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 where all have 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.
By Randall Parker at 2007 January 21 09:06 PM Biotech Cancer | TrackBackFrom the article: People who are philosophically opposed to patents ought to take note of this.
The problem is not the lack of a patent -- it's an FDA system that creates a $1 billion regulatory pathway per drug!. The fact that the system can't get a trivial compound out into commerce when it's potential is enormous is an indictment of how the FDA does business -- not some symptom of a "patent-lack" problem. (Never mind that most supplements don't have patent coverage and do just fine -- thanks to common sense legislation that kept the FDA regulatory bootjacks out of the picture.)
Why can we test a medical device for $15 million but can't even start a drug clinical trial without $300 million in the bank? Does anyone here think there is any difference in determing medical outcomes between the two, statistically speaking? Of course there isn't. If I can prove a device effective with 100 patients I can prove a drug effective with 100 patients. And common sense argues that if I need to give it to 1000 patients to see effect I don't really have an effective drug... I leave to the mathematicians to produce the minimal recs.
Borrowing from the recent Reason stem cell article:
Meanwhile where federal research funding is most lavish and regulation is most onerous, that is where progress in getting treatments to patients is slowing down. The FDA approved only 18 new drugs in 2006, down from an average of 26 per year over the past six years. As the costs for getting through the regulatory gauntlet go up, pharmaceutical companies are narrowing their product lines and bringing fewer treatments to patients.
I may be wrong about this but combination therapies are patentable.
Also, "off label" uses of drugs are permissible under FDA rules. That is if a drug is approved for a specific use (found to be effective for that use and safe) at a certain dose doctors can prescribe it for as treatment for other things since it is deemed safe. (unfortunately insurance usually doesn't cover the cost of experimental protocols)
This is a Canadian project. Why is the US FDA relevant? If Canada has socialized medicine, shouldn't the Canadian Government sponsor drug development?
New uses of existing things can be patented as well.
"Also, "off label" uses of drugs are permissible under FDA rules".
Sure, but without the studies, no one wold ever know if it were efficacious at all, or if it caused an excess of deaths from some other side effect, or if the effect only lasted for a short time, or if it would work better in combination with something like avastin or another agent.
I would not worry too much about that though. The studies will get done.
RE Patent protection. Another approach may be to introduce a variation of the "orphan drug" law that would enable market exclusivity for method of use inventions where the agent is in the public domain and the use is a deadly or otherwise miserable disease.
Thank you ,, but please answer this question>>
what is The effect of the cancer to Mitochondria ?
DCA has been used before in 2001 by other researchers:
United States Patent 6,951,887
Bingham , et al. October 4, 2005
Lipoic acid derivatives and their use in treatment of disease
Abstract
This invention relates to the identification of a novel class of therapeutic agents which selectively target and kill tumor cells and certain other types of diseased cells, and to compositions comprising lipoic acid derivatives which poison the pyruvate dehydrogenase complex specifically in such cells. This invention also provides for methods of using therapeutically effective amounts of the lipoic acid derivatives for the treatment of cancer and other diseases. The lipoic acid derivatives described herein have a wide range of preventive and therapeutic applications.
where in it says:
..."Another embodiment of the invention relates to a method of treating a disease sensitive to lipoate derivatives comprising administering an effective amount of a lipoate compound and a second reagent to treat said disease. This second reagent is preferably an inhibitor of mitochondrial energy metabolism and/or one that induces apoptosis. Such reagents include metabolism inhibitory reagents. Many such reagents are known in the art. One particularly preferred reagent is dichloroacetate. This second reagent may be administered sequentially, simultaneously or separately, so as to amplify patient response to said treatment method."