Respectful Insolence

Since DaveScot has made an appearance or two in the comments here, annoying everyone he comes in contact with, it’s worth pointing out that mine isn’t the only cluestick that could be used to pound some science into him about dichloroacetate, the supposed “cure” for cancer that’s being “ignored” or “suppressed” by Big Pharma. Since my original article on the subject, two more excellent (and realistic) overviews of the promise and peril of DCA as an inexpensive chemotherapeutic agent to treat cancer have appeared, one of them by fellow ScienceBlogger Abel Pharmboy and one actually appearing on Daily Kos, the site that posted one of the original hysterical “we have a cheap cure for cancer but Big Pharma’s ignoring it” posts.

So, DaveScot, meet this trio of cluesticks. Trio of cluesticks, meet DaveScot again.

While we’re at it, a commenter named Phil Monk has posted another example of someone who really, really could use the cluestick on this issue as well, a guy by the name of Damien Zerek. Geez, this guy makes DaveScot look restrained by comparison.

But, seriously, it’d be really, really great if all the hype were true and this stuff were to be shown to cure cancer in humans in the Phase II clinical trial that will soon be done. Aside from the cancer patients whose lives would be saved and their loved ones, I doubt anyone would be much happier than me. (I’d love to see the “no more cancer” as much as anyone; I could always do other kinds of surgery and research for a living.) I also realize that there are legitimate complaints about how this case illustrates shortcomings in our drug development system and that may have been a bit harsh at times while addressing this issue. However, nearly all of my targets richly deserved it (the most prominent possible exception being Ezra Klein). What irritated me so was the trumpeting of “a cure for cancer,” coupled with rants that showed that the people doing the ranting didn’t have a clue about cancer, drug development, clinical trials, or research funding.

Given that, the main reason I posted about DCA yet one more time, even at the risk of boring my readers or annoying certain of my fellow ScienceBloggers again, is because there are now more articles by other bloggers discussing the issue in a much more scientific and and balanced manner (minus the saracasm–well, mostly), and I wanted to publicize them, particularly since they take somewhat different approaches than I did. Abel, as usual, puts things in good perspective, and, hard as it was for me to believe, this Kos diarist, while going into detail on some aspects of the science behind cancer treatments, specifically the p53 oncogene (I emphasized antiangiogenic therapy in my original post), gets in a couple of zingers worthy of Orac:

In addition, I’d like to vehemently squash the notion right out that the NIH is somehow in the pocket of Big Pharma to the degree that they would never fund a study into the efficacy of DCA. This is simply not true, and to peddle in this falsehood makes us liberals look like tin-foil hat-wearing loons. The NIH pays an enormous sum to study cancer every year, including studies into potential anti-cancer drugs.

Preach it, brother!

The non-Orac cluesticks:
The dichloroacetate (DCA) cancer kerfluffle
Dichloroacetate Redux: A Cancer Primer
Cancer cures and the evil of false hope

Please, read them all, if you haven’t seen them already. They basically agree with me, but flesh out the discussion from different perspectives than mine.

ADDENDUM: Walnut has posted his critique on Daily Kos as well.

All Orac posts on DCA:

  1. In which my words will be misinterpreted as “proof” that I am a “pharma shill”
  2. Will donations fund dichloroacetate (DCA) clinical trials?
  3. Too fast to label others as “conspiracy-mongers”?
  4. Dichloroacetate: One more time…
  5. Laying the cluestick on DaveScot over dichloroacetate (DCA) and cancer
  6. A couple of more cluesticks on dichloroacetate (DCA) and cancer
  7. Where to buy dichloroacetate (DCA)? Dichloroacetate suppliers, even?
  8. An uninformative “experiment” on dichloroacetate
  9. Slumming around The DCA Site (TheDCASite.com), appalled at what I’m finding
  10. Slumming around The DCA Site (TheDCASite.com), the finale (for now)
  11. It’s nice to be noticed
  12. The deadly deviousness of the cancer cell, or how dichloroacetate (DCA) might fail
  13. The dichloroacetate (DCA) self-medication phenomenon hits the mainstream media
  14. Dichloroacetate (DCA) and cancer: Magical thinking versus Tumor Biology 101
  15. Checking in with The DCA Site
  16. Dichloroacetate and The DCA Site: A low bar for “success”
  17. Dichloroacetate (DCA): A scientist’s worst nightmare?
  18. Dichloroacetate and The DCA Site: A low bar for “success” (part 2)
  19. “Clinical research” on dichloroacetate by TheDCASite.com: A travesty of science
  20. A family practitioner and epidemiologist are prescribing dichloracetate (DCA) in Canada
  21. An “arrogant medico” makes one last comment on dichloroacetate (DCA)

Posts by fellow ScienceBlogger Abel Pharmboy:

  1. The dichloroacetate (DCA) cancer kerfuffle
  2. Where to buy dichloroacetate…
  3. Local look at dichloroacetate (DCA) hysteria
  4. Edmonton pharmacist asked to stop selling dichloroacetate (DCA)
  5. Four days, four dichloroacetate (DCA) newspaper articles
  6. Perversion of good science
  7. CBC’s ‘The Current’ on dichloroacetate (DCA)

Comments

  1. #1 justawriter
    February 5, 2007

    You do have to remember that Daily Kos is a community with more than 100,000 members and the price for that kind of vibrancy is a certain percentage of lunatic fringe. Over time such a community will either self-correct or fly off into USENET troll-tail-chasing. The Kos community seems to have the resilience and self fortitude to deal with regular outbreaks of temporary insanity.”

  2. #2 Dianne
    February 5, 2007

    Hmm…I’m researching a drug (actually a derivative of a cell surface marker, but never mind that right now) that might be useful as a treatment for cancer* and, despite my and my PI’s best efforts, have yet to interest a drug company in making human grade material for clinical trials. Does that mean that big pharma is oppressing me too? Help, help, I’m being oppressed, I’m being oppressed…

    *It and nothing else is going to be “the cure for cancer” because cancer is not a single disease, but the collective name for a number of different conditions which all have in common the characteristic of run away cell growth with metastatic potential. Talking about “the cure for cancer” is like talking about “the cure for infectious disease”, rather than “the cure for polio” or even “the cure for bacterial illnesses”: it’s very, very unlikely that a single treatment is going to cover all of it.

  3. #3 anonimouse
    February 5, 2007

    Plenty of sunshine, lots of sleep, good hygeine and fresh food will cure cancer. Lorraine Day and Kevin Trudeau said so. Oh yeah, and no TV. And read the Bible. And buy their books, yeah, can’t forget the books.

  4. #4 JujuQuisp
    February 5, 2007

    I wonder what the esteemed Dr. D.A. Cook thinks about this matter. We have yet to hear him chime in on a subject that should be in his ballpark, if he is a real doctor.

  5. #5 Phil Monk
    February 5, 2007

    The news cycle has turned the page.

    Lab disaster may lead to new cancer drug

  6. #6 Robert Smith
    February 5, 2007

    This is really silly. First off doc, the issues with getting FDA approval shouldn’t apply. The drug is already approved for human use. The only issue should be whether it clears cancer cells. It takes a month to get to see an oncologist, and another 2 weeks before he scans you. Thats six weeks where a patient with nsclc could be shrinking his tumor. Doctors, get your pencil moving on the script pad and write the damn script while the patient waits doing nothing to shrink his tumor. CANCER IS NOT many different diseases. It is a single disease that affects 220 cell types. If you were keeping up on the research you would have seen Gostjeva’s (et al MIT) jan 2006 paper on bell shaped nuclei. She compared colon cancer stem cells vs fetak sten cells that were making a new colon. They were identical, both making the same 7 cell types as if they were making a new colon. Laird, USC very recent issue of Nature Genetics, concluded from his study that cancer arises when an embryonic stem cell fails to mature and stabilize, has its genes silenced,,, then reawakens in an adult body and tries to go about making the same organ it was trying to make in the fetus. The fetus and the tumor both run on glycolysis. If you have a drug that can convert the mitochondria to normal operation you should apply it immediately, after all you know its used in babies for crying out loud. “First do no harm” , well we already know that its less harmful than chemo, radiation, and surgery. So while the patient is waiting for the healthcare system, let him take the darn stuff. Which does more harm, waiting for a month and a half with no treatment, or letting the patient try a drug that is already approved and stands to shrink his tumor to a striking degree in the time he waits for the system to begin his slash, burning, and poisioning.

    I hope patients start suing doctors for not writing this script. It appears that it is the only way to save hundreds of thousands of lives.

    An high grade untreated tumor and a fetus have roughly the same growth rate. The cancer is generally immune priveleged for the same reason that a fetus is immune priveleged, the same mechanism,, they are both stem cells and their daughter cells.

    I cannot abide by the present system of years of study being required for non toxic treatments that have the capacity to heal.

    This drug should be written off label by couragous doctors who want to save their patients lives. Any other choice is the doctor simply taking a “not my job” attitude, or a “its not my decision”, or “its not approved” I call it professional chicken—-itis. Write the damn script.

  7. #7 howell
    February 5, 2007

    Re: robert smith-

    Cancer is most definately many diseases. The stem cell-cancer connection is exciting, and may apply to some systems, but reality is much more complicated than the model you present.

    For example, many b-lymphomas clearly arise in mature, fully differentiated cells, which can be clearly seen by the monoclonal rearranged b-cell receptor gene found in the genome of each cancer cell.

    In addition, many oncogenes work only in one or a subset of tissues. The BCR-ABL translocation causes cancer only in the hematopoietic system, even when it is present in every cell in the body.

  8. #8 JujuQuisp
    February 5, 2007

    Interesting….Robert Smith is a known pseudonym that DaveScot uses. I guess he’s too much of a coward to reveal himself here. Very un-marine-like, David Springer.

  9. #9 robert smith
    February 5, 2007

    Four genes have been discovered this year that can cause a normal adult stem cell to revert to an embryonic state. It doesn’t surprise me to see that normal cells can become cancerous. Nanog is one gene, can you name the other three?

    Think just about telomerase for a second. Its upregulated by estrogens, and other things. Telomerase upregulates 70 genes known or suspected in cancer (Liz Blackburn 20006 Lasker, and Gruber Genetics prizes), grant cancer cells replicative immortality (Blackburn et everyone) and activate glycolysis,,, so far confirmin work was in melanoma at UCSF, study on my website towards bottome. You can revert any cell in the body to an embryonic (cancerous) state. Its happening now, and I say again, cancer is the result of making any class of cell into an embryonic cell, and then it goes about its program to make a new organ.

  10. #10 Orac
    February 5, 2007

    Interesting.

    I was unaware of the Robert Smith pseudonym. (I wonder if he’s a Cure fan.) The IP address from which his comment came doesn’t quite match, but it maps to the same (or very close to the same) place in Kansas that previous DaveScot comments did. Oddly enough, it didn’t even occur to me to compare them until you commented.

    In any case, “Robert Smith’s” understanding of cancer, clinical trials, and medical ethics is every bit as poor as DaveScot’s understanding of evolution is.

  11. #11 Robert Smith
    February 5, 2007

    I’m not , “DaveScot”, this is my first time posting here. Please don’t get personal or I’m outta here. If you want to talk science, lets rock.

  12. #12 S. Rivlin
    February 5, 2007

    Mr. Robert Smith,

    DCA is not a FDA approved drug for human use. DCA has many toxic effects in normal tissues and cells (see a list of some of them in another comment of mine in another thread dealing with DCA on this blog). I have a suggestion for you: Order a kilo or two of DCA from Sigma Chemicals, prepare your own solution of the stuff to be administered either by injection or orally and start dispensing it outside the enterance to your neighborhood oncoloy clinic. However, be honest with your poor patients and explain to them that any toxic side effects that may kill them are probably not worse than the nausea they may have with chemotherapy or the death that cancer would bring upon them anyway. Also, do not forget to tell them that you are an expert on cancer, since you read an article in Nature Genetics, where it is written that all the mysteries of cancer have been elucidated.

  13. #13 Robert Smith
    February 5, 2007

    Not FDA approved!!!????? They give it to babies all the time. I say again, you can revert any human cell type to an embryonic state. Do your homeword or I will give everyone a serious quiz every day till semesters end. I again request that you don’t get personal or I will quit posting.

  14. #14 S. Rivlin
    February 5, 2007

    If you are serious, Robert, then cite references more accurately. If babies are given DCA all the time, what it is been given for (don’t forget the references)?

  15. #15 HCN
    February 5, 2007

    I put “dichloroacetate” into the Medlineplus search box and got no results in the Drugs and Supplements catagory. There were some hits under “Metabolic Disorders”, “Neuromuscular Disorders”, “Degenerative Nerve Disorders” and “Genetic Brain Disorders”. I clicked on the last one to get:
    http://www.ninds.nih.gov/disorders/leighsdisease/leighsdisease.htm … where it says “Experimental protocols are currently using dichloroacetate to treat patients with lactic acidosis.”.

    I also search the FDA website. I tried their list of approved drugs, but I did not find it. Then I did a search on the entire site where I found this:
    http://www.fda.gov/orphan/designat/alldes.rtf

    It is a list of orphan drugs… where it shows the applications it is being tested for, and the date of approval. Here are what dichloroacetate is being studied for:
    Treatment of homozygous familial hypercholesterolemia.
    Treatment of congenital lactic acidosis.
    Treatment of lactic acidosis in patients with severe malaria.
    Use as an antidote in the management of systemic monochloroacetic acid poisoning.
    Treatment of severe head injury.

