The drug dichloroacetate (DCA) appears to target cancer cells, causing them to die. It's potency as a cancer killing agent has been tested in tissue cultures and, just recently, in mice -- all with very promising results.
Problem is, this drug has been used for many years to treat rare metabolic disorders and is not patentable as a cancer treatment. Without patent protection, the pharmaceutical industry has no interest in investing millions in clinical trials, even though the drug's impact on cancer could be profound.
To understand how DCA works you must first understand that cancer cells often don't create the energy they need via normal channels. In a healthy cell, energy is mostly produced by mitochondria. In cancer cells, the mitochondria seem to shut down. In its place, cancer cells use an inefficient, cell-wide energy producing process called glycolysis--the same process that produces lactic acid and causes your muscles to cramp.
The DCA drug appears to turn on the mitochondria that were turned off by the cancer. Oddly enough, turning on the mitochondria kills the cancer cells. Scientist has shown this in cell cultures and recently in tumors in rats.
This drug could be an important treatment for cancer. However, in order to know if the drug is effective on cancer in humans, clinical trials need to be run. Since the drug is not patentable and can be produced very cheaply, pharmaceutical companies won't fund those clinical trials. The money will have to come from other sources: Government, charities, research foundations.
- Cheap, safe drug kills most cancers - Excellent article describing the study and patent issues.
- Curing Cancer: A Patent Impossibility - Great blog entry that summarizes the the situation.
- Dichloroacetate, J4 - Explains the science and history of the DCA drug.
- Respectful Insolence: In which my words will be misinterpreted as "proof" that I am a "pharma shill" - Very interesting criticism of the characterizations and assumptions people (includin myself) are making of this report. "Cure" for cancer is never claimed or researched (yet), and costs for trials are way off. I think this guy is making some really good points.
 | Surviving "Terminal" Cancer: Clinical Trials, Drug Cocktails, and Other Treatments Your Oncologist Won't Tell You About |
 | Surviving "Terminal" Cancer: Clinical Trials, Drug Cocktails, and Other Beating Cancer with Nutrition |
Cheap, safe drug kills most cancers
By Andy Coghlan
If links die, read cached copies below.
What makes cancer cells different - and how to kill them
It sounds almost too good to be true: a cheap and simple drug that kills almost all cancers by switching off their “immortality”. The drug, dichloroacetate (DCA), has already been used for years to treat rare metabolic disorders and so is known to be relatively safe.
It also has no patent, meaning it could be manufactured for a fraction of the cost of newly developed drugs.
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.
DCA attacks a unique feature of cancer cells: the fact that they make their energy throughout the main body of the cell, rather than in distinct organelles called mitochondria. This process, called glycolysis, is inefficient and uses up vast amounts of sugar.
Until now it had been assumed that cancer cells used glycolysis because their mitochondria were irreparably damaged. However, Michelakis’s experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died (Cancer Cell, DOI: 10.1016/j.ccr.2006.10.020).
Michelakis suggests that the switch to glycolysis as an energy source occurs when cells in the middle of an abnormal but benign lump don’t get enough oxygen for their mitochondria to work properly (see diagram). In order to survive, they switch off their mitochondria and start producing energy through glycolysis.
Crucially, though, mitochondria do another job in cells: they activate apoptosis, the process by which abnormal cells self-destruct. When cells switch mitochondria off, they become “immortal”, outliving other cells in the tumour and so becoming dominant. Once reawakened by DCA, mitochondria reactivate apoptosis and order the abnormal cells to die.
“The results are intriguing because they point to a critical role that mitochondria play: they impart a unique trait to cancer cells that can be exploited for cancer therapy,” says Dario Altieri, director of the University of Massachusetts Cancer Center in Worcester.
The phenomenon might also explain how secondary cancers form. Glycolysis generates lactic acid, which can break down the collagen matrix holding cells together. This means abnormal cells can be released and float to other parts of the body, where they seed new tumours.
DCA can cause pain, numbness and gait disturbances in some patients, but this may be a price worth paying if it turns out to be effective against all cancers.
The next step is to run clinical trials of DCA in people with cancer. These may have to be funded by charities, universities and governments: pharmaceutical companies are unlikely to pay because they can’t make money on unpatented medicines. The pay-off is that if DCA does work, it will be easy to manufacture and dirt cheap.
Paul Clarke, a cancer cell biologist at the University of Dundee in the UK, says the findings challenge the current assumption that mutations, not metabolism, spark off cancers. “The question is: which comes first?” he says.
| Surviving "Terminal" Cancer: Clinical Trials, Drug Cocktails, and Other Beating Cancer with Nutrition |
Excellent summary of the situation.
