Page 1 of 2 12 LastLast
Results 1 to 10 of 13

Thread: A cheap drug that kills most cancers?

  1. #1
    Senior Member Mike C's Avatar
    Join Date
    Jul 2001
    Location
    Deutschland
    Posts
    4,892

    A cheap drug that kills most cancers?

    This is almost too good to be true, but New Scientist has just updated this remarkable story. Damn, my uncle just recently died of lung cancer.

    http://www.newscientist.com/article/...t-cancers.html

    It sounds almost too good to be true: a cheap and simple drug that kills almost all cancers by switching off their “immortality”. The drug, dichloroacetate (DCA), has already been used for years to treat rare metabolic disorders and so is known to be relatively safe.
    It also has no patent, meaning it could be manufactured for a fraction of the cost of newly developed drugs.
    Evangelos Michelakis of the University of Alberta in Edmonton, Canada, and his colleagues tested DCA on human cells cultured outside the body and found that it killed lung, breast and brain cancer cells, but not healthy cells. Tumours in rats deliberately infected with human cancer also shrank drastically when they were fed DCA-laced water for several weeks.
    DCA attacks a unique feature of cancer cells: the fact that they make their energy throughout the main body of the cell, rather than in distinct organelles called mitochondria. This process, called glycolysis, is inefficient and uses up vast amounts of sugar.
    Until now it had been assumed that cancer cells used glycolysis because their mitochondria were irreparably damaged. However, Michelakis’s experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died (Cancer Cell, DOI: 10.1016/j.ccr.2006.10.020).

    "So I have stayed as I am, without regret, seperated from the normal human condition." Guy Sajer

  2. #2
    Senior Member Mike C's Avatar
    Join Date
    Jul 2001
    Location
    Deutschland
    Posts
    4,892
    Investigators at the University of Alberta have recently reported that a drug previously used in humans for the treatment of rare disorders of metabolism is also able to cause tumor regression in a number of human cancers growing in animals. This drug, dichloroacetate (DCA), appears to suppress the growth of cancer cells without affecting normal cells, suggesting that it might not have the dramatic side effects of standard chemotherapies.

    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.

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

    "So I have stayed as I am, without regret, seperated from the normal human condition." Guy Sajer

  3. #3
    Senior Member Mike C's Avatar
    Join Date
    Jul 2001
    Location
    Deutschland
    Posts
    4,892
    http://www.depmed.ualberta.ca/dca/newsweek.pdf

    Informative Newsweek article.
    "So I have stayed as I am, without regret, seperated from the normal human condition." Guy Sajer

  4. #4
    Senior Member
    Join Date
    Jul 2006
    Location
    Placerville, CA
    Posts
    8,259

    Thumbs up

    Quote Originally Posted by Mike C
    This is almost too good to be true,

    http://www.newscientist.com/article/...t-cancers.html
    Thanks Mike. This seems so promising that, had I a cancer or someone I knew with one, I'd either start taking it or strongly recommend its use.
    "The world will not perish for want of wonders but for want of wonder."
    J.B.S.Haldane

  5. #5
    Senior Member rdf's Avatar
    Join Date
    Jul 2001
    Location
    Someplace between Nowhere and Goodbye
    Posts
    12,972
    I wish I could have gotten ahold of it a couple years ago, when my dad had lung cancer. It's a nasty *ucking disease, and anything that can help those with cancer now or in the future is a very welcome accomplishment in my heart.
    Please donate a dollar a day at http://justadollarplease.org.
    Copy and paste this message to the bottom of your signature.

    Thanks!

  6. #6
    Mike and others,

    Let me review the data.

    The Michelakis study of dichloroacetate (DCA) effects on cancer was published in Cancer Cells. The abstract can be seen below (Bonnett, et al., 2007). Although you cannot download the paper itself, unless you pay $30, you can find parts of it on some web sites, i.e. http://www.thedcasite.com/the_michelakis_paper_dca.html . Bonnett, et al. transplanted 33106A549 cells into nude athymic rats (so that they would not reject the transplanted cancer cells) and gave them free access to water containing DCA 75 mg/l for 5 weeks after cell injection and at 2 weeks after cell injection for 3 weeks. Control untreated rats showed exponential tumor growth while DCA treated rats had smaller tumors, evidence of apoptosis in the tumors, and decreased proliferation markers. They found upregulation of K channels (Kv1.5) and downregulation of survivin in DCA-treated rats. They also looked at rats treated for 12 weeks and rats that were given DCA after the tumor was allowed to grow. In both cases, the tumors were smaller. The DCA apparently did not have any toxic effects as reflected in blood tests.

