have sold DCA to more than 2000 people, with no reports of serious side effects, via his website www.buydca.com.
However, on the 17 July he posted the following message on the site. "Two agents from the FDA visited us today and ordered that we stop making and selling DCA. Unfortunately, the site www.buydca.com will be shut down. It is against US government law to sell substances with the suggestion that they are cancer treatments unless they are approved by the FDA. DCA can still be obtained from pharmacies with a prescription and from chemical companies."
The FDA confirmed that agents from their Office of Criminal Investigations had visited Tassano, but declined to comment further.
'Improvements reported'
In an interview with New Scientist, Tassano told us: "We've seen cancers where it doesn't seem to respond at all [to DCA], but a lot of people have reported improvements in their symptoms."
"I'm disappointed [that the FDA has shut the website down], but not surprised. It is an unapproved cancer treatment and we have become very high profile. I guess the pressure has got to be too much for the FDA," he said.
Tassano continues to host discussions on the supposed virtues of the chemical, which has not yet undergone human trials as a cancer therapy, on his original site www.thedcasite.com.
Researchers studying DCA as a potential cancer drug welcomed the FDA's action. "The FDA is doing the absolutely right thing to help protect vulnerable cancer patients from the unregulated use of a drug that should be studied in properly designed clinical studies," says Chi Van Dang at Johns Hopkins University Medical School in Baltimore, Maryland, US.
Worrying reports
Kate Law, Cancer Research UK's clinical trial director, agrees: "Reports of people buying personal supplies of DCA from sources such as the internet were very worrying."
"It is important that all new treatments are carefully investigated to make sure they are effective and safe for use in patients. DCA is no exception, so we are pleased that the FDA has taken the decisive action to limit the sale of DCA over the internet," she says.
Clinical trials of DCA are expected to take place in the near future. Evangelos Michelakis of the University of Alberta in Edmonton has just resubmitted protocols to Health Canada, and hopes to gain approval to for a safety trial of DCA in human cancer patients in the coming weeks.
Meanwhile, Van Dang has just received notice of funding to carry out additional studies of DCA in animals with cancer, with the intention of conducting clinical trials in lymphoma patients within three years.