Curing Cancer: A Patent Impossibility
By Bill Walker
If links die, read cached copies below.
The good news this month is that a Canadian team under Dr. Michelakis at the University of Ottawa has discovered that a simple, inexpensive chemical is a powerful anticancer agent, effective against a broad range of cancers. (Read their paper in the January Cancer Cell, subscription required). The bad news is that it is a simple, inexpensive chemical long used in medicine, and is not patentable. Thus there is no mechanism for getting the chemical (dichloroacetate, DCA) past the billion-dollar barrier of FDA approval. (The FDA actually only approved 17 drugs last year, and the drug industry spent 40 billion dollars on R&D).
Scientists have known since 1930 that cancer cells use glycolysis instead of aerobic respiration for energy. In other words, they don’t turn on their mitochondria and burn their glucose with oxygen, as do normal cells; they just convert it to lactic acid. While glycolysis provides about fifteen times less energy per blood sugar molecule, it works under the oxygen-deprived conditions inside early tumors. It also has the advantage of bypassing the mitochondria entirely, which allows the cancer cells to suppress the cell’s self-destruct mechanisms.
DCA forces the cell to turn on its mitochondria. This was the primary medical use of DCA in the past, to treat patients with rare metabolic deficiencies. For a normal cell, being "forced" to turn on mitochondria isn’t such a big deal… they’re already on.
But for a cancer cell, the mitochondria are time bombs. When the cancer’s mitochondria turn on, they run out of control, creating high hydrogen peroxide levels inside the mitochondria. This leads to a cascade of chemical reactions that eventually activates two different self-destruct ("apoptosis") pathways in the cell.
The ability to reactivate self-destruction is one of the "holy grails" of cancer research. There are other approaches to induce apoptosis in cancer cells, and perhaps some of them would actually work if they were combined with DCA. Also, even if it is eventually found that cancer can mutate and develop DCA resistance, the long period of regression could allow newer but slow anticancer concepts (such as telomerase inhibition) to finish off the remaining cancer cells.
So far Dr. Michelakis has demonstrated the effectiveness of DCA against various human cancer cell lines in a cell culture, and against human tumors growing on immune-suppressed rats. The drug has already been tested on human beings for many years as a treatment for a genetic enzyme deficiency. There are millions of terminal cancer victims on this planet. So, logically, the next step would be to find some volunteers and start trying to find the optimum human dose range, combinations of other apoptosis inducers that work synergistically with DCA, supplements to reduce side effects, etc.
Logically in our libertarian minds, perhaps. In the real world, nothing of the kind will happen. The FDA will not allow people in the orderly and profitable process of agonizing death by incurable cancers to try nonapproved drugs. No drug company, no matter how large, can afford to spend a billion dollars and 19 years getting a nonpatentable treatment through the bureaucratic minefield. There is no FDA-approved way to get there from here.
Someday a dedicated medical team working beyond the reach of the FDA (perhaps in Mainland China, which already contains numerous clinics that cater to foreign medical refugees) will defeat cancer1. In the intervening years or decades, terminal cancer patients in the US will be restricted to the same old patent medicines.
Note
1. If you’re a dedicated medical team working beyond the reach of the FDA, the rats in the study were given the same dose of DCA as human patients with enzyme disorders, 50–100 milligrams of drug per kilogram of body weight, dissolved in their water.
January 22, 2007
Bill Walker works in HIV and gene therapy research in Rochester, Minnesota.
| Surviving "Terminal" Cancer: Clinical Trials, Drug Cocktails, and Other Treatments Your Oncologist Won't Tell You About |
Dichloroacetate - Disease Mechanism III: Abnormalities in Energy Metabolism
By P. Chang
An Energy Buffer
Drug Summary: Dichloroacetate stimulates an enzyme called PDC that is essential for the production of energy in cells. Because inefficient energy production is believed to contribute to the progression of HD, dichloroacetate therapy could result in increased energy production, and could possibly help delay HD progression.
The altered huntingtin protein seen in the nerve cells of people with HD has been known to cause a decrease in the amount of energy available in cells by disrupting energy metabolism. (For more on metabolism, click here.) The mitochondria of HD cells appear to be damaged by the altered huntingtin and are unable to perform aerobic respiration, a form of energy metabolism. The mitochondrial damage forces cells to resort to anaerobic respiration, a less efficient form of energy metabolism. The inability to perform efficient aerobic respiration leads to decreased energy production. This energy deficit in HD cells leads to various consequences: the cell is unable to perform its different functions as efficiently as it used to and is more vulnerable to toxicity by various molecules.
Researchers believe that increasing the efficiency of aerobic respiration, and in turn, increasing the energy available to the cell, is one way of slowing the progression of HD.