    In the study, Bonnet, et al. (2007) proposed cancer suppresses "a mitochondrial K channel axis" that inhibits apoptosis of cancer cells. They claim that DCA has several effects on mitochondrial K-channels (KV1.5). One is stimulation of glucose metabolism which reduces (depolarizes) mitochondrial membrane potential and opens the K-channels. They also claim that DCA upregulates KV1.5 by NFAT-1 dependent mechanisms and this induces apoptosis, decreases proliferation, and inhibits tumor growth. They support their hypothesis by using siRNA to reduce PDK2 expression and claim that this mimicked the effect of DCA. Based on this, they claim that their results indicate that DCA would be a good candidate for an anti-cancer drug.

    Dr. Michelakis had earlier published a 2006 paper reporting that K channels (KV1.5, KV2.1) play a role in pulmonary hypertension. In this paper, he also makes a number of claims for the role of K+ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis. In 2004, Michelakis was an author on a paper that reported that DCA reversed pulmonary hypertension (McMurtry, et al., 2004). So, this proposal of DCA effects through depolarization and upregulation of KV1.5 is similar to what he had earlier suggested for pulmonary hypertension. Incidentally, if this is the mechanism by which DCA is working, there are probably many ways to upregulate KV1.5 expression and depolarize mitochondria. They actually used one of the most sophisticated ways, by using siRNA to down regulate PD2K

    While these findings are very interesting, they are a far cry from a "cure" of cancer that is completely innocuous to "normal cells". Both the media and bloggers have over-hyped the effectiveness of the drug and underplayed its potential side effects. An article from Wikipedia (Source) was more balanced and included references that reported side-effects of pain, numbness, and gait disturbances in some patients that received DCA. A few people have tried to post cautionary articles but unfortunately most reporters and bloggers were more interested in expounding their theory that drug companies will not make money from this compound and therefore will actively suppress this treatment.

    Many internet articles have exaggerated DCA's killing effects on cancer cells and failed to mention its side effects. Note that DCA shrank the tumors but did not eradicate them. Bonnett, et al. (2007) did not mention that DCA causes liver cancer in rats (Caldwell, et al., 2006; Delinsky, et al., 2005; Komulainen, 2004; Tao, 2004; Pereira, et al. 2001; Thai, et al., 2001; Tao, et al. 2000; and others). DeAngelo, et al. (1996) studied chronic effects of DCA on male Fischer 344 rats. Drinking water containing 1.6 gram/liter produced observable signs of toxicity in the nervous system, liver, and myocardium. Although this dose is 20 times than the 0.078 gram/liter dose used by Bonnet, et al., DeAngelo, et al. also looked 0.5 gram /liter and found a statistically significantly increase in hepatocellular neoplasia (carcinoma and adenoma) at 100 weeks. At 10 mg/kg/day, 50% of F344 rats developed liver cancer.

    The nerve toxicity may result from DCA producing thiamine deficiency. In 2001, Spruijt, et al. studied peripheral nerve conduction in patients with mitochondrial diseases treated with DCA. They found that peripheral neuropathies developed in 12 of 27 patients, and worsening of nerve conduction in the patients that had abnormal baselines. In 2004, Mori, et al. gave DCA to four children with MELAS (a mitochondrial cytopathy disease). At serum levels of 40-136 micrograms/ml, DCA caused persistent headaches, abdominal pain, muscle weakness, and stroke-like episodes in 4 patients (Mori, et al., 2004). It caused mild liver dysfunction in all four patients, hypocalcemia in three of the patients, and peripheral neuropathy in one patient. More recently, Kaufman, et al. (2006) randomized 30 patients with MELAS to DCA or control. During the initial 24-month treatment period, 15 of the 15 patients randomized to DCA (25 mg/kg/day) had to stop the treatment because of peripheral nerve toxicity.

    In summary, neither the efficacy nor the safety of DCA has been established. Few of the bloggers and reporters who wrote the articles about DCA did a literature search. Reprehensibly, the authors of the study (and the reviewers of the study) did not do an adequate review of the literature. As one blogger pointed out (Source), the articles may be providing false hope to people with cancer. But, this is worse than giving false hope. It is hyping a drug that may be toxic. Since people who are dying with cancer are willing to try any drug, particularly one that is said to be innocuous, this has the potential to harm people.

