New Idea on Making DCA work better at lower doses

Home Forums General DCA Discussion New Idea on Making DCA work better at lower doses

This topic contains 33 replies, has 7 voices, and was last updated by  Anonymous 5 years, 11 months ago.

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  • #3274

    robmx
    Participant

    DCA stopped working for me. At first it reduced my Metastatic Colon Cancer tumor by 70% over four months and then it just kept my situation stable for 14 months and caused peripheral neuropathy which caused me to stop taking DCA.

    In investigating why this happened I have found a possible reason and a possible way to make DCA work far better at much lower doses which may also cancel the peripheral neuropathy problem.

    It seems that cancer cells in a petrei dish are easily killed by DCA at very low doses. It is only in Vitro, in you or me, that DCA needs a much larger dosage. Why? Maybe because unlike normal cells many cancer cell lines have a tumor suppressor gene, SLC5A8, supressed by DNA methylation and this can be reversed by a DNA methylation inhibitor such as Vidaza.

    Vidaza is already an FDA approved chemotherapy and if used at a much reduced dosage could have the affect that we want with DCA.

    That is reverse the methylation supression of SLC5A8 and make tumor cells receptive to DCA just like normal cells which allows a much lower dose of DCA to work much better than a large dose.

    I have Kras Wild Type Colon Cancer and it seems that a lot of the cell lines in my cancer do not have SLC5A8 supressed. That explains why my tumor at first reduced quickly in size but later, once those easy to kill cell lines with SLC5A8 in good working order were killed, DCA had to work much harder to kill off the remaining SLC5A8 deprived cells which did not allow easy access for DCA. Therefore cancer cells were able to grow as fast as DCA killed them creating a stable situation for 14 months.

    BUT because of  the high dose of DCA I was taking I developed peripheral neuropathy and had to stop DCA.

     

    Maybe if SLC5A8 allows one to take DCA for a very extended time and works much better at lower dosage a combination of DCA and SLC5A8 could be a cure for some cancers. Who knows.

    http://www.ncbi.nlm.nih.gov/pubmed/21499304

    http://www.pnas.org/content/100/14/8412.full

    http://www.vidaza.com/patient/default.aspx

     

    #3833

    robmx
    Participant

    In the last paragraph of my post you should substitute Vidaza for SLC5A8. 

    #3848

    domik007
    Participant

    I agree with you … I think study from PubMed points in right direction. Only problem is that most of DNA methylation inhibitors are very expencive… I did found some in China for cheap but you can never be sure about what you getting …

    #4435

    tonydewitt
    Participant

    Rob & Dom,

    I agree that DNMT inhibitors are expensive, but two factors could drastically lower their cost:

    (1) The patent (by Celgene, Inc.) for Azacytidine has expired, meaning that anyone can make a generic version of it – why this hasn't happened already puzzles me.

    (2) Clavis Pharma has developed a variant of both Azacytidine and Gemcitabine (called CP-4200 and CP-4126 respectively) that has a lipid attached to the original molecule, which supposedly improves cell permeability, thereby improving the delivery of the medicine to the cells. As with item #1 above, one would expect the price to be lower than the current medication (which can cost $1,000 per dose). See the ClavisPharma site for more details.

    Best wishes.

    #4620

    Anonymous

    To All,

    Gene silencing via methylation and reversing this with agents like Vidaza or Decitabine is worth exploring.  Companies like Celgene often charge extreme $$ for their products. A good example is  thalidomide, which cost pennies to treat leprosy but then a new use patent by Celgene for its use in  PC (prostate cancer) resulted in huge price for the same drug.  

    I will  follow-up on the methylation silencers and see if any are available. Perhaps we might wish to add one of these to our current study of DCA in human cancer that is starting this week in Nassau, The Bahamas under the aegis of Drs. Lunn, Roberts,  Adalsteinsson, and myself. 

     Stephen B. Strum, MD, FACP

     

    Board Certified: Internal Medicine, Medical Oncology

    #4621

    Anonymous

    Addendum to the post just submitted. 