One way by which scientists measure the efficiency of metabolism is cells is by measuring the cells’ lactate levels. Lactate, a by-product of anaerobic respiration, is often found in higher concentrations in cells with decreased metabolism efficiency. High levels of lactate indicate that anaerobic respiration (the less efficient form of energy production) is the primary form of metabolism. On the other hand, low lactate levels indicate that aerobic respiration is the primary form of metabolism used by the cells.
Dichloroacetate in energy metabolism
Dichloroacetate has been found to decrease lactate production in cells by stimulating the pyruvate dehydrogenase complex (PDC), a critical group of enzymes involved in energy metabolism. The PDC is a large complex that is composed of multiple copies of three enzymes - E1, E2, and E3. The PDC serves as the vital enzyme involved in pyruvate oxidation, the step in aerobic respiration in which pyruvate is converted to acetyl-CoA. Pyruvate is a product of glycolysis, the first step in energy metabolism where sugar molecules from the carbohydrates we eat are transformed into pyruvate to be used for further processing in metabolism.
Each of the three enzymes that make up the PDC performs specific reactions that collectively transform pyruvate to acetyl-CoA. Acetyl-CoA is then transported into the mitochondria and enters the Kreb’s Cycle, a step in aerobic respiration. Once acetyl-CoA enters the Kreb’s Cycle, it undergoes various reactions that ultimately end in the production of large quantities of ATP. The PDC acts as a gatekeeper that facilitates and regulates the entry of pyruvate in to the Kreb’s Cycle.
In essence, the PDC determines whether the pyruvate molecules will be transformed into acetyl-CoA. If pyruvate is converted to acetyl-CoA, the cells can use the acetyl-CoA to undergo aerobic respiration. If pyruvate is unable to be converted to acetyl-CoA, the pyruvate is used in anaerobic respiration. If the PDC is damaged, fewer pyruvate molecules are converted to acetyl-CoA, which results in a decrease in the rate of aerobic respiration and a decrease in the number of ATP molecules produced. Instead, the pyruvate molecules stay in the cytosol and undergo anaerobic respiration, producing increased amounts of lactate. An abnormal lactate buildup results in various symptoms such as severe lethargy (tiredness) and poor feeding, especially during times of illness, stress, or high carbohydrate intake.
How is PDC activity regulated?
A family of enzymes called PDC Kinases acts to add phosphate groups to the E1 enzyme of the PDC. Adding a phosphate group to E1 inhibits the activity of the PDC complex. Acetyl-CoA usually activates these PDC kinases as a way to stop production of more acetyl-CoA when it is already present in large amounts and continued production is no longer needed.
Dichloroacetate therapy has been used to increase the efficiency of aerobic respiration. Researchers have reported that dichloroacetate stimulates the PDC by inhibiting the kinase that inactivates the PDC. Once the kinase is inhibited, the PDC continues to be activated and is able to perform its function of converting pyruvate to acetyl-CoA for use in aerobic respiration.
Given that impaired energy metabolism is implicated in the progression of HD, dichloroacetate treatment may improve metabolism and slow HD progression. In mouse models of HD, it is thought that the altered huntingtin protein interferes with the PDC kinases, causing a decrease in active PDC in nerve cells. This additional finding of decreased active PDC in HD nerve cells further supports the possibility of using dichloroacetate to stimulate the PDC and improve cell metabolism.
Dichloroacetate safety
There is some concern about the toxicity of dichloroacetate. Accumulations of dichloroacetate in groundwater have been described by some reports as a potential health hazard. However, concern about dichloroacetate toxicity is mainly based on data obtained in rats who were administered dichloroacetate at doses thousands of times higher than those to which humans are usually exposed. In these animals, chronic administration of dichloroacetate was found to cause liver problems and tumors. (Stacpoole, 1998.) In contrast, the dosage given to most humans is much lower than that administered to the rats. In clinical trials where dichloroacetate is used as a medical drug, no major side effects have been reported. Dichloroacetate is currently the most effective treatment for a disease known as congenital lactic acidosis (CLA). People with CLA have defective PDC enzymes and are thus unable to efficiently produce energy. In one study, patients with CLA were treated with 25-50 mg of dichloroacetate per 1 kg of body weight. No major complications were observed in the participants. (Stacpoole, 1997.) However, more research is currently being done to study the possible toxicity of dichlororacetate.
Issues of dichloroacetate toxicity have also arisen in research not directly related to HD. Dichloroacetate has also been found to protect against neuronal damage in the striatum of rats whose nerve cells have been deprived of blood flow. (Peeling, et al., 1996.) However, a recent report on an ongoing trial of dicholoroacetate treatment in people with mitochondrial disorders has reported that some patients developed new pathological symptoms and some had worsening in the transmission of nerve impulses. (Haas, et al., 2000.) Long-term trials are necessary to clarify the side effects associated with dichloroacetate and its role in HD treatment.