    Each one of these has a “Date Designated”, followed by the words “Date Approved”. Each of the “Date Designated” have a date indicated, there is NOTHING listed for “Date Approved”.

    Experimental and orphan does not mean approved.

    So if you have some other information of what DCA is approved for and used routinely in use to treat, please tell us. Thank you.

    (by the way, the spam filters kick on if you post more than two weblinks in a comment)

  16. #16 Robert Smith
    February 5, 2007

    Ok so go ahead and debate the approval status in the United States rather than the science. I’d rather argue the science however. Its available most everywhere else,, even over the counter in some countries. I gladly stand corrected on the approval status of the drug, in the U.S. Check Canada if you please. It would be nice to see all countries where it is approved. The stuff has been used since dirt. Now, lets talk about the importance of restoring the mitochondria of cancer cells to normal operation and the resultant activation of the P-53 suicide gene. Yes you can get it from Sigma Aldrich, but its available elsewhere too and has industrial uses.

  17. #17 Orac
    February 5, 2007

    Read my post above and the numerous links therein. The science is being discussed.

    You clearly have no clue over why clinical trials are necessary. There is no evidence that DCA works in humans against cancer. As is explained in my previous post and in the three posts by others, many are the candidate drugs that looked as though they were effective against mouse tumors that failed to be nearly as impressive in human trials.

    As for the Warburg effect, the science is interesting, and it’s a promising target, but only 60-90% of tumors demonstrate the Warburg effect, and you haven’t factored drug resistance. The reason other chemotherapies all too often fail is because tumor cells develop resistance. There is no reason to think that tumors sensitive to DCA wouldn’t also develop resistance.

    Finally, cancer stem cells are a fascinating concept that probably have relevance to many tumors, but their existence by no means invalidates the contention that cancer is not one disease.

  18. #18 Coin
    February 5, 2007

    I gladly stand corrected on the approval status of the drug, in the U.S. Check Canada if you please.

    http://www.depmed.ualberta.ca/dca/

    At this point, the University of Alberta, the Alberta Cancer Board and Capital Health do not condone or advise the use of dichloroacetate (DCA) in human beings for the treatment of cancer since no human beings have gone through clinical trials using DCA to treat cancer. However, the University of Alberta and the Alberta Cancer Board are committed to performing clinical trials in the immediate future in consultation with regulatory agencies such as Health Canada. We believe that because DCA has been used on human beings in Phase 1 and Phase 2 trials of metabolic diseases, the cancer clinical trials timeline for our research will be much shorter than usual.

    CTV.ca, Jan 22

    The time required for the DCA trials will be shorter compared to brand new drugs that have never been tried in humans before. DCA has already passed phase one trials and can enter directly phase 2 trials in patients with cancer. In addition, at least for Canada, DCA has to be purified, sterilized and appropriately formulated before it can receive approval from Health Canada for oral use in humans. The agony of the public for their loved ones already suffering from advanced forms of cancer can be dramatic but the appropriate steps need to be followed.

    Google’s really pretty easy to use.

  19. #19 Robert Smith
    February 5, 2007

    Good Canada will have a very effective treatment far before the U.S. Great. I don’t give a damn about what the FDA thinks with regard to a drug that will show little toxicity AT THE DOSE REQUIRED. I do care that people are dying for want of a pretty safe compound as compared to chemno and i’ve identified one of many holes and gaps in time with current therapies that could be filled with DCA. The idiocy of considering that cancer is 220 plus diseases with all the corresponding subtypes still amuses me. This thinking went down the toilet recently. So the oncologists soon won’t be able to quote that claptrap when delivering the final death sentence to the patient and his family. Appropriate steps are pure s–t when you are watching people take their last gasp of air. Here is a tip for you, after the doctor delivers your final huge blast of radiation for “pain relief”, and tells you you have about 30 days till you meet Jesus, know that instead of that giant rad burst he could have told you to get on a plane and go somewhere where you could try one last thing. Wouldn’t that be a real pro-life society? Wouldn’t it be nice if the FDA would do a trial in real time without months, even years of bull_s— planning and crap. We already know this stuff shuts down glycolysis. I equate your proposal that it will mutate, to the similar claims cynics made about the telomerase enzyme as the first telomerase inhibitor heads through phase 1/2 human trials. They claimed that telomerase in cancer cells would mutate. This was a joke of course. If telomerase mutated , it wouldn’t be able to extend the TTAGGG repeats on the telomeres and the cell would die. I think you’ll see a minimum of three drug apps in short order due to the U of Alberta study. In countries where they still have some freedom to try to live, family members will learn from the experiences of their older family members and friends and they will take DCA. Stem cells run on glycolysis. Shut it down and they die. If there is a “subtype” left over, they won’t be fast growing because they aren’t running on glycolysis and will probably respond well to conventional medival torture.

  20. #20 HCN
    February 6, 2007

    Robert Smith said “First off doc, the issues with getting FDA approval shouldn’t apply. The drug is already approved for human use. ”

    Do tell us exactly where it is approved and for what. Because as far as we can tell, it is not in North America (oops, sorry, technically that includes Mexico, and I did not check there).

    A quick check on Pubmed shows some studies warning about the toxity. Yikes! Like here:
    http://www.neurology.org/cgi/content/abstract/66/3/324 where it says it was stopped early because ” The clinical trial was terminated early because of peripheral nerve toxicity”.

    What do you have to offer… some blatherings without any evidence? Take a hint: You can post up to two web links without the spam filter taking effect. Try it, please!

    Start at http://www.pubmed.gov

  21. #21 Robster
    February 6, 2007

    “First do no harm” , well we already know that its less harmful than chemo, radiation, and surgery.

    DCA, given as an anticancer drug would be a form of chemo, RS. Also, DCA is a powerful acid, and, IIRC, severe burning pain is listed as a side effect for IV us. Furthermore, DCA has been reported to cause peripheral nerve toxicity (common with several classes of oncolytics). Also, as Abel points out, it is a liver carcinogen in rodents. It is far from being harmless. Sedation has also been reported, suggesting CNS effects as well.

    Beyond this, there are genetic differences (polymorphisms) that can alter DCA metabolism. Simply put, a dose that works in one patient may not work in another. This can be overcome with genetic screening of patients, though this will increase the cost of treatment.

    Here is a good review on DCA toxicity.

    In fact, a close relative of DCA, trichloroacetic acid is used to burn off genital warts. I have used it many a time in experiments to fix cancer cells to plastic cell culture plates. Flakes of powdered TCA, when they come into contact with skin, causes serious burns.

  22. #22 Robster
    February 6, 2007

    Oh, and as has been pointed out repeatedly, there is no proof that DCA cures cancer, either in rodents or humans. Only that it has been reported to cause tumor shrinkage in rodents. This is far from proof that it is a cure-all for humans. I hope it is, but will have to wait for evidence. We don’t just toss every maybe-effective drug into the clinic without first determining what the maximum tolerable dose is, basic safety and efficacy information for that dose, and then an expanded safety trial. If you don’t know the right dose, you can’t use it. As discussed above, DCA therapy isn’t all puppies and rainbows. Trust me on this one, for all the drugs you can use to treat various cancers in mice, only a fraction can be used safely in humans, with even fewer giving favorable effects.

  23. #23 Orac
    February 6, 2007

    DCA, given as an anticancer drug would be a form of chemo, RS.

    Indeed. If it works againts human cancer, DCA would just be another form of chemotherapy if it were used against cancer. “Robert Smith” seems not to understand that.

  24. #24 Robert Smith
    February 6, 2007

    Hey guys he wasn’t running straight DCA through their veins, he put it in the rodents drinking water. 75mg per Liter, and gave them free access to the water. So it was diluted. Did you look at the ph of 75mg/L ? The toxicity numbers you are getting are for pretty large doses aren’t they. There are papers out there that don’t show the toxicity that was found in rodents and dogs. How big a dose were they giving in the tox studies compared to this U of Alberta study? Yes there is no proof that DCA cures cancer. I would have liked to see the work carried on for another few weeks too, but funding from govt sources, even in Canada is scarce. Notice the reporter from CTV claims this is the third such promising compound that has gong nowhere because it wasn’t patentable by pharma. 75g per liter, what is the ph?

  25. #25 David Scott
    February 6, 2007

    Poor Dave Springer. He must be so mad that there are so many sites on the internet containing so many comments that he can’t edit or censor.

  26. #26 Orac
    February 6, 2007

    Hey guys he wasn’t running straight DCA through their veins, he put it in the rodents drinking water.

    Even if DCA turns out to be effective at oral doses against human cancers, it would still be chemotherapy. There are a number of chemotherapeutic agents that are dosed orally.

  27. #27 robert smith
    February 6, 2007

    not at all , chemo is a poison first, a blanket poison usually. How can anyone make a statement like that!! Dear budda!! The stuff switches the mitochondria back on in normal mode. That means the cancer cell doesn’t have enough energy to support its embryonic growth rate, and it futin dies. Like I said, a 2 month trial with an oral dosage and the cancer is dead and gone.

  28. #28 Orac
    February 6, 2007

    Apparently Robert Smith knows just as little about chemotherapy as he knows about clinical trials. Chemotherapy refers to the use of chemical to treat disease. Period. In more modern usage with respect to cancer, which has come to be the primary definition of the word “chemotherapy,” it refers to the use of chemical compounds to treat cancer. Period.

    In cancer, most chemotherapeutic agents are selective poisons; i.e., they are more poisonous to cancer cells than they are to normal cells. The best chemotherapies are much more toxic to cancer cells than to normal cells; unfortunately, many cancer chemotherapeutics demonstrate only slightly more toxicity to cancer cells than to normal cells. However, the main work in oncology these days involves developing chemotherapeutic agents with more selectivity towards cancer and less toxicity to normal cells.

    DCA is chemotherapy. It happens to be a poison that inactivates a specific enzyme, the end result of which in cancer cells is the switch to an oxidative metabolism, the generation of more reactive oxygen species intracelluarly, and increased tumor cell apoptosis, among other things. It, too, is a selective poison. The difference is that its level of selectivity is potentially much higher than most chemotherapeutic agents in present use, but that’s the only difference. It’s still chemotherapy. Trying to label it as not being chemotherapy is, quite frankly, ridiculous and betrays a profound lack of understanding of cancer chemotherapy on your part.

  29. #29 Unsympathetic reader
    February 6, 2007

    One comment on the “cured cancer hundreds of times over in rats” debate I’ve read in blogs on this subject. Bear in mind that this generally refers to cancers developed by the injection of human or other tumor cell lines into inbred mouse lines specially developed to accept foreign cells. These aren’t rats that developed cancer “naturally” but through xenografts – foreign cancers. And yes, the literature is littered with examples of test compounds that show effects on the xenograft cancer cells but had no efficacy in the clinic. Many failed cancer drugs worked on xenografts. Many test compounds developed during cancer drug lead optimization stages but which never even made it into the clinic (ie. the vast majority) work on xenografts. And no wonder, because these aren’t “native” tumors or cancers, they are living in quite a different environment from whence they came (They are, in many cases, like hothouse flowers — Already in a ‘delicate’ state). Because of the low predictive success of these model systems, data from xenograft experiments are always taken with a grain of salt. Shrinking or “curing” xenograft tumors with test compounds happens pretty frequently — Finding practical drugs that work on humans is rare.

  30. #30 Unsympathetic reader
    February 6, 2007

    Adding to Orac’s comments: DCA is also being proposed as potential sensitizer that may increase the efficacy of other chemotherapy.

  31. #31 Hyperion
    February 6, 2007

    Mr. Smith unknowingly makes another important point against the use of DCA without further testing: Nobody knows what an effective dose would be, and there does not seem to be much data on the drug’s pharmacokinetics, which is something that you would really want to know before giving it to a patient. Without knowing its pharmacokinetics, there’s no way of even knowing whether an oral dose would have any effect, or whether oral absorbtion might result in an effective dose reaching certain regions but not others.

    As the use of DCA in humans has been associated with peripheral neuropathy, one would presumably wish to use a dose and route of administration that minimizes systemic exposure while ensuring that an effective dose reaches the tumor. Without knowing what constitutes an effective dose for a tumor of given size and type, and without knowing the pharmacokinetic profile of the agent, there is no way to safely administer this drug in a beneficial manner. This is why no one (hopefully) is going to prescribe this for cancer patients in the absence of definitive evidence. After all, nobody wants to have to say to a patient:

    “I’m sorry Mr. Smith, but now in addition to your lung cancer, it appears that the DCA we gave you has resulted in peripheral neuronopathy, delaying any future chemotherapy options, and has damaged the mucous membrane in your stomache and GI tract, thus precluding any use of NSAID painkillers in the future.”

  32. #32 Robster
    February 6, 2007

    rAmen, Hyperion, rAmen.

  33. #33 S. Rivlin
    February 6, 2007

    DaveScot has just found another reason to promote the use of DCA against cancer. In a response to a new item on his Uncommon Descent Blog http://www.uncommondescent.com/archives/2030#comments
    he commented by suggesting to solve the global warming with a global cooling http://www.uncommondescent.com/archives/2030#comment-89709
    I think this is unbelieveable.