    I am spending time on the DCA site hoping to find people who have had solid responses to DCA.  This would require that the patient was not being treated with another agent of possible known activity at the same time.  Therefore, Robmx's story above could be of major significance depending on the circumstances of his DCA use.  I have privately emailed some of those reporting on DCA efficacy but have not received any replies. Perhaps these patients have deteriorated, passed away or just dropped off the DCA site. I would ask that anyone that believes that they have had a major response to DCA MONOTHERAPY please contact me via private mail (PM).  Our group has submitted one case report of a complete remission to DCA monotherapy in a man with  NHL (non-Hodgkin's lymphoma) who had failed rituximab-CHOP.  He remains in complete remission x almost 5 years.  SADLY, we have had our manuscript rejected by two journals so far.  We are hoping that 3 is the magic number and await the latest decision on this publication for the  peer-reviewed literature. 

     Stephen B. Strum, MD, FACP

     

    Board Certified: Internal Medicine, Medical Oncology

    #4626

    Dan52
    Participant

    The results of this study too seem to enhance the effects of DCA by using it with omeprazole at least for some type of cancers. It's not clear to me the exact used DCA dosage:  "Cotreatment with dichloroacetate and omeprazole exhibits a synergistic antiproliferative effect on malignant tumors." ( http://www.ncbi.nlm.nih.gov/pubmed/22740984 ).

    #4628

    Anonymous

    Dan52, 

    That paper by Ishiquro is one that can be added to:

     

    De Milito A, Iessi E, Logozzi M, Lozupone F, Spada M, Marino ML, Federici C, Perdicchio M, Matarrese P, Lugini L et al: Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res 2007, 67(11):5408-5417.

     

     

     

    Ishiguro T, Ishiguro R, Ishiguro M, Iwai S: Co-treatment of dichloroacetate, omeprazole and tamoxifen exhibited synergistically antiproliferative effect on malignant tumors: in vivo experiments and a case report. Hepatogastroenterology 2012, 59(116):994-996.

     

     

     

    Luciani F, Spada M, De Milito A, Molinari A, Rivoltini L, Montinaro A, Marra M, Lugini L, Logozzi M, Lozupone F et al: Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J Natl Cancer Inst 2004, 96(22):1702-1713.

     

     

     

    Seyfried TN, Shelton LM: Cancer as a metabolic disease. Nutrition & metabolism 2010, 7:7.

     

    A real concern in light of another article by Stockwin is to show without equivocation that DCA has anti-cancer activity in humans in vivo by itself.  Then go forward with various combinations. 

     

     

    Stockwin LH, Yu SX, Borgel S, Hancock C, Wolfe TL, Phillips LR, Hollingshead MG, Newton DL: Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC. Int J Cancer 2010, 127(11):2510-2519.

     

     Stephen B. Strum, MD, FACP

     

    Board Certified: Internal Medicine, Medical Oncology

     

    #4646

    Dan52
    Participant

    Generally speaking and assuming DCA has anticancer properties, I see two main problems:

    1) DCA works fine at high concentration/dosage but this causes neuropathy

    2) DCA works fine at high concentration/dosage but this takes time (months?) to be

    accomplished.

    When DCA fails to work that may be caused by the fact that the compound was not allowed to arrive to the cancer cells because of too low DCA concentration and not by the fact the DCA (by itself) doesn't work.  As previously already mentioned, SLC5A8 gene seems (in vitro) a very good DCA transporter to cancer cells but to obtain that we should be forced to use also Vidaza-like chemiotherapics drugs. I wonder if there's any alternative to this scenario.

     

    #4647

    Anonymous

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    Dan, 

    Major issues are that there are few clinical studies of lower dose DCA in cancer. The doses causing neuropathy of severe degree have been in the range 25-50  mg/kg per day. 

    How long it takes DCA to work I am sure would be dependent on the avidity of the tumor for glucose via aerobic glycolyis (impaired fermentation).  In patient TM, he noted changes within the first two weeks of starting DCA. 