    Wise.

    References
    1. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B and Michelakis ED (2007). A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11: 37-51. The unique metabolic profile of cancer (aerobic glycolysis) might confer apoptosis resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential (DeltaPsim) and low expression of the K+ channel Kv1.5, both contributing to apoptosis resistance. Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases DeltaPsim, increases mitochondrial H2O2, and activates Kv channels in all cancer, but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a promising selective anticancer agent. Pulmonary Hypertension Program and Vascular Biology Group, Department of Physiology, University of Alberta, Edmonton, AB T6G 2B7, Canada. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=17222789
    2. Caldwell JC and Keshava N (2006). Key issues in the modes of action and effects of trichloroethylene metabolites for liver and kidney tumorigenesis. Environ Health Perspect 114: 1457-63. Trichloroethylene (TCE) exposure has been associated with increased risk of liver and kidney cancer in both laboratory animal and epidemiologic studies. The U.S. Environmental Protection Agency 2001 draft TCE risk assessment concluded that it is difficult to determine which TCE metabolites may be responsible for these effects, the key events involved in their modes of action (MOAs) , and the relevance of these MOAs to humans. In this article, which is part of a mini-monograph on key issues in the health risk assessment of TCE, we present a review of recently published scientific literature examining the effects of TCE metabolites in the context of the preceding questions. Studies of the TCE metabolites dichloroacetic acid (DCA) , trichloroacetic acid (TCA) , and chloral hydrate suggest that both DCA and TCA are involved in TCE-induced liver tumorigenesis and that many DCA effects are consistent with conditions that increase the risk of liver cancer in humans. Studies of S-(1,2-dichlorovinyl) -l-cysteine have revealed a number of different possible cell signaling effects that may be related to kidney tumorigenesis at lower concentrations than those leading to cytotoxicity. Recent studies of trichloroethanol exploring an alternative hypothesis for kidney tumorigenesis have failed to establish the formation of formate as a key event for TCE-induced kidney tumors. Overall, although MOAs and key events for TCE-induced liver and kidney tumors have yet to be definitively established, these results support the likelihood that toxicity is due to multiple metabolites through several MOAs, none of which appear to be irrelevant to humans. National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA. Caldwell.Jane@epa.gov http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16966105
    3. DeAngelo AB, Daniel FB, Most BM and Olson GR (1996). The carcinogenicity of dichloroacetic acid in the male Fischer 344 rat. Toxicology 114: 207-21. The chlorinated acetic acids, in particular dichloroacetic acid (DCA), are found as chlorine disinfection by-products in finished drinking water supplies. DCA has previously been demonstrated to be a mouse liver carcinogen. Chronic studies are described in which male Fischer (F344) rats were exposed to DCA in their drinking water. In the first study, 28 day old rats were exposed to a regimen of 0.05, 0.5 and 5.0 g/l DCA. When animals in the high dose group began to exhibit peripheral hind leg neuropathy, the dose was lowered in stages to 1 g/l. These animals were sacrificed at 60 weeks due to the severe, irreversible neuropathy and were not included in this analysis. The remaining groups of animals were treated for 100 weeks. In the second study, rats were initially exposed to 2.5 g/l DCA which was lowered to 1 g/l after 18 weeks. The mean daily concentration (MDC) of 1.6 g/l was calculated over the 103 week exposure period. Time-weighted mean daily doses (MDD) based on measured water consumption were 3.6, 40.2 and 139 mg/kg bw/day for the 0.05, 0.5 and 1.6 g/l DCA respectively. Based upon the pathologic examination, DCA induced observable signs of toxicity in the nervous system, liver and myocardium. However, treatment related neoplastic lesions were observed only in the liver. A statistically significant increase of carcinogenicity (hepatocellular carcinoma) was noted at 1.6 g/l DCA. Exposure to 0.5 g/l DCA increased-hepatocellular neoplasia, (carcinoma and adenoma) at 100 weeks. These data demonstrate that DCA is an hepatocarcinogen to the male F344 rat. Calculation of the MDD at which 50% of the animals exhibited liver neoplasia indicated that the F344 male rat (approximately 10 mg/kg bw/day) is ten times more sensitive than the B6C3F1 male mouse (approximately 100 mg/kg bw/day). A "no observed effects level' (NOEL) of 0.05 g/l (3.6 mg/kg/day) was the same as for the mouse (3-8 mg/kg/day). National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=8980710