  34. #34 Robert Smith
    February 6, 2007

    You guys must have eaten your nasty boy beans this morning,,, and last night. The peripheral neuropathy was observed at a dosage of 25mg/kg/day, for up to 2 years. The rats got water at 75mg/liter. Typical of surgeons to try to call this drug something worse than surgery. You guys do so need an ego to do what you do but it can mess you up on the learning curve for new stuff.

    Chemo is poison to the entire system. DCA subjects took it at 25mg/kg/day for up to two years before the peripheral neuropathy got too bad and they dropped out. And it was reversible with time. Try taking todays chemotherapy for two years, try it with cisplatin, see how you feel after 6 weeks. Of note, and in regard to the work I cited on cancer being of embryonic origin, they have found cancer stem cells in near every cancer, here is the latest one::Researchers find pancreatic cancer’s stem cells

    New York Times Syndicate

    02-01-07

    Ann Arbor, Mich. — University of Michigan researchers have discovered the stem cells in pancreatic cancers, a breakthrough that could lead to better treatments of one of the deadliest cancers, according to research that will be published in Thursday’s journal of Cancer Research.

    “It’s the worst cancer you can get,” said Diane Simeone, the study’s lead author and surgical director of the university’s Multidisciplinary Pancreatic Tumor Clinic. “There hasn’t been significant progress in effectively treating pancreatic cancer for a long time. I am optimistic this may be a real breakthrough in how we treat pancreatic cancer in the future.”

    Stem cells are the most basic cells, and researchers believe a small, but resistant, number of cancer stem cells fuel the growth of tumors. Many people relapse or die because current treatments don’t kill all the cancer stem cells in the tumor. The discovery of the stem cells means researchers can now study how to destroy them, according to Simeone.

    Michigan researchers were the first to discover cancer stems cells in a solid tumor of the breast in 2003. Since then, researchers have also discovered the stem cells in brain, central nervous system, colon cancers and leukemia, which has led to continued research into more effective therapies.

    The breakthrough in pancreatic cancer is especially important because almost everyone who is diagnosed with the disease dies from it because diagnosis often occurs after the disease has spread. An estimated 32,000 people will be diagnosed this year with cancer of the pancreas, a gland in the abdomen that secretes digestive enzymes, insulin and other hormones.

    The only therapy for pancreatic cancer is surgery to remove the tumor, and only 15 percent of people can undergo the treatment.

    “If this is heading in the direction to find a cure for this nasty disease, then huge kudos to the doctors that discovered this,” said Brownstown Township resident Terry Fornwall, who was diagnosed with pancreatic cancer three years ago, had surgery and has been in remission for 18 months.

    Clinical trials for new therapies could come within three to four years, which thrilled advocates.

    “Any time there is information out there that suggests new treatment options for any type of cancer, our community has renewed hope,” said Kristen Bernat, facilitator of the Pancreatic Support Group at Gilda’s Club Metro Detroit. “It is important for newly diagnosed patients to know that there are new treatments out there
    *******
    Gerorgie bush’s ban, and it is a ban if you know any researchers involved, his ban is a foot on the throat of cancer researchers, and on the throat of cancer victims. I figure he’s killed about 35,000 people a year with the bans effects on the delays in regenerative medicine, God knows how many due to cancer. We really have to study all cell types to understand cancer folks. For the insolent ones, I pass lower g.i. smell in your general direction.

  35. #35 S. Rivlin
    February 6, 2007

    Mr. Smith,

    Why to wait 3-4 years for therapy trials when we can give pancreatic cancer patients DCA right now?

  36. #36 Robert Smith
    February 6, 2007

    I think we will see countries who use this drug all the time for lactic acidosis in malaria victims, from heart/lung conditions, etc. start using it right away for cancer. It also imporves cardiac output I’m told, but am not familiar with that aspect of it.

  37. #37 HCN
    February 6, 2007

    Which countries use DCA all the time for lactic acidosis in malaria?

  38. #38 S. Rivlin
    February 6, 2007

    HCN,

    The malaria story is based on one publication by a group of scientists from Thailand:

    Metabolism. 1994 Aug;43(8):974-81.
    Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment.
    Krishna S, Supanaranond W, Pukrittayakamee S, Karter D, Supputamongkol Y, Davis TM, Holloway PA, White NJ.
    Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

    This study is 12 years old and DCA was never established as a treatment for the dangers of malaria. The more I read Robert Smith’s comments, the more he sounds like David Springer, who also brought up the malaria story as proof of DCA use and the argument that DCA is a FDA approved drug.

    As to your original question, I guess Thailand is one country where DCA was used, once, in an experiment for lactic acidosis in malaria. BTW, lactic acidosis is a symptom of derailed energy metabolism. Neutralizing acidosis (treating the symptom) does not correct the cause of the derailment.

  39. #39 Davis
    February 6, 2007

    Okay, I’m annoyed enough to delurk. Robert Smith, are you even reading the responses to your comments? Each and every one of your points has been rebutted by people who clearly know their stuff. Yet you keep repeating your claims without addressing the arguments made against them.

  40. #40 JujuQuisp
    February 6, 2007

    DaveScot needs to go back to UncommonlyDense and preach the virtues of Green Tea. Quit arguing about things you know nothing about, DaveScot..err, I mean “Robert Smith”. That subscription to Scientific American that your wife bought for you is really not doing you any good. Have her cancel it now.

  41. #41 Coin
    February 6, 2007

    Robert Smith wrote:

    Good Canada will have a very effective treatment far before the U.S.

    You seem to be referring to the links I posted above. But my understanding of those quotes is that Canada has the same (or greater?) regulatory hurdles to DCA being approved for cancer treatments that America does. I do not have any personal knowledge of how drug approval works in either the U.S. or Canada, but a plain reading of those links indicates that the Canadian authorities are waiting on the exact same phase II trial that the American FDA is, after which the Canadian authorities will have to approve the specific formulation of oral DCA settled on for human consumption.

    Incidentally, could someone who’s familiar with these things please explain, because I’m curious– am I reading this right that Canada Health is the Canadian equivalent of the FDA? Those articles are written as if Canada Health uses the same Phase I/II/III system that is used in America– can one single test simultaneously qualify as a Phase II trial in both America and Canada, or other countries for that matter? How does this work?

  42. #42 S. Rivlin
    February 6, 2007

    HCN,

    Here’s one country in which DCA was used once (experimentally) against Malaria’s lactic acidosis:

    Metabolism. 1994 Aug;43(8):974-81.
    Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment.Krishna S, Supanaranond W, Pukrittayakamee S, Karter D, Supputamongkol Y, Davis TM, Holloway PA, White NJ.
    Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

    This article was cited by DaveScot a.k.a. Robert Smith on his Uncommon Descent Blog, where he also claimed that DCA is an FDA-approved drug.

  43. #43 S. Rivlin
    February 6, 2007

    BTW, could it be that DaveScot (David Springer) is genetically related to Sylvia Browne?

  44. #44 Phil Monk
    February 6, 2007

    In terms of availabity and usage, sometimes a molecule is designated as a chemical instead of a drug, at least in Canada.

    As an example, methadone powder is not a drug in Canada. It has no Drug Identification Number (DIN), which all approved drugs have in Canada.

    While its use is strongly regulated, in terms of who can prescribe it and who can dispense it, the powder itself is not considered a drug.

    The same may be true for dichloroacetate. I have read many times that it is used for lactic acidosis while also reading that it is in phase I & II. This could explain the anomaly.

  45. #45 Robster
    February 6, 2007

    You guys must have eaten your nasty boy beans this morning,,, and last night.

    Typical. We disagree and he calls us nasty. Do we need to call the whaaambulance?

    The peripheral neuropathy was observed at a dosage of 25mg/kg/day, for up to 2 years. The rats got water at 75mg/liter.

    And what will the appropriate dose for human cancer patients be? How about the schedule? How does 75mg/L in a rat compare to 25 mg/kg/day in a human? How long will the patient require treatment?

    Admit it. You don’t know. We don’t know yet, so we run clinical trials to find out.

    Typical of surgeons to try to call this drug something worse than surgery. You guys do so need an ego to do what you do but it can mess you up on the learning curve for new stuff.

    And yet, in some cases, surgery is the right course. And I’m not even a surgeon! (PhD in Toxicology. All my patients are in tissue culture flasks)

    Chemo is poison to the entire system.

    ALL things are poisons at the right dose. Chemo uses selective poisons to kill cancer cells. DCA is the SAME thing. If DCA works, it works by poisoning cancer cells. Enough DCA will poison and kill a patient. The question is, how much will kill off a tumor without killing the patient, severely damaging their liver, or damaging their GI tract? We don’t know.

    DCA subjects took it at 25mg/kg/day for up to two years before the peripheral neuropathy got too bad and they dropped out. And it was reversible with time.

    And how is this different from taxol? Peripheral neuropathy that goes away after treatment is ended? Same thing.

    Try taking todays chemotherapy for two years, try it with cisplatin, see how you feel after 6 weeks.

    It depends on the dose. The dose required to kill cancer cells may not be one that is clinically useful.

    Do you understand the need for trials?

  46. #46 Dianne
    February 6, 2007

    Am I going to have to be the first one to break it to Mr Smith that the NYT is not a peer reviewed journal? Pancreatic cancer, like all cancers, has been cured many times in mice and cell culture. Unfortunately, the treatments didn’t work in humans or were more toxic than the disease. It’ll be nice if this one leads somewhere, but don’t hold your breath.

  47. #47 Dianne
    February 6, 2007

    The peripheral neuropathy was observed at a dosage of 25mg/kg/day, for up to 2 years.

    What was not noted, unfortunately, was any sign of clinical effectiveness. In the study referenced (here, again, to remind people of which study we are talking about), 15/15 patients were taken off the study drug (DCA) because of toxicity. At the toxic dose, no clinical efficacy (ie no improvement in the MELAS symptoms) was seen. So the therapeutic window is nonexistent. At least for that disease. That doesn’t mean that low dose DCA might not be good for something, but it is by no means non-toxic or a panacea.

  48. #48 HCN
    February 6, 2007

    S Rivlin wrote “This article was cited by DaveScot a.k.a. Robert Smith on his Uncommon Descent Blog, where he also claimed that DCA is an FDA-approved drug”

    Well, I was kind of waiting for Mr. Smith to answer that question. Since I did see papers where it was STUDIED in Ghana and Kenya (studied, as in not ALL of the time!).

    With the statement that DCA is used all of the time in other countries for malaria, and that it is approved by the FDA and that is used on babies… all of which were shown to be false with just a little bit of research (I am an engineer with no training in any biology, but I do know how to use Pubmed and other search engines)….

    My next question to Robert Smith and/or DaveScot is:

    Do you write statements down as fact without doing just a smidgen of research?

  49. #49 tgibbs
    February 6, 2007

    If telomerase mutated , it wouldn’t be able to extend the TTAGGG repeats on the telomeres and the cell would die.

    Not necessarily. Enzymes are large macromolecules. They will invariably tolerate many mutations with little or no impairment of enzymatic function. Most inhibitors work by binding to the enzyme, but they do not bind in exactly the same way as the substrate, so there is generally the potential for a mutation that impairs the binding of the inhibitor without interfering with the binding of the enzyme to its natural state. Usually, the only way to find out how likely this is to happen is to try it. There is one telomerase inhibitor that works by a different strategy, binding not to the enzyme but to the DNA target, hiding it from the telomerase enzyme. This is a clever strategy that really only works for enzymes that bind to nucleic acids such as DNA (which is not the case for the presumed target of DCA). In theory, it will be hard for the enzyme to mutate around this kind of block, because the drug isn’t actually binding to the enzyme. On the other hand, there are potentially other types of mutations in other cellular proteins that could interfere with this type of mechanism, such as a mutation of some other enzyme that causes it to inactivate the drug. Again, whether this is likely will have to be determined in the clinic.

    But this is irrelevant to DCA, which seems to be acting as a typical small molecule enzyme antagonist. This is a type of drug to which resistance is commonly observed. It’s always possible that we’ll “get lucky,” and the binding site of the enzyme will have little tolerance for mutations, but it’s not particularly likely.

    Basically, compounds that are effective against cancer at this level–in cell culture and in experimental animal models–are pretty much a dime a dozen. They are certainly worth following up, but it’s pretty much like getting the first 3 numbers on a 5-number lottery. It’s not time to order the Porsche quite yet.

    The peripheral neuropathy was observed at a dosage of 25mg/kg/day, for up to 2 years. The rats got water at 75mg/liter.

    At 75 mg/L in drinking water, the rat is probably consuming around 5 mg/day. That’s not exactly a huge safety margin if toxicity in man starts showing up at 25 mg/day. Keep in mind that effective human doses of drugs tend to run around a 6th of the rat dose–when expressed as milligrams per kilogram. A rat weighs maybe half a kilo or so, so a 60 kilo human might have to take 120 times the rat dose, or 600 mg/day to achieve the same therapeutic effect. Of course, this is only a rough estimates. Perhaps we’ll get lucky and find out that human cancers will be more sensitive that rat cancers (although the reverse is often true). And of course, people with cancer tolerate serious side effects from other chemotherapeutic drugs.