    We really do not have data on DCA access to the site of the cancer. What you state above as fact is not established.  The idea of using a demethylating agent like Vidaza to reactivate  SLC5A8 and carry DCA to the cancer cell is attractive.  Per a previous email to this site, I wonder if a consortium of cancer patients wanting to try this might come together as a group and obtain Vidaza to be used with DCA and under the auspices of trained physicians, and with appropriate baseline and  follow-up studies. If this is not done, we will simply have more conjecture, speculation and lack of substantiation, as we have seen over so many years. 

    Other agents to synergize with DCA may also come into play. Omeprazole, Tamoxifen,  5-FU are some agents showing synergy in cell lines with DCA. 

    My regards, 

    Stephen Strum, MD

    #4648

    tonydewitt
    Participant

    Dr. Strum,

    Clavis Pharma has developed a variant of both Azacytidine and Gemcitabine (called CP-4200 and CP-4126 respectively). The value added improvement to these older medications is the addition of a lipid that assists in cell permeability. Since the uptake of the medicine into cells seems to be the major concern, I'd respectfully suggest that these newer agents should be tested instead. 

    Best wishes.

    #4651

    Dan52
    Participant

    Dear Dr Strum,

    I'm not sure what you mean with "We really do not have data on DCA access to the site of the cancer. What you state above as fact is not established.". It seems to me that the Michelakis first DCA study ( http://www.sciencedirect.com/science/article/pii/S1535610806003722#sec1 ) may report some data about such as: "To determine the effect of DCA on metabolism, we measured glycolysis (Gl), glucose oxidation (GO), and fatty acid oxidation (FAO) in A549 cells (10 plates/experiment, n = 3). DCA significantly increased GO rates (+23%), with a concomitant decrease in both Gl and FAO (Figure 2C). As expected from the DCA-induced shift of pyruvate metabolism away from lactate and toward acetyl-CoA and the Krebs cycle, the lactic-acid levels in the culture medium of the DCA-treated cells decreased (Figure 2D, n = 10 plates/group) and the intracellular pH increased (Figure 2E, n = 5 plates, 60 cells/group)."

    but other studies don't seem to find the same data, such as: "("Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC." , http://www.ncbi.nlm.nih.gov/pubmed/20533281 ): "In this study, we undertook a retrospective of DCA in vitro activity to verify and extend previously reported mechanistic

    data.19 We conclude that (i) DCA is relatively inactive in vitro and inhibits cell viability with an IC50 similar to that observed with sodium pyruvate and sodium acetate, (ii) the anti-cancer activity is not selective as DCA displays similar activity toward

    normal cells, (iii) growth suppression generally occurs without apoptosis induction, (iv) DCA depolarizes mitochondria of both normal and tumor cells, and (v) the potassium transporter Kv1.5 has less overall involvement. However, DCA showed

    increased activity against cells with mitochondrial defects and effectively synergized with agents known to target mitochondria or interfere with glucose metabolism. These data suggest that clinical evaluation of DCA may benefit from selecting patient

    populations or combination regimes in accordance with the mechanism described here."

    Maybe are you referring to these different results.

    #4653

    Anonymous

    Dan, 

    Let me reply in context of what you said above: 

    " "To determine the effect of DCA on metabolism, we measured glycolysis (Gl), glucose oxidation (GO), and fatty acid oxidation (FAO) in A549 cells"

    DCA and its interaction in cell cultures is not the same as DCA in a complex human in vivo system.  Lots of things work well to kill cancer in human cell cultures. In fact, so many herbal cpds, supplements, etc kill cancer cells in culture that 2 or 3 of them together should cure all cancers.  Clearly these findings are possible leads but not conclusions.  The proof of the pudding is in the eating, so to speak. 

    "but other studies don't seem to find the same data, such as: "("Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC."

    This is a <font face="Helvetica">real issue for me as to what is the defect in cancer cells. Did Warburg really mean that cancer cells have a defective respiration and that is the prime reason for the Warburg "effect"  </font>i.e., that cancer cells preferable use aerobic glycolysis akin to fermentation?  If there is a defect in the mitochondria of cancer cells (which appears to be the case per many publications), is that defect irreversible?  If it is, then how can DCA work to kill cancer cells by restoring mitochondrial function leading to generation of ROS, induction of caspases, release of cytochrome C?  I do not have the answer to this but the literature is full of this hotly debated controversy re Warburg. 