    4. Delinsky AD, Bruckner JV and Bartlett MG (2005). A review of analytical methods for the determination of trichloroethylene and its major metabolites chloral hydrate, trichloroacetic acid and dichloroacetic acid. Biomed Chromatogr 19: 617-39. Trichloroethylene (TCE) and some of its metabolites are potentially carcinogenic compounds that the general population is commonly exposed to in drinking water. Concentrations of TCE, dichloroacetic acid (DCA) and trichloroacetic acid (TCA) given to laboratory animals in cancer bioassays are high, whereas drinking water levels of the compounds are very low. It is not clear whether the trace amounts of TCE, DCA and TCA in drinking water pose a cancer risk to humans. The accuracy of pharmacokinetic studies relies on the analytical method from which blood and tissue concentration data are obtained. Models that extrapolate cancer risks of TCE and its metabolites from laboratory animals to humans, in turn, rely on the results of pharmacokinetic studies. Therefore, it is essential to have reliable analytical methods for the analysis of TCE and its metabolites. This paper reviews the methods currently in the literature for the analysis of TCE, DCA, TCA and, to a lesser extent, chloral hydrate (CH). Additional aspects of analytical methods such as method validation, species preservation and future directions in the analysis of TCE and its metabolites are also discussed. University of Georgia, College of Pharmacy, Department of Pharmaceutical and Biomedical Sciences, Athens, GA 30602, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15828053
    5. Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, Millar WS, Hong X, Gooch CL, Mao X, Pascual JM, Hirano M, Stacpoole PW, DiMauro S and De Vivo DC (2006). Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 66: 324-30. OBJECTIVE: To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). BACKGROUND: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS. METHODS: The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety. RESULTS: During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms. CONCLUSION: DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS. Department of Neurology, Columbia University, New York 10032, USA. pk88@columbia.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16476929
    6. Komulainen H (2004). Experimental cancer studies of chlorinated by-products. Toxicology 198: 239-48. Chlorinated drinking water contains a number of different by-products formed during the chlorination process from organic matter. The carcinogenicity of only a fraction of them have been evaluated in experimental animals. The focus has been on compounds and groups of compounds that are most abundant in chlorinated drinking water or the in vitro toxicity data have suggested genotoxic potential. From trihalomethanes, chloroform causes liver tumors in mice and female rats and renal tumors in male mice and rats. Tumor formation by chloroform is strongly associated with cytotoxicity and regenerative cell proliferation in tissues and that has been considered to be one determinant of its carcinogenicity. From halogenic acetic acids, dichloroacetic acid (DCA) and trichlotoacetic acid (TCA) are hepatocarcinogenic in mice and DCA in male rats. Their genotoxicity is equivocal and nongenotoxic mechanisms, such as peroxisome proliferation and hypomethylation of DNA in the liver, likely contribute to tumor development. From chlorinated furanones (CHFs), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is a multisite carcinogen in rats (e.g. in thyroid glands and liver) and it has caused DNA damage in vivo. MX may be a complete carcinogen because it also has promoter properties in vitro. Chlorinated drinking water may also contain brominated by-products providing the raw water contains bromide. At least some of them (bromodichloromethane, bromoform) have been shown to be carcinogenic in laboratory animals. Altogether, although several by-products have been shown to have carcinogenic potential in laboratory animals, it not yet possible to state which compounds or groups of by-products cause the cancer risk in chlorinated drinking water. The cellular mechanisms of their effects and these effects at low concentrations are still poorly understood. The few studies with mixtures of these by-products suggest that the mixture effects may be complex and unpredictable (inhibitory, additive, synergistic). National Public Health Institute, Division of Environmental Health, Laboratory of Toxicology, P.O. Box 95, FIN-70701 Kuopio, Finland. hannu.komulainen@ktl.fi http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15138047