    But I wouldn’t order the Porsche just yet.

  50. #50 tgibbs
    February 6, 2007

    Oops, typo…that should be 100 mg/kg for the extrapolated human dose. Four times the dose at which peripheral neuropathy was a problem.

  51. #51 Robert Smith
    February 6, 2007

    actually GRN163l binds tightly to the RNA template of telomerase and makes it useless for extending telomeres. I hope the previous posters will compare the toxicity data of DCA against that of cisplatin. I hope you will read the DCA paper in Cancer Cell so that you see how it works. Keep in mind cancer cells are essentially embryonic stem cells that are running on glycolysis. Gasoline also kills cancer cells , but DCA isn’t gasoline, and its not cisplatin either.

  52. #52 Robert Smith
    February 6, 2007

    I question that,,, DCA has a tendency to build up to high levels with daily dosage if I recall correctly, wouldn’t you want to decrease dose after a certain level. And yes that level is adjusted for traditional chemo too. I think a mouse drinks on average 20-30 ml a day. Is that right? So he’s getting less than 1 mg per day. I don’t see how you can make a generalization about needing 6 times the mouse dose in humans. Its a small molecule with good distribution and a building residue.

  53. #53 Robert Smith
    February 6, 2007

    sorry 3 mg per day max, we are all having math problems today. Why not just start it out at the same dose as the mouse, 75mg/liter in drinking water. See what happens? If its building up too high in the blood, decrease the dose till you get an effective level.

  54. #54 rodrigo
    February 6, 2007

    So, Robert, if we “decrease the dose till you get an effective level”, are we not conducting trials? Why would you want to conduct them in patients without control, at the whim of doctors who might not be properly recording dosages/efects/whatever instead of doing them with the carfeuly constructed rules that drug trials use to assure one gets proper, reproducible, trustworthy results?

  55. #55 Ichthyic
    February 6, 2007

    You guys must have eaten your nasty boy beans this morning,,, and last night. The peripheral neuropathy was observed at a dosage of 25mg/kg/day, for up to 2 years. The rats got water at 75mg/liter. Typical of surgeons to try to call this drug something worse than surgery. You guys do so need an ego to do what you do but it can mess you up on the learning curve for new stuff.

    oooh, well said Mr. “Let’s not get personal or I am outta here”

    guffaw.

    still haven’t learned how to do links yet either, have you?

    you wanted to discuss the science, it was discussed, you ignored it and went on to attack everybody who challenged you on it personally.

    hmmm.

  56. #56 Robert Smith
    February 6, 2007

    Exactly, you would carry on a discussion of deminimus tripe while people are dying. This is my last post. You guys go ahead without a counter point to your cynical narrow view that you learned in med school 25 years ago. Bye and good luck in shells of your safe little worlds.

  57. #57 Coin
    February 6, 2007

    This is my last post.

    Is that a promise?

  58. #58 HCN
    February 6, 2007

    Actually I am disappointed that Mr. Smith has decided to leave. I wanted to know where they routinely give DCA to children, and exactly where he got his information from (he never did post a link).

    I also want to know why someone thinks why safety concerns should come second to pushing the approval of a medical treatment.

  59. #59 HCN
    February 6, 2007

    Erg… dealing with children and phone calls! I mean… Why should safety concerns not be considered when dealing with medical treatments?

  60. #60 Orac
    February 7, 2007

    Bye and good luck in shells of your safe little worlds.

    Another one flees, tail between his legs. Of course, he’ll never admit that he just didn’t know what he was talking about.

  61. #61 Robster
    February 7, 2007

    He’ll be back with a new sock puppet eventually.

  62. #62 tgibbs
    February 7, 2007

    I question that,,, DCA has a tendency to build up to high levels with daily dosage if I recall correctly, wouldn’t you want to decrease dose after a certain level. And yes that level is adjusted for traditional chemo too. I think a mouse drinks on average 20-30 ml a day. Is that right? So he’s getting less than 1 mg per day. I don’t see how you can make a generalization about needing 6 times the mouse dose in humans. Its a small molecule with good distribution and a building residue.

    Many drugs build up with regular dosing, and an appropriate dosing regimen is designed to take that into account. Normally, the dose of a drug and dosing interval is selected so that with regular dosing you approximate a steady state level in the body such that the blood levels of drug remain within a therapeutic range. Normally this means selecting an appropriate dose in the first place and sticking with it, rather than decreasing the dose later on, although if you are in a hurry to reach steady state you can give a higher dose on the first day. Of course, that presuposes that you know what the effective blood levels are and understand the pharmacokinetics.

    And I did not say that you need 6 times the mouse dose in humans. I said that you need one sixth the rat dose (for a mouse, it’s about a 12th)–when the dose is appropriately expressed as mg drug per kg weight of the person or animal. So rather than a 60 kg person requiring 120 times the amount of drug (in mg) required for a 0.5 kg rat, the human will require only 20 times the amount needed for the rat. That is of course, only typical. As I said, you could always “get lucky” and find that the human effective dose is much lower than predicted from animal testing. But that is not something that you can count on.

    Why not just start it out at the same dose as the mouse, 75mg/liter in drinking water.

    Because while this may be an easy, if not terribly reproducible, way of dosing an animal in a cage who has nothing to drink but what you give him, humans may choose to drink something other than your drug solution. And if you did give your patient nothing to drink except your drug solution, their daily consumption would be somthing like 150 mg–again, well above the level that has been reported to produce peripheral neuropathy.

  63. #63 maryha
    February 7, 2007

    I just couldn’t sleep because I have a yukky cold & laying down menas not breathing.
    But I have been thoroughly entertained by this, uh, dialogue!! Best giggling I’ve done in years! But seriously, folks, I, too, happened to be looking into this DCA thing (don’t remeber now, how I got into it). I downloaded several articles and I learned a lot. Basically, you’re all correct, I’m not a scientist, just love it and wish I was, but alas, learning disabilities prevented me from finshing college! Mr. Smith (or who ever he is) is just hot-headed and not too logical. I wondered if he hadn’t lost a loved one to cancer.
    You’re all very knowledable and remind us that there are many elusive and harmful variables and risks in running amuck with any chemical. And yes, in all fairness to ‘the little people’, the FDA and drug companies do have quite the little ball of red tape, big bucks, bureacracy and rooms full of codes to slog through to get anything approved. And first a drug comapny has to see dollar singsn in their eyes.
    The fact still remains, many a happy accident of science has occurred by trying something old in a new way.
    I, too, do not know how to provide links but I’m willing to share the various articles I downloaded into WORD that shed light on how this whole process got started, who’s been doing what and what’s next up in Canada, with DCA. It’s a little further along than Mr. (a’hem) Smith was able to illuminate for you. He is right about one thing. It is a relatively common item that is no longer able to be patented, so Pharmas have no incentive. But DCA has been tested on on genetically cultured human cells. It’s been around a while and IS in use for other things Lactic Acidosis, mainly.
    I wish I could include all the info I found. I often go first to Wikipedia and to get a foundation of understanding about things. There is a serious effort to get cancer trials into Phase 2, up in Canada. I’ll start with the least scientific article, but it sheds light on what, and who, is proceeding with further research into using DCA to treat a variety of cancers, and why.

    Dichloroacetate or DCA is a potentially new anti-cancer agent
    by Johnson Smith
    Published 01/25/2007 in All Cancers , Daily news , Research | Rating:
    Canadian researcher Evangelos Michelakis, associate professor of medicine at the University of Alberta in Edmonton, has stumbled upon something quite remarkable — a potentially new anti-cancer agent called dichloroacetate, or DCA.
    DCA is nothing new — it’s long been used for treatment of rare metabolic disorders — but using it to fight cancer puts an entirely new spin on the potential of this drug.
    “This is one of the most exciting results I’ve ever had,” Michelakis said. “But I can’t be overenthusiastic until it works on a human.”
    Michelakis and his colleagues have successfully used DCA to shrink human lung, breast, and brain tumors in both lab rats and test tubes. And while this type of research may not ordinarily generate a lot of excitement, this specific study is creating a buzz because DCA has been safely used in humans for decades, without adverse side effects.
    “One of the big concerns about drugs is that they can harm people but we already know this drug is safe,” Michelakis says. “It doesn’t even affect normal cells.”
    One of the fundamental premises of cancer biology is that mitochondria — the energy producing units of cells — are permanently damaged by cancer. What DCA does is revive the mitochondrial function, encouraging the death of cancer cells.
    The overwhelming hope is that DCA will move right to human testing. But the overwhelming fear is that it will not — because of economic reasons. There is no longer a patent on DCA so it is not owned by any one company. With little chance of one group making a large profit, there may be no incentive for pharmaceutical companies to invest in research.
    Sadly, this drug — that appears to work remarkably well — may never benefit cancer patients. All because no one stands to make billions of dollars from it.
    Permanent link:
    http://www.topcancernews.com/news/541/1/

    Check out : Dichloroacetate Abstracts (a smattering, not a systematic culling)
    http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1533324
    URL: go medline + pmid
    Am Heart J. 1997 Nov;134(5 Pt 1):841-55.

    Dichloroacetate as metabolic therapy for myocardial ischemia and failure.
    Bersin RM, Stacpoole PW.
    Sanger Clinic and the Department of Medicine, University of Florida College of Medicine, Gainesville 32610, USA.
    URL: go medline + pmid
    Metabolism. 1989 Nov;38(11):1124-44.
    The pharmacology of dichloroacetate.
    Stacpoole PW.
    Department of Medicine, University of Florida, College of Medicine, Gainesville 32610.
    Dichloroacetate (DCA) exerts multiple effects on pathways of intermediary metabolism. It stimulates peripheral glucose utilization and inhibits gluconeogeneis, thereby reducing hyperglycemia in animals and humans with diabetes mellitus. It inhibits lipogenesis and cholesterolgenesis, thereby decreasing circulating lipid and lipoprotein levels in short-term studies in patients with acquired or hereditary disorders of lipoprotein metabolism. By stimulating the activity of pyruvate dehydrogenase, DCA facilitates oxidation of lactate and decreases morbidity in acquired and congenital forms of lactic acidosis. The drug improves cardiac output and left ventricular mechanical efficiency under conditions of myocardial ischemia or failure, probably by facilitating myocardial metabolism of carbohydrate and lactate as opposed to fat. DCA may also enhance regional lactate removal and restoration of brain function in experimental states of cerebral ischemia. DCA appears to inhibit its own metabolism, which may influence the duration of its pharmacologic actions and lead to toxicity. DCA can cause a reversible peripheral neuropathy that may be related to thiamine deficiency and may be ameliorated or prevented with thiamine supplementation. Other toxic effects of DCA may be species-specific and reflect marked interspecies variation in pharmacokinetics. Despite its potential toxicity and limited clinical experience, DCA and its derivatives may prove to be useful in probing regulatory aspects of intermediary metabolism and in the acute or chronic treatment of several metabolic disorders.
    PMID: 2554095 http://toxsci.oxfordjournals.org/cgi/content/abstract/14/2/327
    Toxicological Sciences – Volume 14, Number 2 Pp. 327-337

    Chronic Toxicity of Dichloroacetate: Possible Relation to Thiamine Deficiency in Rats
    PETER W. STACPOOLE*, H. JAMES HARWOOD, JR, DON F. CAMERON, STEPHEN H. CURRY(th), DON A. SAMUELSNO, PHILLIP E. CORNWELL and HOWARDE E. SAUBERLICH
    • Departments of Medicine (Division of Endocrinology and
    Metabolism), University of Florida, Colleges of Medicine, Pharmacy and Veterinary Sciences Gainesville, Florida 32610 Departments of Pharmacology, University of Florida, Colleges of Medicine, Pharmacy and Veterinary Sciences Gainesville, Florida 32610 Departments of Anatomy, University of Florida, Colleges of Medicine, Pharmacy and Veterinary Sciences Gainesville, Florida 32610 (th)Departments of Clinical Pharmacokinetics, University of Florida, Colleges of Medicine, Pharmacy and Veterinary Sciences Gainesville, Florida 3261 0Departments of Veterinary Opthalmology, University of Florida, Colleges of Medicine, Pharmacy and Veterinary Sciences Gainesville, Florida 32610 Department of Nutrition Sciences, University of Alabama Birmingham, Alabama 35294
    Received April 21, 1989; Chronic Toxicity of Dichloroacetate: Possible Relation to Thiamine Deficiency in Rats. STACPOOLE, P. W., HARWOOD, H. J., JR., CAMERON, D. F., CURRY, S. H., SAMUELSON, D. A., CORNWELL, P. E., AND SAUBERLICH, H. E. (1990). Fundam. Appl. Toxicol. 14, 327-337. The chronic use of dichloroacetate (DCA) for diabetes mellitus or hyperlipoproteinemias has been compromised by neurologic and other forms of toxicity. DCA is metabolized to glyoxylate, which is converted to oxalate and, in the presence of adequate thiamine levels, to other metabolites. DCA stimulates the thiamine-dependent enzymes pyruvate dehydrogenase and a-ketoacid dehydrogenase. We postulated that the neurotoxicity from chronic DCA administration could result from depletion of body thiamine stores and abnormal metabolism of oxalate, a known neurotoxin. For 7 weeks, rats were fed ad lib. Purina chow and water or chow plus sodium DCA (50 mg/kg or 1.1 g/kg) in water. A portion of the DCA-treated animals also received intraperitoneal injections of 600 æ thiamine three times weekly or 600 æ thiamine daily by mouth. Thiamine status was assessed by determining red cell transketolase activity and, in a blinded manner, by recording the development of clinical signs known to be associated with thiamine deficiency. At the 50 mg/kg dose, chronic administration of DCA showed no clinical toxicity or effect on transketolase activity. At the 1.1 g/kg dose, however, DCA markedly increased the frequency and severity of toxicity and decreased transketolase activity 25%, compared to controls. Coadministration of thiamine substantially reduced evidence of thiamine deficiency and normalized transketolase activity. Inhibition of transketolase by DCA In vivo was not due to a direct action on the enzyme, however, since DCA, glyoxylate, or oxalate had no appreciable effects on transketolase activity in vitro. After 7 weeks, plasma DCA concentrations were similar in rats receiving DCA alone or DCA plus thiamine, while urinary oxalate was 86% above control in DCA-treated rats but only 28% above control in DCA plus thiamine-treated animals. No light microscopic changes were seen in peripheral nerve, lens, testis, or kidney morphology in either DCA-treated group, nor was there disruption of normal sperm production in the DCA-treated group. We conclude that stimulation by DCA of thiamine-requiring enzymes may lead to depletion of total body thiamine stores and to both a fall in transketolase activity and an increase in oxalate accumulation In vivo. DCA neurotoxicity may thus be due, at least in part, to thiamine deficiency and may be preventable with thiamine treatment.
    — Alan2012 14:52, 1 February 2007 (UTC