    "We conclude that (i) DCA is relatively inactive in vitro and inhibits cell viability with an IC50 similar to that observed with sodium pyruvate and sodium acetate, (ii) the anti-cancer activity is not selective as DCA displays similar activity toward normal cells, (iii) growth suppression generally occurs without apoptosis induction, (iv) DCA depolarizes mitochondria of both normal and tumor cells, and (v) the potassium transporter Kv1.5 has less overall involvement."

    That's an upsetting bunch of statements, that if true, would leave me wondering how the patient TM had such a brilliant tumoricidal effect within 2 weeks of starting DCA, and continues in complete remission x almost 5 years.  Also, Michelakis' paper on DCA vs Glioblastoma patients is highly suggestive of an anti-cancer response. 

    "However, DCA showed increased activity against cells with mitochondrial defects and effectively synergized with agents known to target mitochondria or interfere with glucose metabolism. These data suggest that clinical evaluation of DCA may benefit from selecting patient populations or combination regimes in accordance with the mechanism described here."

    This raises the question–YES or NO–does DCA have any anti-cancer activity in and of itself or does it require a synergistic combination?  The human trial in the Bahamas, begun this week, hopefully will answer this within 2-3 months.  

    What is brutally painful for me is to see the millions of dollars spent for studies lasting 15 years that upon review are full of flaws or that shows a difference in survival of 4 months that results in FDA approval and a new drug cost of $40,000 per year.  

    If a treatment for ANYTHING works, you do not need thousands of patients and thousands of statisticians massaging data to show a statistical difference at a p value of < 0.001.  This is for me a rape of the scientific process.  It is much ado about nothing. Semmelweiss would never had his observations turned into a consideration for washing one's hands before delivering babies, and Flemming would have not bothered about the mold growing in his Petri dishes.  M.C. Li, a private oncologist would never have discovered that methotrexate could cure choriocarcinoma in women, nor would the first docs using MOPP for prostate cancer realized they had a winner.  

    In a nutshell, if the study in the Bahamas, funded largely by Life Extension Foundation, shows that DCA can shut down the functional uptake of FDG glucose per PET/CT and that correlates with improvement CLINICALLY in human beings, that will indicate DCA has anti-tumor activity.  Then,  in my opinion, we can logically and rationally go on to increase our understanding about how to make DCA work better.  

    If this approach would have been done with  3-BP over the last 8 years, we would have been far more advanced and perhaps many of those dead from cancer would be still around.  Our healthcare approach to cancer sucks. 

     

    Advanced cancers: eradication in all cases using 3-bromopyruvate

    therapy to deplete ATP

    Young H. Ko,, Barbara L. Smith, Yuchuan Wang, Martin G. Pomper,

    David A. Rinic, Michael S. Torbenson, Joanne Hullihen, Peter L. Pedersen

     

    Biochemical and Biophysical Research Communications 324 (2004) 269–275

     

    I am giving talks in Los Angeles this weekend about PC that relates to "new findings" that were described by others and myself 15 years ago.  This does not make me feel good, but instead leads me to conclude that the old boy's club of Academia too often furthers its own cause due to ego and greed, very much like what we see in our Senators and Congressman that care more about their party then about doing their job well. 

     

    I hope that by the end of this year I can report some exciting news about DCA efficacy. In the meantime, I really feel that those who self-medicated with DCA and report brilliant responses to cancer are no better than the doctors criticized by me above.  If anyone knows the physical pain and mental anguish that a diagnosis of cancer brings, these patients should.  Not to show 4+ enthusiasm to have someone that cares review their records to confirm efficacy blows my mind.  It does recall to me how the Cancer Control Society went from all-embracing to outraged when my review of Laetrile cures revealed  (a) a mistaken diagnosis of cancer,  (b) a patient cured by surgery and  (c) a patient who simply had radiation esophagitis from treatment of a laryngeal cancer and who got "better" on DCA.  The truth will set you free does not work for many people.  