Research on Dichlororacetate
Gansted, et al. (1999) investigated whether dichloroacetate can improve the condition of people with mitochondrial myopathies (MM). The researchers hypothesized that dichloroacetate treatment in people with MM will result in improved energy metabolism. Because a decrease in metabolism is hypothesized to also be associated with HD, results of studies on MM and dichloroacetate may lead clues to the efficacy of dichloroacetate in HD treatment.
The mitochondrial myopathies are a group of neuromuscular diseases caused by damage to the mitochondria. Some of the more common mitochondrial myopathies include Kearns-Sayre syndrome, myoclonus epilepsy with ragged-red fibers (MERRF), and mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS). Mitochondrial myopathies are often caused by mutations in the DNA encoding the electron transport protein complexes, resulting in decreased ATP production. Aerobic respiration is not as efficient, so the cells of people with MM have to resort to more anaerobic respiration for their energy needs. The increased anaerobic respiration results in accumulations of lactate during exercise and contributes to exercise intolerance.
Dichloroacetate treatment was administered for 15 days to 7 people with MM. The study showed that dichloroacetate administration lowered lactate levels in most of the patients, indicating that dichloroacetate may improve metabolism efficiency. However, three patients reported that dichloroacetate caused a considerable sedative effect.
Andreassen, et al. (2001) reported that dichloroacetate has therapeutic effects in two mouse models of HD. One model, called the R6/2 mice, had C-A-G repeat lengths of 141 to 152. These mice exhibited HD-like symptoms such as decreased weight, motor dysfunction, brain atrophy, neuronal inclusions, and an increased occurrence of diabetes. The second mouse model, called the N171-82Q mice, had 82 C-A-G repeats in their Huntington genes. These mice exhibited symptoms similar to those of the R6/2 mice except that their symptoms were less severe and more delayed in onset.
Dichloroacetate treatment began at 4 weeks of age and was terminated at 12 weeks of age. A dose of 100mg/kg of body weight was administered daily. The study showed that dicholoroacetate-treated mice of both models showed significantly improved survival and motor function, as well as delayed weight loss and nerve cell loss. The development of diabetes was also delayed. Dichloroacetate was also found to maintain normal amounts of the active form of PDC. However, formation of neuronal inclusions was not altered by dichloroacetate treatment. The results of this study raise the possibility that dichloroacetate might be a potential HD treatment with therapeutic benefits for people with HD.
-P. Chang, 7/5/04
For further reading:
1. Peeling, et al. Protective effect of dichloroacetate in a rat model of forebrain ischemia. Neuroscience Letters. 1996; 208: 21-24. Peeling, et al. reported that dichloroacetate was able to protect against neuronal damage in the striatum of rats whose nerve cells have been deprived of blood flow.
2. Haas, et al. Results of the UCSD open label dichloroacetate trial in congenital lactic acidosis. In: Zullo SJ, ed. Mitochondrial Interest Group Minisymposium (Mitochondria: Interaction of Two Genomes). Bethesda, MD: NIH, 2000 p.2. Haas, et al. reported that some patients treated with dichloroacetate had developed new pathological symptoms and some had worsening in the transmission of nerve impulses.
3. Gansted, et al. Dichloroacetate treatment of mitochondrial myopathy patients. Neurology. 1999; 52 (Suppl 2): A544. This article reports that dichloroacetate treatment resulted in lowered lactate levels (and consequently, increased energy production) in people with mitochondrial myopathies.
4. Andreassen, et al. Dichloroacetate exerts therapeutic benefits in transgenic mouse models of Huntington’s disease. Annals of Neurology. 2001; 50(1): 112-6. This article reports that dichloroacetate treatment resulted in various beneficial effects in mouse models of HD.
5. Stacpoole, et al. Clinical Pharmacology and Toxicology of Dichloroacetate. Environmental Health Perspectives. 1998; 106: Supplement 4. This article reports that rats treated with dichlororacetate at dosages thousands of times higher than normally prescribed to humans exhibited various pathological side effects.
6. Stacpoole, et al. Treatment of congenital lactic acidosis with dichloroacetate. Archives of Disease in Childhood. 1997; 77: 535-541. This article reports that dichloroacetate treatment resulted in lower lactate levels in people with congenital lactic acidosis.
| Surviving "Terminal" Cancer: Clinical Trials, Drug Cocktails, and Other Treatments Your Oncologist Won't Tell You About |
| Surviving "Terminal" Cancer: Clinical Trials, Drug Cocktails, and Other Beating Cancer with Nutrition |