    Abstract
    Dichloroacetate (DCA) is a xenobiotic of interest to both environmental toxicologists and clinicians. The chemical is a product of water chlorination and of the metabolism of various drugs and industrial chemicals. Its accumulation in groundwater and at certain Superfund sites is considered a potential health hazard. However, concern about DCA toxicity is predicated mainly on data obtained in inbred rodent strains administered DCA at doses thousands of times higher than those to which humans are usually exposed. In these animals, chronic administration of DCA induces hepatotoxicity and neoplasia. Ironically, the DCA doses used in animal toxicology experiments are very similar to those used clinically for the chronic or acute treatment of several acquired or hereditary metabolic or cardiovascular diseases. As a medicinal, DCA is generally well tolerated and stimulates the activity of the mitochondrial pyruvate dehydrogenase enzyme complex, resulting in increased oxidation of glucose and lactate and an amelioration of lactic acidosis. By this mechanism, the drug may also enhance cellular energy metabolism. DCA is dehalogenated in vivo to monochloroacetate and glyoxylate, from which it can be further catabolized to glycolate, glycine, oxalate, and carbon dioxide. It remains to be determined whether important differences in its metabolism and toxicology exist in humans between environmentally and clinically relevant doses
    • Mughal FH. Chlorination of drinking water and cancer: a review. J Environ Pathol Toxicol Oncol. 1992 11(5-6):287-292.Sep-Oct; [PubMed]
    • Stacpoole PW. The pharmacology of dichloroacetate. Metabolism. 1989 Nov;38(11):1124-1144. [PubMed]
    • Henderson GN, Yan Z, James MO, Davydova N, Stacpoole PW. Kinetics and metabolism of chloral hydrate in children: identification of dichloroacetate as a metabolite. Biochem Biophys Res Commun. 1997 Jun 27;235(3):695-698. [PubMed]
    • Bersin RM, Stacpoole PW. Dichloroacetate as metabolic therapy for myocardial ischemia and failure. Am Heart J. 1997 Nov;134(5 Pt 1):841-855. [PubMed]
    • Curry SH, Lorenz A, Chu PI, Limacher M, Stacpoole PW. Disposition and pharmacodynamics of dichloroacetate (DCA) and oxalate following oral DCA doses. Biopharm Drug Dispos. 1991 Jul;12(5):375-390. [PubMed]
    • Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL, Kerr DS. Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child. 1997 Dec;77(6):535-541. [PubMed]
    • Stacpoole PW, Harman EM, Curry SH, Baumgartner TG, Misbin RI. Treatment of lactic acidosis with dichloroacetate. N Engl J Med. 1983 Aug 18;309(7):390-396. [PubMed]
    • Stacpoole PW, Wright EC, Baumgartner TG, Bersin RM, Buchalter S, Curry SH, Duncan CA, Harman EM, Henderson GN, Jenkinson S, et al. A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group. N Engl J Med. 1992 Nov 26;327(22):1564-1569. [PubMed]
    • Curry SH, Chu PI, Baumgartner TG, Stacpoole PW. Plasma concentrations and metabolic effects of intravenous sodium dichloroacetate. Clin Pharmacol Ther. 1985 Jan;37(1):89-93. [PubMed]
    • Stacpoole PW, Moore GW, Kornhauser DM. Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. N Engl J Med. 1978 Mar 9;298(10):526-530. [PubMed]

    Reprinted from ehp.org
    http://www.ehponline.org/members/1998/Suppl-4/989-994stacpoole/stacpoole-full.html
    Environmental Health Perspectives Supplements Volume 106, Number S4, August 1998

    Clinical Pharmacology and Toxicology of Dichloroacetate
    Peter W. Stacpoole,1,2 George N. Henderson,1 Zimeng Yan,1 and Margaret O. James3
    1Department of Medicine,
    2Department of Biochemistry and Molecular Biology, College of Medicine,
    3Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida
    • Introduction
    • Pharmacodynamics
    • Kinetics and Metabolism
    • Summary and Conclusions

    Abstract
    Dichloroacetate (DCA) is a xenobiotic of interest to both environmental toxicologists and clinicians. The chemical is a product of water chlorination and of the metabolism of various drugs and industrial chemicals. Its accumulation in groundwater and at certain Superfund sites is considered a potential health hazard. However, concern about DCA toxicity is predicated mainly on data obtained in inbred rodent strains administered DCA at doses thousands of times higher than those to which humans are usually exposed. In these animals, chronic administration of DCA induces hepatotoxicity and neoplasia. Ironically, the DCA doses used in animal toxicology experiments are very similar to those used clinically for the chronic or acute treatment of several acquired or hereditary metabolic or cardiovascular diseases. As a medicinal, DCA is generally well tolerated and stimulates the activity of the mitochondrial pyruvate dehydrogenase enzyme complex, resulting in increased oxidation of glucose and lactate and an amelioration of lactic acidosis. By this mechanism, the drug may also enhance cellular energy metabolism. DCA is dehalogenated in vivo to monochloroacetate and glyoxylate, from which it can be further catabolized to glycolate, glycine, oxalate, and carbon dioxide. It remains to be determined whether important differences in its metabolism and toxicology exist in humans between environmentally and clinically relevant doses. — Environ Health Perspect 106(Suppl 4):989-994 (1998).
    http://ehpnet1.niehs.nih.gov/docs/1998/Suppl-4/989-994stacpoole/abstract.html
    Key words: dichloroacetate, pyruvate dehydrogenase, chlorination, drug metabolism, glyoxylate, oxalate, neuropathy
    ________________________________________
    This paper is based on a presentation at the Symposium on the Superfund Basic Research Program: A Decade of Improving Health through Multi-Disciplinary Research held 23-26 February 1997 in Chapel Hill, North Carolina. Manuscript received at EHP 11 December 1997; accepted 21 April 1998.
    This work was supported by grants ESO R017355, ESO P427375, and RR00082 from the National Institutes of Health. We thank F. Clark and V. Busch for editorial assistance.
    Address correspondence to P.W. Stacpoole, PO Box 100226, University of Florida, 1600 Southwest Archer Road, Gainesville, FL 32610-0226. Telephone: (352) 392-2321. Fax: (352) 846-0990. E-mail: stacpool@gcrc.ufl.edu
    Abbreviations used: ATP, adenosine triphosphate; AUC, area under the plasma concentration curve; CH, chloral hydrate; CLA, congenital lactic acidosis; Cmax, peak plasma concentration; Cmin, minimum plasma concentration; CoA, coenzyme A; DCA, dichloroacetate; MCA, monochloroacetate; PDC, pyruvate dehydrogenase complex; PDH, pyruvate dehydrogenase; TCA, tricarboxylic acid.
    ________________________________________
    Introduction
    Dichloroacetate (DCA) is one of a host of organohalides to which humans have long been chronically exposed. Environmental sources of DCA include chlorinated drinking water (1-3) and groundwater contamination by certain industrial solvents and other chlorinated precursors (4). DCA is also a metabolite in the biotransformation of several pharmaceuticals (5,6) and has been administered orally and parenterally for decades as an investigational drug for the treatment of numerous cardiovascular and metabolic disorders. Collectively, these data indicate that daily human exposure to DCA encompasses a 10,000-fold concentration range, from approximately 4 µg/kg consumed in finished drinking water to approximately 50 mg/kg administered for therapeutic purposes.
    A comparative assessment of the kinetics, metabolism, and toxicology of DCA in animals and humans has recently been summarized (7). Here we focus on the clinical pharmacology and safety of this unusual chemical, based in large part on investigations conducted in healthy volunteers or in children and adults with various congenital or acquired metabolic diseases for which DCA is administered acutely or chronically as a drug.
    Pharmacodynamics
    From a medicinal standpoint, a principal site of action of DCA is the pyruvate dehydrogenase (PDH) enzyme complex (PDC) located in the mitochondrial inner membrane. PDC catalyzes the reversible decarboxylation of pyruvate to acetyl coenzyme A (CoA), which is the rate-limiting step in the aerobic oxidation of glucose, pyruvate, and lactate in animal cells (Figure 1).

    Figure 1. Site of action of dichloroacetate. DCA inhibits the mitochondrial enzyme PDH kinase, thereby maintaining the PDH complex in its unphosphorylated catalytically active state and facilitating the aerobic oxidation of glucose.
    PDC undergoes rapid posttranslational modulation in activity, due in part to reversible phosphorylation. PDC kinase phosphorylates and inactivates PDC, whereas PDC phosphatase dephosphorylates the complex and restores catalytic activity. DCA inhibits the kinase, thereby locking PDC in its unphosphorylated active form. This effect occurs within minutes of oral or parenteral administration of DCA, which is rapidly transported across cell membranes via the monocarboxylate carrier (8) and is concentrated in mitochondria (5).
    The ability of mitochondria to oxidize substrates and produce adenosine triphosphate (ATP) by oxidative phosphorylation is integral to normal homeostasis and to the ability of cells to survive in the face of impending energy failure. Experimental and clinical investigations with DCA suggest that the drug primes the tricarboxylic acid (TCA) cycle with acetyl groups and the respiratory chain with electrons donated by the reducing equivalents generated by the PDC- and TCA-cycle-catalyzed reactions, thereby promoting ATP synthesis (Figure 2) (5). The ability of DCA to stimulate the efficient conversion of substrate fuel (glucose or lactate) into energy provides a biochemical rationale for its utility in ameliorating acquired or congenital causes of lactic acidosis and other pathologic conditions associated with mitochondrial energy failure. Indeed, studies by many investigators have firmly established DCA as the most potent lactate-lowering agent ever used clinically and a potential treatment for myocardial ischemia or failure (9).