     

    Meanwhile, I await the verdict from the Journal of Translational Medicine to see if our paper on DCA inducing a complete remission in  NHL (non-Hodgkin's lymphoma) will be accepted.  

     

    Lastly, if Jim Tassano and members of this forum wish to hold a WebEx conference on DCA sometime in the next month, I would be glad to put this together. That can make an impersonal email forum a lot more humanistic. 

     

    Stephen B. Strum, MD, FACP

     

    Board Certified: Internal Medicine, Medical Oncology

    #4660

    Dan52
    Participant

    Thank you Dr Strum.

    As for WebEx, in case not already known and if storing new data on this site is needed, this site can't be updated ( http://www.thedcasite.com/dca-forum/topic/updating-this-site ). This is only a virtual space but for many of us it has a lot of meaning. Like an old, important stone  Thedcasite will have a part in DCA history.    

    #4670

    Dan52
    Participant

    Just for info, this very recent study ("Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo.", http://www.ncbi.nlm.nih.gov/pubmed/22954700 ) compares LPA (alpha-lipoic acid) and DCA reporting that "These data suggests that LPA can reduce (i) cell viability/proliferation, (ii) uptake of [18F]-FDG and (iii) lactate production and increase apoptosis in all investigated cell lines. In contrast, DCA was almost ineffective.".

    #4680

    Anonymous

    Dan, thanks for posting this.  The study was done in cell cultures ("in vitro") and in mice.  We don't know what happens in humans ("in vivo").

    Still, the implications are interesting.  Suppose a patient supplements DCA with LPA, to reduce neuropathy side effects.  If their cancer responds well to the therapy, we don't know what causes it.  DCA alone, LPA alone, or the combination of the two.

    #4681

    Anonymous

     EliG, and Dan, 

    So many patients use R-Lipoic acid and continue to have growth of cancer. I wish it was this easy.  To make matters more confusing there are a lot of peer-reviewed papers showing that  ALA (alpha lipoic acid) induces cancer cell death. And there are conservatively at least 1,000 peer-reviewed papers on other vitamins and supplements and herbal products that all show major tumor cell kill.  There are investigators at prestigious cancer centers who have cured cancer in cell lines and in animal models 100 times over.  But this does not translate to human cancer.  

    What makes sense to me is to take what we learn from the human experience and to build on it.  This goes back to the times of Semelweiss and his observation that washing hands in carbolic acid after performing an autopsy and then delivering babies resulted in a major decrease in child bed fever.  This focuses on the astute observer rather than the 15,000 patient randomized controlled trial that takes a Ph.D. in statistics to show "non-inferiority" in a study with the "astounding" results of a median difference of survival of 3 months.  This is what we are faced with and I am highly critical of it since a lot of this is driven by the friggin dollar.  

    Stephen Strum, MD

    #4714

    robmx
    Participant

    Latest on my Metastatic Colon Cancer and the use of DCA and other things.

    It has been more than a year since I stopped regular chemo, Avastin and Folfiri which worked well for me reducing my tumors by 67% but the chemo was horrible.

    It has been 9 months since I started DCA and Vidaza together. Jan, Feb and March. My last injection of Vidaza was first week of March. Last DCA was March 31st. 

    My regimen since then has been a baby aspirin per day. I eat what I want, I swim an hour a day and I ride my bike 4 miles most days. 

    I have had a CT scan early April, small reduction in my lung tumor. Early July CT scan no change and early October scan I will get the results of on Oct 16th, my oncologist is on vacation. I have the disk of the scan but will not look at it.

    I feel fine and have no symptoms of my cancer.

    November 1st it will be six years since initial diagnosis of Colon Cancer.

    April 1st next year it will be four years since diagnosis of Metastatic Colon Cancer to my Hylar region and right lung. 

    May 21st next year it will be four years since I first used DCA which REDUCED my tumor by 30% in the FIRST two months of use and another 25% in the next two months. 

    Also I used DCA from May 21st 2009 till November 3rd 2010. In the first four months I got the reductions mentioned above and in the next 14 months had stable disease. 