    Figure 2. Cellular metabolism of glucose and oxidative phosphorylation. By activating the PDC, DCA primes the TCA cycle with acetyl-CoA molecules derived from glucose. Reducing equivalents, in the form of reduced nicotine adenine dinucleotide and reduced flavin adenine dinucleotide from the PDC and TCA, reactions donate electrons (e-) to the respiratory chain, leading to the reduction of oxygen to water and to the synthesis of ATP from adenosine diphosphate. Reproduced from Stacpoole et al. (13) with permission of the BMJ Publishing Group.
    Kinetics and Metabolism
    Dichloroacetate is rapidly and virtually completely absorbed following oral dosing and about 20% is bound to human plasma proteins (10). In all species examined to date, the first dose is cleared from plasma more rapidly than subsequent doses, although the mechanism for this effect is unknown. Also unclear is the quantitative importance of its varied metabolic routes and the influence of repeat administration thereon. Glyoxylate is an intermediate in DCA metabolism, and oxalate and CO2 are terminal end products. Neither glyoxylate nor oxalate stimulate PDC activity (5). However, because the actions of DCA in humans often persist several days after its clearance from plasma (5), it is possible that other reactive intermediates of DCA accumulate intracellularly at active sites and bind covalently to target proteins, or that DCA (or a metabolite) induces enzymes responsible for its pharmacodynamic effects.
    DCA is extensively metabolized in rodents and humans, with little of the dose excreted unchanged (7). Although most drug metabolism studies have been prompted by concern about DCA as a potential environmental pollutant, nearly all experiments to date have administered doses to animals and humans in the therapeutic (i.e., milligram per kilogram) rather than the environmental (microgram per kilogram) range. Thus, it remains unknown whether the kinetics and metabolism of the compound differ at these extremes of human exposure.
    Adults
    To investigate the in vivo metabolism of DCA in humans, we recently developed and validated a gas chromatography/mass spectrometry technique that simultaneously measures DCA and its metabolites monochloroacetate (MCA), glyoxylate, glycolate, and oxalate in human plasma (11). Following administration of [13C1,2] DCA, the drug and its metabolites are derivatized to their methyl esters by reacting them with a 12% BF3-methanol mixture. Lactate, a glycolytic end product that is frequently measured following DCA administration, can also be quantitated by this technique.
    Healthy men and women 18 to 65 years of age receive sequential oral DCA doses of 25 mg/kg and 250, 25, and 2.5 µg/kg daily for 5 consecutive days. The highest and lowest doses are also administered intravenously for 5 days. The order of oral versus intravenous administration for these doses is randomized. This spectrum of DCA doses allows us to compare the kinetics and metabolism in each gender during exposure to both environmentally and clinically relevant levels, i.e., over a 10,000-fold concentration range. A 2- to 3-month washout period occurs between studies, as our previous investigations (10,12) demonstrated that an initial DCA dose in healthy subjects increases the plasma t1/2 of a subsequent dose, even after a washout period of several weeks.
    These ongoing studies were initiated using the 25 mg/kg dose for two practical reasons: first, to optimize our chances of identifying metabolites of [13C]DCA in plasma and urine, and second, to generate comparative data with our pediatric investigations early on. Table 1 summarizes the mean data analyzed to date from 18 subjects who received oral or intravenous DCA for 5 days. On days 1 and 5, detailed kinetic investigations were performed over 24-hr sample collection periods. Subjects received a 1:1 mixture of [13C] and [12C]DCA on these days and [12C]DCA on days 2 to 4.
    In general, the kinetic profile of a 25-mg/kg dose appears to be independent of gender and administration. Peak plasma concentration (Cmax) did not change appreciably between genders or between the first and fifth intravenous doses, but the Cmax after the final oral dose (158±99 µg/ml) was 68% greater than after the initial dose (94±45 µg/l). We speculate this difference may reflect faster gastrointestinal absorption of DCA upon repeated administration, perhaps by induction of some transport mechanism. Chronic dosing in all subject categories led to a striking increase in t1/2, and this was associated with a fall in plasma clearance and an increase in the area under the plasma concentration curve (AUC). Urinary DCA accounts for approximately 1 to 2% of the administered initial dose and approximately 3 to 5% of the fifth dose, based on 24-hr urine collections.

    Figure 3 shows representative plasma concentrations of [13C]DCA (Figure 3A) and its metabolites (Figure 3B) after a 25-mg/kg dose infused over 10 min. Note the rapid rise and fall of MCA, which in some subjects may reach levels up to 10% of the DCA Cmax on a molar basis. Glyoxylate and oxalate concentrations, although measurable, are usually lower than MCA during the first 4 hr after dosing.

    Figure 3. Plasma concentrations of (A) [13C]dichloroacetate and (B) its metabolites after a 25-mg/kg infusion of [13C]DCA. Note the rapid appearance and disappearance in plasma of MCA following the administration of DCA.
    Children
    The term congenital lactic acidosis (CLA) refers to a group of rare inborn errors of metabolism variably characterized by progressive neuromuscular deterioration and accumulation of lactate and hydrogen ions in blood, urine, or cerebrospinal fluid, frequently resulting in early death. The incidence and prevalence in the United States are approximately 250 and 1000 cases, respectively. Most identifiable causes involve inherited or spontaneous mutations in PDC or in one or more enzymes of the respiratory chain. More than 50 CLA infants and children worldwide have received oral or intravenous DCA (13) in open-label investigations. Drug dose and treatment duration varied widely. Twelve patients received DCA for at least 1 year and three received it for at least 5 years. Thus, the cumulative DCA treatment experience in CLA infants and children is greater than 41 patient-years.
    A controlled clinical trial is now being conducted to test the central hypotheses that DCA is safe and improves the quality of life and metabolic status of infants and children with CLA due to PDC or respiratory chain defects. Safety is determined principally by finding that chronic DCA does not cause hepatocellular, peripheral nerve, ocular, or renal toxicity (all of which have been reported in dosed animals) or toxicity related to other organ systems. Quality of life is quantified by such key biologic indices of drug efficacy as improvement in neurologic, neurobehavioral, and physical function and by reduction in the frequency and severity of hospitalizations due to acid-base decompensation or other CLA-related complications. Biologic markers of cellular energy metabolism that are measured include blood and cerebrospinal fluid lactate (which should fall because of DCA’s mechanism of action) and height (which should increase because of the amelioration of the metabolic acidosis). Improvement in these markers should track closely with quality of life indices. In addition, the kinetics and metabolism of [13C] and [12C]DCA are examined prospectively and are interpreted in light of the dynamic and toxicologic effects of the compound.
    [13C]DCA kinetics are performed at entry with a 2.5-µg/g dose of compound and 3 to 4 times with 12.5 mg/kg DCA during the initial 24-month period. The dose of 2.5 µg/kg is chosen because it is too small to exert any important pharmacodynamic effect and because it reflects the amount expected to be consumed by environmental exposure. Thus, the study affords the opportunity to examine repeatedly the kinetics and metabolism of DCA during both environmental and clinical dose phases.
    Table 2 and Figure 4 show representative data on DCA kinetics and metabolism in CLA patients. The patient in Table 2 received 12.5 mg/kg every 12 hr by mouth. Cmax levels were usually achieved 1 hr after the dose and minimum plasma levels were obtained at the dosing interval. In a second patient, Figure 4 illustrates the expected change in plasma drug clearance. In sharp contrast to our prior studies in adults with acquired causes of lactic acidosis (14,15) or in healthy volunteers, both Table 2 and Figure 4 demonstrate that repeated dosing in children appears to lead to progressive increases in Cmax. Figure 5 illustrates the plasma metabolism of an oral 12.5 mg/kg dose of DCA (1:1 isotope ratio) in a child with CLA. As with healthy adults, MCA is an immediate and short-lived product, whereas glyoxylate and oxalate have more protracted time courses.

    Figure 4. Change in dichloroacetate kinetics after 6 months in a patient with congenital lactic acidosis. Note the increase in the peak plasma concentration and the decrease in plasma clearance in DCA following chronic oral administration.
    Figure 5. DCA metabolites for [13C]dichloroacetate in a patient with congenital lactic acidosis: first DCA treatment. The plasma concentration of MCA peaks and decays rapidly following a single dose of DCA.
    In the CLA study, children are administered 50 mg/kg chloral hydrate (CH) by mouth to induce short-term conscious sedation for various neurologic tests. During the course of our DCA kinetic experiments, we noted the presence of a major interfering substance in some plasma samples. We determined this substance was CH and, in the course of these investigations, discovered that DCA is a major metabolite of CH in humans (6). We also found that CH and DCA may compete for similar routes of biotransformation. This conclusion is based in part on the observation that prior administration of CH delays the plasma clearance of DCA.
    The discovery that humans catabolize CH to DCA has important implications for the kinetics, dynamics, and toxicology of both compounds. Both are found in microgram per liter quantities in municipal drinking water and are considered by the U.S. Environmental Protection Agency to be environmental hazards. The interesting possibilities are raised that the mental status changes induced by CH and (in some individuals) DCA may have a common mechanism and that CH may alter intermediary metabolism in the host by virtue of its conversion to DCA.
    Toxicology
    A valid assessment of the human risk of DCA is confounded by the fact that most animal toxicology has focused on its chronic administration to subprimates, usually at doses nearer to those used clinically than to levels anticipated from environmental exposure of the chemical, its precursors, or its catabolites. The animal toxicology of DCA has recently been reviewed (7). In brief, the liver, kidney, nervous system, testes, and eye are potential target organs of chronic DCA toxicity. Studies in rats and mice have shown that DCA can induce hepatocellular injury, hypertrophy, hyperplasia, adenomas, and carcinomas after chronic oral exposure to levels similar to those administered clinically (7).
    To date, evidence of DCA toxicity in humans is limited and is primarily restricted to the nervous system and the liver. Approximately 50% of healthy adults receiving single or repeated oral or intravenous doses of 25 or 50 mg/kg DCA exhibit anxiolytic or sedative effects. These symptoms usually occur within 60 min of drug administration and may last several hours (16,17). Mild drowsiness or diminished anxiety have also been observed in a few patients with diabetes mellitus (18) or lactic acidosis (14) treated briefly with DCA. These central nervous system changes occur unpredictably and without obvious predilection for any particular gender, race, age group, or route of drug administration.
    A reversible peripheral neuropathy occurred after several months of daily oral 50 to 100 mg/kg DCA treatment in two children with CLA due to PDC deficiency or a respiratory chain defect (7). Return to pretreatment neurologic states was achieved, both clinically and by nerve conduction velocity testing, within 6 months of discontinuing DCA. In the patient with PDC deficiency, resolution of the neuropathy led to retreatment with DCA at doses of 10 to 25 mg/kg/day, which has been continued for over 2 years without evidence of peripheral neuropathy.
    Mild (~2-fold) asymptomatic elevation of serum transaminases has been noted in at least two children with CLA (17) and may reflect hepatocellular damage. Both patients received 25 to 75 mg/kg DCA daily for several months. Reduction in the highest dose to the lowest dose in one subject led to normalization of transaminase levels. There is no clinical evidence that DCA is toxic to the eyes, kidneys, or gonads or induces neoplasia in any human tissue.
    Summary and Conclusions
    Together, the results of these and other (5,7) investigations indicate that the kinetics and biotransformation of DCA are qualitatively similar when the chemical is administered to children or adults at therapeutically relevant doses, as depicted in Figure 6. DCA, and/or an intermediate, strongly inhibits its own metabolism, but the mechanism for this is unknown. Likewise, the quantitative significance of the putative pathways of its metabolism in any species remains to be determined, as do the early molecular events in the dehalogenation of DCA. The chemical appears to be relatively nontoxic when administered acutely and parenterally to healthy adults or to critically ill patients with acquired causes of lactic acidosis, but its long-term safety can be more adequately addressed by chronic treatment of children with CLA.
    Figure 6. Biotransformation of dichloroacetate. This scheme postulates the existence of two principal in vivo routes of dichloroacetate catabolism: by reduction to MCA and by oxidation to glyoxylate. The sites and mechanism(s) for dehalogenation are uncertain. Glyoxylate and its catabolites are all naturally occurring endogenous molecules. Formation of glycine provides a route of entry of DCA into the general carbon pool of the host.
    DCA is unique among chlorinated hydrocarbons in that research on its kinetics, metabolism, and toxicology has been driven by both environmental and therapeutic concerns. The interesting consequence is that much of the animal experimentation has been conducted using doses much closer to those used clinically than to levels to which human populations may be exposed, either by chlorination of municipal drinking water or by groundwater contamination as occurs, for example, at certain Superfund sites. Thus, very little animal and almost no human studies have examined the pharmacology or toxicology of DCA at environmentally relevant concentrations. Therefore, the appropriateness of extrapolating animal toxicology studies to humans in determining the health risk from DCA exposure is problematic thus far. In fact, this caveat may apply to the extrapolation of nonhuman toxicologic data generated for a number of chlorinated hydrocarbons, including precursors of DCA. In the case of DCA, however, its status as an investigational drug for both pediatric and adult diseases affords an invaluable opportunity to prospectively assess its chronic toxicity in humans.
    References and Notes
    1. Miller JW, Uden PC. Characterization of nonvolatile aqueous chlorination products of humic substances. Environ Sci Technol 17:150-157 (1983).
    2. Uden PCC, Miller JW. Chlorinated acids and chloral in drinking water. J Am Water Works Assoc 75:524-527 (1983).
    3. Mughal FH. Chlorination of drinking water and cancer: a review. J Environ Pathol Toxicol Oncol 11:287-292 (1992).
    4. Jolley RL. Basic issues in water chlorination: a chemical perspective. In: Water Chlorination: Chemistry, Environmental Impact and Health Effects. Vol 5. Chelsea, MI:Lewis Publishers, 1985;19-38.
    5. Stacpoole PW. The pharmacology of dichloroacetate. Metabolism 38:1124-1144 (1989).
    6. Henderson GN, Yan Z, James MO, Davydova N, Stacpoole PW. Kinetics and metabolism of chloral hydrate in children: identification of dichloroacetate as a metabolite. Biochem Biophys Res Commun 235:695-698 (1997).
    7. Stacpoole PW, Henderson, GN, Yan Z, Cornett R, James MO. Pharmacokinetics, metabolism and toxicology of dichloroacetate. Drug Metab Rev (in press).
    8. Jackson VN, Halestrap AP. The kinetics, substrate, and inhibitor specificity of the monocarboxylate (lactate) transporter of rat liver cells determined using the fluorescent intracellular pH indicator, 2´,7´-bis(carboxyethyl)-5(6)-carboxyfluorescein. J Biol Chem 271:861-868 (1996).
    9. Bersin RM, Stacpoole PW. Dichloroacetate as metabolic therapy for myocardial ischemia and failure. Am Heart J 134:841-855 (1997).
    10. Chu P-I. Pharmacokinetics of Sodium Dichloroacetate. PhD dissertation. Gainesville, FL:University of Florida, 1987.
    11. Yan Z, Henderson GN, James MO, Stacpoole PW. Determination of dichloroacetate and its metabolites in human plasma by gas chromatography-mass spectrometry. J Chromatography B703:75-84 (1997).
    12. Curry SH, Lorenz A, Chu P-I, Limacher M, Stacpoole PW. Disposition and pharmacodynamics of dichloroacetate (DCA) and oxalate following oral DCA doses. Biopharm Drug Disp 12:375-390 (1991).
    13. Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL, Kerr DS. Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child 77:535-541 (1997).
    14. Stacpoole PW, Harman EM, Curry SH, Baumgartner TG, Misbin RI. Treatment of patients with lactic acidosis with dichloroacetate. N Engl J Med 309:390-396 (1983).
    15. Stacpoole P, Wright EC, Baumgartner TG, Misbin RI, Bersin RM, Buchalter S, Curry SH, Duncan C, Hackett R, Harman EM, et al. A controlled clinical trial of dichloroacetate treatment in patients with lactic acidosis. N Engl J Med 327:1564-1569 (1992).
    16. Curry SH, Chu P-I, Baumgartner TG, Stacpoole PW. Plasma concentrations and metabolic effects of intravenous sodium dichloroacetate. Clin Pharmacol Ther 37:89-93 (1985).
    17. Stacpoole PW. Unpublished observation.
    18. Stacpoole PW, Moore GW, Kornhauser DM. Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. N Engl J Med 298:526-530 (1978).
    ________________________________________
    Last Update: July 15, 1998
    ——————————————————

    And From http://www.scienceblogs.com/terrasig/
    The Dichloroacetate (DCA) Cancer Kerfuffle
    Category: Cancer
    I’ve stood at the periphery of the dichloroacetate (DCA) story mostly because my attention has been needed elsewhere as of late. However, I was very interested in the blogosphere attention given to the Cancer Cell paper from a group led by Dr Evangelos Michelakis at the University of Alberta in Edmonton. The University of Alberta has now set up a website with links to all press coverage on this report as well as a donation page for those who want to support further clinical studies of DCA for cancer.
    Long story made short, DCA is a mitochondrial respiratory modulator that reduces lactic acid production and has been used to treat rare mitochondrial diseases such as congenital lactic acidosis (CLA). Otto Warburg proposed in 1930 that cancer cells continue to use the process of glycolysis even in the abundance of oxygen and that targeting the glycolytic production of lactate might selectively kill cancer cells. Cancer researchers have long debated whether aerobic glycolysis is a cause of cancer, or simply an effect of cellular transformation. My cursory read of the Michelakis paper seems to suggest that DCA can kill cancer cells in culture and A549 lung carcinoma cells injected under the skin of athymic rats (immunocompromised animals that allow cancer cells from another species to be propagated).
    The mechanism appears to be prevention of pyruvate from being converted to lactate; instead, pyruvate is shunted to acetyl-CoA where it can enter the Krebs cycle (see Fig 1 of the paper). This step is normally catalyzed by pyruvate dehydrogenase (PDH) but is inhibited by pyruvate dehydrogenase kinase (PDK). DCA appears to inhibit the inhibitor (PDK), with acetyl-CoA giving rise to higher levels of the electron donor, NADH. NADH enters the electron transport chain at Complex I and creates reactive oxygen species (ROS) that trigger the mitochondrial changes required for programmed cell death, or apoptosis.
    Not discussed in other reports is that genetic evidence supports a role for this enzyme in that small-interfering RNA to a PDK isoform mimics this effect of DCA, at least in cultured cells, again by increasing mitochondrial production of ROS via Complex I. (An aside, if DCA ever becomes a cancer therapy, herein lies a reason why antioxidants should not be used with it, as is often cautioned with conventional anticancer therapies as well).
    I have an unusual interest in mitochondrial respiration since my graduate department had a few mitochondrial experts and I interviewed for a rotation with a physician-scientist who has been studying DCA for metabolic diseases since the 1970s and has conducted clinical trials with the compound.
    So, what I think is most exciting about the Michelakis paper is that it provides support for aerobic glycolysis as being a cause of cancer, or at least a process that is permissive for maintenance of the neoplastic phenotype. This is a major conceptual advance and accounts for why it is published in Cancer Cell.
    But I’m sort of taken aback by how the blogosphere has jumped on DCA as the cure for cancer and how there appears to be paranoia that the pharmaceutical industry will view DCA as a threat since it cannot be patented and, presumably, would not be interested in developing the agent.
    Where I would caution too much overinterpretation is upstream from these development concerns: many, many compounds that show anticancer activity in animals turn out to fail in human trials. For example, as my colleague Orac cautioned similarly, his points #1 and #2 in his much-discussed post should be kept in mind. Orac notes his hero, Judah Folkman, pioneer of the concept of antiangiogenic therapies for cancer – Folkman has been working on this idea since 1971 and Gina Kolata of the New York Times apparently misquoted Nobel laureate, Jim Watson, as saying in 1998 that Judah Folkman would cure cancer in two years. Antiangiogenic therapies are finally making advances in the clinic almost ten years later, but still remain far from “cures” and still often require combination with conventional cytotoxic agents to have a significant clinical effect.
    So, I fear that the DCA story is being blown out of proportion, no matter how promising the animal experiments appear to be. Note in Figure 8A of the Michelakis paper that DCA does not completely cure the animals, but reduces tumor growth by about 60 or 70%. It is impressive that DCA does cause reduction in tumor bulk after tumors are allowed to form, but we are many, many steps away from a human treatment.
    Also, no one really seems to be paying attention to the fact the DCA is known liver carcinogen in rats and mice, possibly in the ballpark of concentrations necessary for effects in the Michelakis paper. (EPA and NIEHS have been interested in negative health effects of DCA since it is a by-product of municipal water chlorination where it ends up being a concentrations far too low to be either beneficial or dangerous).
    It is also misleading to say that no drug company will be interested in DCA – although it cannot be patented as a molecule, its use and ultimate formulation can be, and it could even be developed under the Orphan Drug Act in the US, where companies are given substantive tax breaks and marketing incentives to develop low-profit-potential agents. For example, this is how the non-patentable sodium phenylbutyrate was developed to treat childhood urea cycle disorders. Many human cancers meet orphan disease criteria (less than 200,000 US patients per year) and some of the biggest “blockbuster” drugs today (i.e., erythropoietin) were developed originally as orphan drugs.
    Sharon Begley of the Wall Street Journal also had an article on 26 January that suggests another way that such trials for DCA might be funded: non-profits foundations that fund small pharma companies (reprinted free here in the Pittsburgh Post-Gazette). This is an interesting article worth reading for its own virtues, independently of the DCA discussion.
    So, if DCA can successfully treat human cancers, I predict 1) a drug company will sponsor the agent for the FDA approval process and 2) they will find a way to make a good profit with it.
    The question, however, is will DCA successfully treat human cancers?

  64. #64 S. Rivlin
    February 7, 2007

    Robert Smith,

    I know you still reading the comments even if you decided to stop participating.

    Here’s the math regarding dosage of DCA. First allow me to correct you regarding the volume of water a rodent drinks. A mouse (approximately 25 g of body weight) cannot drink more than its BW in water (30 ml). This amount of water is correct for the rat (most rats used in the lab are 250-300g of BW). Thus, the calculations below are for the rat, not the mouse (the Canadian group that published the paper on DCA used rats):

    A rat of 250 g BW that drinks 30 ml H2O containing 75 mg DCA per liter will take in 2.25 mg DCA. This can be translated to 9 mg DCA/kg BW. A human whose body weight is 70 kg will thus receive a daily dose of 630 mg of DCA. My suggestion to you is to try on yourself this dose of DCA for a week and if you can still blog after a week, report to us on the effects of DCA on healthy humans.

  65. #65 Robster
    February 7, 2007

    Many drugs build up with regular dosing, and an appropriate dosing regimen is designed to take that into account.

    Exactly. That is probably one of the most important concepts in pharmacology.

    IIRC what little I have read about DCA breakdown, it is thought that there is a feedback mechanism that causes DCA to accumulate rapidly. This won’t work the same for all people because of genetic variations within the population. Some people will have faster or slower buildup based on their genes. This could severely affect DCA’s clinical usefulness.

  66. #66 Robert Smith
    February 7, 2007

    He Rivlin, why don’t you shove some of it up your ass, and see how you feel afterwards. At 75mg per liter, that 140Kg human is going to drink 2 liters of water a day roughly, so he will really get 150mg of the shit. There, I’m done posting again until one of you pisses me off again. If you guys aren’t too cheap and lazy, buy Gostjeva’s paper on bell shaped nuclei, and for Lairds work at USC in Nature Genetics,, well you would have to pay for that too. Hint for the stupid, google on Gostjeva bell shaped nuclei. Check out last months work out of U of Kansas. You guys are missing the boat in your own field. You assmoles are so intent on giving me shit that you are missing the whole point of DCA. Its shutting down the energy supply in cancer stem cells. You dumb F*wwerl,ls

  67. #67 trrll
    February 7, 2007

    A rat of 250 g BW that drinks 30 ml H2O containing 75 mg DCA per liter will take in 2.25 mg DCA. This can be translated to 9 mg DCA/kg BW. A human whose body weight is 70 kg will thus receive a daily dose of 630 mg of DCA. My suggestion to you is to try on yourself this dose of DCA for a week and if you can still blog after a week, report to us on the effects of DCA on healthy humans.

    Generally, effective doses do not scale well with body weight over a large range. The scaling for a lot of drugs follows about the 2/3 power of body weight–basically scaling as surface area rather than volume. The additional scaling factor going from rat to human is about 1/6th, so the dose would be more like 105 mg, still high enough to raise reasonable risks of toxicity.

    I don’t think that anybody is suggesting that this isn’t a promising strategy for chemotherapy, or that DCA should not be further studied as an anticancer drug. It is merely that those of us who have followed the field over the years have seen one compound after another trumpeted as a miracle drug for cancer treatment, only to have it turn out in human trials to produce only a modest extension of survival, or work for only a small subset of patients. Meanwhile, our family and friends continue to die from cancer. After a while you get a bit jaded about the cancer cure that is always just around the corner. These overpublicized reports fuel the paranoid notion that the cure for cancer has been discovered, but that physicians are covering it up to maintain their income from treating cancer patients, and encourages patients to abandon working (at least sometimes) therapies in favor of quack cures. The notion that doctors really don’t want to find a cure for cancer ignores the fact that doctors–including oncologists–and their families get cancer too. I had an oncologist relative who fought prostate cancer for a couple of decades, and probably tried every known therapy–surgery, beam irradiation, chemo, radioactive seeds, microwaves. You can bet that if there was a miracle cure around, he would have found it. The therapies extended his life, but they didn’t get rid of the cancer.

    Even researchers who don’t have cancer know that there is a good chance that it is in their future. I don’t think that you will find many people in biology or medicine willing to pass up a good shot of finding a real cure, or even a significant improvement in therapy.

  68. #68 Warren
    February 7, 2007

    If you want to be terribly cynical about financial motives for drug development by all means be that way. Just remember that insurance companies stand to profit immensely from cheap, unpatented cures for common cancers. The customers will use only cheap drugs and will live longer so they keep on paying premiums longer.

    And insurance companies have enough clout to get research approved.

  69. #69 anonimouse
    February 7, 2007

    I have always been amazed that alties think that there’s some kind of massive coverup of miracle cures for things like cancer for the very reason trrll mentioned. Besides, if the treatment worked, you should be able to prove it in clinical trials – the likes of which most alties don’t get involved with. The few that do never seem to show any results from their work.

  70. #70 Unsympathetic reader
    February 7, 2007

    Robert Smith writes: You guys are missing the boat in your own field. You assmoles are so intent on giving me shit that you are missing the whole point of DCA. Its shutting down the energy supply in cancer stem cells.

    I thought the proposed mechanism was that the compound leads to the restoration of mitochondrial-dependent apoptosis. That is different from simply shutting down an ‘energy supply’. Also, I don’t recall reading about cancer stem cells being tested in the experiments. In fact, I’m not sure that cancer stem cells necessarily have metabolic defects that would be susceptible to DCA treatment.

  71. #71 S. Rivlin
    February 8, 2007

    Hey Robert,

    I knew you were lurking and reading. I could sense your BP going up and then poof, you couldn’t hold it in any longer, you had to revert to your daily language. Whether it is 150 mg/day, more or less, with all the reading you have done, you still don’t understand what DCA is doing. You still think that it is specifically targeting cancerous cells and you still blabering about cancer cells are stem cells. Go and untangle the mixup in your head before you explode again and make a joke of yourself.

  72. #72 Robert Smith
    February 8, 2007

    Rivlin, you sweet little arssmole. You are mising the point still. Telomerase overexpression is stemness in cancer, it activates glycolysis, as well as 70 cancer genes, as well as granting replicative immortality to cancer cells, and glycolysis, glycolysis is cancers rocket fuel. The literature roughly equates the growth of a first trimester fetus with that of a mid to high grade untreated tumor. DCA appears to be killing cancer cells in mass, in spite of their stemness granted from telomerase overexpression. In spite of the activation of glycolysis its doiong this, and a wise man would note that the dose can be managed for efficacious blood levels. You are mistaken (so it will be proven) if you don’t think this is specifically targeting cancer cells. You can overdose on water dipstick. $2.00 a day dosage rivlin boy, why isn’t it worth a try. You just keep on calling the priest and the coroner at the same time for your patients and pat yourself on the back for covering your ass. Liability and all. Wouldn’t want to miss a boat payment or the jewelry for our fat spoiled wives.