    I am amazed! After being a Colon Cancer patient for six years I feel fine. I have been told that I had six months to live and nine months to live based on statistics and yet here I am. I credit DCA for most of this.

    Think of it. At this point, six years into my cancer fight, I have gone a year without regular chemo, seven months since last Vidaza and more than six months since last DCA.

    And I feel great.

     

     

    #4716

    tonydewitt
    Participant

    Rob,

    God bless you in your recovery – certainly anyone who can eat anything wanted, swim an hour a day and ride a bike 4 miles most days is doing better than most of us. Between your posts about your progress and Dr. Strum's posts about the misdirection of cancer studies, I really hope that we get it right someday, i.e. knowing what works & what doesn't work, and when. I assume that in addition to consuming medicine, the initiation of said medicine is important as well (along with dosing and frequency, of course).

    Best wishes on your continued progress – please keep us informed as to how you are doing.

    #4717

    robmx
    Participant

    Wait one moment. I am not recovering, I am not cured, I am not in remission as far as I know. I am doing OK. My tumors have not been growing, at least not as of early July.

    But I will not know how I have been doing for the last three months till October 16th. 

    I am cautiously optimistic only because I feel fine but that is NO evidence of what really is happening with my disease. 

    I am starting to act as if I had a future and have to remind myself that I have a terminal disease. Of course life is a terminal disease so I say have at it.

    #4718

    tonydewitt
    Participant

    Sorry Rob, I meant that you are recovering in terms of what you reported regarding reduction in your tumors and increase in your quality of life – nowhere did I imply that you are cured. Again, surviving for six years with a terminal disease is something to be proud of, most people are told that they will be dead in a few months and actually are.

    #4719

    Dan52
    Participant

    Rob, glad you're fine and thanks for all info you provided.

    Maybe you have already seen I added the link to the official study about DCA and Vidaza ( http://www.thedcasite.com/dca-forum/topic/dca-and-vidaza-2 ). If I'm allowed and if you agree, may I please ask you some detail about that protocol, e.g. DCA and Vidaza dosages, on/off days (I presume Vidaza must be prescribed by a doctor, isn't it?). 

    #4720

    robmx
    Participant

    Vidaza is prescribed by a doctor off label. It is not approved for use against Colon Cancer but any doctor can use any drug that has been approved for any indication for another AFAIK. I had a doctor who aggreed that my protocal was "valid" and worked with me. 

    I did Vidaza for five days in a row early January at a dose of 1/2 that which is prescribed for chronic myelomonocytic leukemia. Then again at 2/3rds dose for five days early Febuary and again at full dose for five days early March (5th-10th).

    From Jan 1st till March 31st I took a gram of DCA a day in single dose. I missed maybe three days of DCA.

    I took a lot of B vitamins thoughout.

    There is a doctor at John Hopkins who I discovered in March that says that Vidaza will cause Colon Cancer to stop growing or matasticizing. 

    http://www.onclive.com/publications/obtn/2012/June-2012/Epigenetics-Breathes-New-Life-Into-Older-Cancer-Drugs

    He says he has patients like me who are stable with Colon Cancer and he does not know how long it works. It seems a smaller dose is BETTER. A single small dose can cause stable disease for an extended period. I made the mistake of increasing my dose I now believe. 

    At the moment I am in the process of finding out just how long the Vidaza will keep me stable. I will not do anything until my tumors grow.

    No aspirin, nothing else.

    #4721

    robmx
    Participant

    OOPS. The no aspirin line refers to the three months I was on Vidaza and DCA. I am taking a baby aspirin per day now. That is all, no supplements, no vitamins NADA.

    #4722

    tonydewitt
    Participant

    Rob,

    True, an approved drug can be used off-label at the doctor's discretion. Anecdotally, I've read about Vidaza being active against bladder and breast cancer as well, so I'm not surprised that it helped you with colon cancer. Since it works on a cellular level, and awakens crucial suppressor genes, I'd expect that it (or the newer version by Clavis Pharma CP-4200) would be eventually used more widely.

    Best wishes.

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