  73. #73 Robert Smith
    February 8, 2007

    If you want to do something, take a look at how telomerase overexpression activates glycolysis,UCSF study on melanoma, its toward the bottom of this website http://www.geocities.com/prime3end , then , actually read the 15 pages of the study in Cancer Cell. You may then get a clue. You still don’t understand that we are dealing with stem cells and their daughter cells, nor are you grasping the glycolysis dependence of both stem cells, cancer cells, and their offspring. Sure there can be side effects from eating too many beans and from water. But if there is a doc out there who can’t manage dosage of DCA with the use of todays scanning technology to look for effect,, its due to the lack of will rather than the lack of the proper tools. If Dr. Elizabeth Blackburn still has her webcasts online I suggest you listen to them for a keen insight into cancers stemness. Look at the work on GRN163L against cancer stem cells at Johns Hopkins. And for those of you who think the RNA template of telomerase is going to somehow mutate, think again. If it mutates it won’t extend telomeres. Blackburn showed that an intact RNA template on telomerase is required to get the bad gene upregulation, the replicative immortality, and the activation of glycolysis. I ask you to engage in a quest to read some of these works. I know you never heard of Blackburn, etal,, but they won the 2006 Lasker Prize for the discovery of teloemrase and their subsequent work on same. The Lasker is the highest U.S. prize that you can win for research. She also won the 2006 Gruber Genetics prize for same.

    To qualify the above, only a few percent of cancer cells are cancer stem cells. But there is a good chance to kill them with anything that shuts down glycolysis as well as DCA. The lack of effect in MELAS and the trial ending after 2 years because of PN shit to do with cancer. AT the rate of kill that U of Alberta saw, all patients would be cured before they even got a tingle in their fingers.

  74. #74 anonimouse
    February 8, 2007

    Robert,

    I would humor your scientific explanations if you didn’t append anti-doctor hate and conspiracy theories to the end of your posts. Or not. Actually, more like not. I’d still think you were full of it.

  75. #75 S. Rivlin
    February 8, 2007

    Robert,

    You sound like a parrot in a cage who repeats the sounds it hears. If you really read seriously through the dozen of comments here, you should have already picked up on the idea that no one is objecting to DCA as a potential treatment of cancerous cells. The main objection is to the way by which you suggect to bring the drug to the point where it can be used as an anti-cancer treatment. You suggest to overlook all the safegaurds that science, good, sound science, has put together to prevent snake oil healers from promoting their marchadise as the best cure for whatever. Specificity is the secret for any successful treatment of any given disease. DCA specificity in treating cancer has not been shown or proven beyond the treatment of cancerous cells in a petri dish or human cancer cell line in the abdomen of a rat. It does not matter how much you recite this paper or that article. Telomerase, glycolysis, stem cells and assmoles have nothing to do with safety.

  76. #76 Unsympathetic reader
    February 8, 2007

    “Stemness”?

    Not to be confused with cancer stem cells, yes?

  77. #77 Robert Smith
    February 8, 2007

    Then start the trial at your hospital friend, get moving on it. If you work for a catholic hospital, they clear 2-3 billion in profit every year. Tell them its time to spend some money for the sick. Fire the administrators, and put mother teresa types back in charge and maybe then.

  78. #78 Robert Smith
    February 8, 2007

    you are the ones stuck in parrot mode, most of you anyway. you are only looking for negatives and most of them don’t apply to dca when you sit down to design an in house “trial”. I actually like doctors, but through the liability issues they have had to forcibly purge the researchers heart out of themselves. DCA might be an oppportunity to do something that makes a difference. Oh, and parrot my ass, I’ve worked with researchers all over the world, in my home arena you’d be paying to hear me speak. You guys are retired,,, or what?

  79. #79 S. Rivlin
    February 8, 2007

    Why would I pay to hear you speak when the sample you have already provided here would require you to pay me to listen to your drivel. You clearly are clueless on how clinical trials are applied for, approved and conducted. Beside, I thought you have decided not to post here anymore.

  80. #80 anonimouse
    February 8, 2007

    “in my home arena you’d be paying to hear me speak”

    No. But I’d attend for free. Are you sponsored by the Conspiracy Theorists Club or The Quacky Pseudoscientist Society?

  81. #81 Robert Smith
    February 8, 2007

    anonimouse,

    and rivlin, defeated on the science, they can only throw scat. Although I have pinned you with science, you are too mad now to check the works I mentioned. When you do, you will know what cancer is, and you will have a better clue on how to defeat it. Till then you have your head in a bucket of the past. REad the studies boys and girls.

  82. #82 anonimouse
    February 8, 2007

    The works you mentioned in that post where you said you weren’t Robert Smith but I guess you are Robert Smith?

    The posts that talk about DCA but mention nothing about whether it can actually, you know, cure cancer?

    Are you playing the part of a moronic imbecile or are really that clueless?

  83. #83 HCN
    February 8, 2007

    I suspect he is that clueless. He says things like:

    “First off doc, the issues with getting FDA approval shouldn’t apply. The drug is already approved for human use. ”

    When asked for documentation, he does not provide.

    Then he says “Not FDA approved!!!????? They give it to babies all the time. ”

    When asked where and for what they give it to babies, he does not provide any answers.

    Then he says “Its available most everywhere else,, even over the counter in some countries. I gladly stand corrected on the approval status of the drug, in the U.S. Check Canada if you please.”…

    Where he admits it is not approved North America, but used elsewhere. When asked for evidence of this, again he does not provide it.

    He keeps making pronouncements that are blatently false about DCA… There is absolutely no reason to accept any “science” he has written about to have any basis in reality.

    And there is this knee-slapper: “Oh, and parrot my ass, I’ve worked with researchers all over the world, in my home arena you’d be paying to hear me speak.”

    If he had done even a the teeny tiny bit of research he would not have made the silly statements I quoted above (and I did just cut and paste from his postings).

  84. #84 Robert Smith
    February 8, 2007

    Time will show who is the imbecile, and it won’t be me. You morons want to address the rate of kill in the U of Alberta trial? Want to talk about what the projected time for complete clearance might have been with 70% clearance in 3 weeks? Shame on you for posting your crap attacks without looking at the promise in this. Are you all cutters and oncodocs who get their only education from big pharma drug salesladies with cute bottoms?

  85. #85 anonimouse
    February 9, 2007

    Are you all cutters and oncodocs who get their only education from big pharma drug salesladies with cute bottoms?

    Yes. The Illuminati controls medicine. Happy now?

  86. #86 HCN
    February 9, 2007

    Robert Smith (in frustration after being shown is a complete idiot, not just a half wit) wrote: “Are you all cutters and oncodocs who get their only education from big pharma drug salesladies with cute bottoms?”

    Actually I’m just an aerospace engineer. I have absolutely no medical education at all… but I do understand how to do basic research and why safety is an issue that should never be ignored.

    I also am not a big fan of salesladies, because I am a very heterosexual female.

  87. #87 anonimouse
    February 9, 2007

    I also am not a big fan of salesladies, because I am a very heterosexual female.

    As opposed to a somewhat heterosexual…er, nevermind.

  88. #88 HCN
    February 9, 2007

    :p

    I also masticate…

    my food.

    So there!

  89. #89 anonimouse
    February 9, 2007

    I also masticate…

    That is a shocking revelation. I can never look at you the same way again.

  90. #90 DaveScot
    February 9, 2007

    Funny thing is, Orac, I’m in Texas not Kansas. Maybe you ought to double check that. I hope you exercise more due diligence in your work than you do here.

    Now speaking of people I hope are more competent in their work than their internet blathering…

    Jujuquisp claims to be

    Jesse Van Bommel, Anestethiologist, Covenant Healthcare Systems, Inc. 400 W Riverwoods Pkwy Glendale, WI 53212

    He’s been stalking me for months and is lately trying to link me to various other names on the internet.

    Great comment by Robert Smith. At least jujuquisp is so far at least linking me with bright people. And jujuquisp, DA Cook is an orthopedic surgeon. Duh. Cancer would hardly be his line of work. Get a clue you moron.

  91. #91 DaveScot
    February 9, 2007

    Funny thing is, Orac, I’m in Texas not Kansas. Maybe you ought to double check that. I hope you exercise more due diligence in your work than you do here.

    Now speaking of people I hope are more competent in their work than their internet blathering…

    Jujuquisp claims to be

    Jesse Van Bommel, Anestethiologist, Covenant Healthcare Systems, Inc. 400 W Riverwoods Pkwy Glendale, WI 53212

    He’s been stalking me for months and is lately trying to link me to various other names on the internet.

    Great comment by Robert Smith. At least jujuquisp is so far at least linking me with bright people. And jujuquisp, DA Cook is an orthopedic surgeon. Duh. Cancer would hardly be his line of work. Get a clue you moron.

  92. #92 Robert Smith
    February 11, 2007

    DaveScott,

    Thanks for exposing these morons as speaking well out of their professions. They were so hateful and arrogant, I should have known they were speaking from ignorance. So what is their agenda I wonder. I entice them to read the works I’ve mentioned, I won’t bother linking to them because they wouldn’t understand them if they read them. Thanks for the compliment DaveScott. http://www.geocities.com/prime3end

  93. #93 John M. Lynch
    February 11, 2007

    >Thanks for exposing these morons as speaking well out of their professions

    You mean just like Dave “DaveScot” Springer (as an electronic technician) mouthing off about cancer treatment and evolution?

  94. #94 anonimouse
    February 12, 2007

    Dave gives the high-tech business a bad name.

  95. #95 robert scott
    February 15, 2007

    I have no idea about who dave scott is or what he does. I don’t understand why you guys hate this guy so much. What did he do? Is this a long standing fued that I have walked into? I am NOT he. So give me afuckin break pal.

  96. #96 anonimouse
    February 15, 2007

    I think you meant to use your “Robert Smith” alter-ego, dude.

    Man, I hate when I’m pretending to be somebody else and get out of character!

  97. #97 Robster
    February 15, 2007

    Heheh. You fail.

  98. #98 Robert Smith
    February 19, 2007

    Robert Smith is of course an alias, but Dave Scott isn’t me or an alias I use, LOL,, except in the above post. I swear to God I’m not the poster Dave Scott. Is that good enough for you. Look you jagoffs, look at the science I posted. Lets argue the science you gaggle snipes, you apparently have great difficulty embracing anything new. Notice how U of Alberta is proceeding with all speed to a trial on DCA. How many of you know someone who has been working with DCA for 20 years? Mr. Lynch, your credentials in evolution are impressive. How long have you worked with DCA and the mitochondria? Are you one of those evolutionary thinkers who believes the world is only 6000 years old in the name of Jesus?

  99. #99 Robster
    February 19, 2007

    U of Alberta is proceeding with the trial? Good. Hope it works. That would be great. But the trials have to come before clinical use. The animal trials only suggest possibility, not probability.

  100. #100 robert smith (not scotte, LOL)
    February 20, 2007

    If I get sick before then, I’ll be taking it starting with 5mg per day for a week, then 12.5 mg day for week, then 25 mg thereafter, with a doc monitoring my liver tests and blood levels. Soooo many cancer patients do not survive, even after the torture of chemo, chemo brain, the burning radiation that has unintended targets, the surgery,, yuk… I’d rather be a test animal even if I die sooner anyway. I’ve seen the current options, too many times.

  101. #101 NAP
    March 15, 2007

    Concerning DCA, it has been used in humans for decades, especially children with MELAS, a disorder of metabolism. It is a molecule, not a compound. It does not need FDA approval, since it is already in use. I took it myself with no problems for three weeks, and am now restarting it.

  102. #102 Orac
    March 15, 2007

    One question: How do you know that what you have is really DCA?

    In any case, I have looked at the research. Read the very first link listed at the end of the post, where I discuss the Michelakis paper in detail. Then look at the last link, where I describe how brain metastases from breast cancer do not exhibit the Warburg effect and thus would likely not be sensitive to DCA. Sadly, it is more likely than not that it will not work in humans, or, if it does work, its effects will be much more modest than what was observed in the rats. More importantly, even if it is effective, we have no idea what the effective dose against cancer is in humans. My guess, if other chemotherapeutic drugs are any indication (and, make no mistake about it, DCA is a chemotherapeutic drug), is that the effective dose against cancer in humans will be much higher than the dose to treat MELAS, meaning that toxicity will likely be a concern. In any case, without clinical trials, we won’t know. If you’re taking too little, you’re in essence wasting your money and exposing yourself to risk (even if small) for no potential benefit. If you take more, you start to risk toxicity, such as the neuropathy described–and you still won’t know if that’s worth it, because it’s unknown whether DCA is effective against cancer in humans.

    I’m all for the clinical trials, but it’s way premature to say that this stuff will be useful in humans. As I’ve pointed out, the vast majority of drugs found to have anticancer activity in rats or mice either fail to have activity in humans or have only modest activity. It’s highly unlikely that DCA is any “cure.”

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