    7. Moudgil R, Michelakis ED and Archer SL (2006). The role of k+ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis: implications in hypoxic pulmonary vasoconstriction and pulmonary arterial hypertension. Microcirculation 13: 615-32. Potassium channels are tetrameric, membrane-spanning proteins that selectively conduct K+ at near diffusion-limited rates. Their remarkable ionic selectivity results from a highly-conserved K+ recognition sequence in the pore. The classical function of K+ channels is regulation of membrane potential (EM) and thence vascular tone. In pulmonary artery smooth muscle cells (PASMC), tonic K+ egress, driven by a 145/5 mM intracellular/extracellular concentration gradient, contributes to a EM of about -60 mV. It has been recently discovered that K+ channels also participate in vascular remodeling by regulating cell proliferation and apoptosis. PASMC express voltage-gated (Kv), inward rectifier (Kir), calcium-sensitive (KCa), and two-pore (K2P) channels. Certain K+ channels are subject to rapid redox regulation by reactive oxygen species (ROS) derived from the PASMC's oxygen-sensor (mitochondria and/or NADPH oxidase). Acute hypoxic inhibition of ROS production inhibits Kv1.5, which depolarizes EM, opens voltage-sensitive, L-type calcium channels, elevates cytosolic calcium, and initiates hypoxic pulmonary vasoconstriction (HPV). Hypoxia-inhibited K+ currents are not seen in systemic arterial SMCs. Kv expression is also transcriptionally regulated by HIF-1alpha and NFAT. Loss of PASMC Kv1.5 and Kv2.1 contributes to the pathogenesis of pulmonary arterial hypertension (PAH) by causing a sustained depolarization, which increases intracellular calcium and K+, thereby stimulating cell proliferation and inhibiting apoptosis, respectively. Restoring Kv expression (via Kv1.5 gene therapy, dichloroacetate, or anti-survivin therapy) reduces experimental PAH. Electrophysiological diversity exists within the pulmonary circulation. Resistance PASMC have a homogeneous Kv current (including an oxygen-sensitive component), whereas conduit PASMC current is a Kv/KCa mosaic. This reflects regional differences in expression of channel isoforms, heterotetramers, splice variants, and regulatory subunits as well as mitochondrial diversity. In conclusion, K+ channels regulate pulmonary vascular tone and remodeling and constitute potential therapeutic targets in the regression of PAH. Vascular Biology Group, Division of Cardiology, University of Alberta, Edmonton, Canada. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=17085423
    8. McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K and Michelakis ED (2004). Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95: 830-40. The pulmonary arteries (PA) in pulmonary arterial hypertension (PAH) are constricted and remodeled;. They have suppressed apoptosis, partly attributable to suppression of the bone morphogenetic protein axis and selective downregulation of PA smooth muscle cell (PASMC) voltage-gated K+ channels, including Kv1.5. The Kv downregulation-induced increase in [K+]i, tonically inhibits caspases, further suppressing apoptosis. Mitochondria control apoptosis and produce activated oxygen species like H2O2, which regulate vascular tone by activating K+ channels, but their role in PAH is unknown. We show that dichloroacetate (DCA), a metabolic modulator that increases mitochondrial oxidative phosphorylation, prevents and reverses established monocrotaline-induced PAH (MCT-PAH), significantly improving mortality. Compared with MCT-PAH, DCA-treated rats (80 mg/kg per day in drinking water on day 14 after MCT, studied on day 21) have decreased pulmonary, but not systemic, vascular resistance (63% decrease, P<0.002), PA medial thickness (28% decrease, P<0.0001), and right ventricular hypertrophy (34% decrease, P<0.001). DCA is similarly effective when given at day 1 or day 21 after MCT (studied day 28) but has no effect on normal rats. DCA depolarizes MCT-PAH PASMC mitochondria and causes release of H2O2 and cytochrome c, inducing a 10-fold increase in apoptosis within the PA media (TUNEL and caspase 3 activity) and decreasing proliferation (proliferating-cell nuclear antigen and BrdU assays). Immunoblots, immunohistochemistry, laser-captured microdissection-quantitative reverse-transcription polymerase chain reaction and patch-clamping show that DCA reverses the Kv1.5 downregulation in resistance PAs. In summary, DCA reverses PA remodeling by increasing the mitochondria-dependent apoptosis/proliferation ratio and upregulating Kv1.5 in the media. We identify mitochondria-dependent apoptosis as a potential target for therapy and DCA as an effective and selective treatment for PAH. Department of Medicine and Pediatrics, University of Alberta, Edmonton, Canada. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15375007
    9. Mori M, Yamagata T, Goto T, Saito S and Momoi MY (2004). Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS. Brain Dev 26: 453-8. The long-term effects of the sodium salt of dichloroacetic acid (DCA) were evaluated in four patients with mitochondrial encephalomyelopathy with lactic acidosis and stroke-like episodes (MELAS) carrying A3243G mutation. Oral administration of DCA in MELAS patients was followed for an average of 5 years 4 months. Serum levels of lactate and pyruvate were maintained at around 10 and 0.6 mg/dl, respectively. Serum levels of DCA were 40-136 microg/ml. Symptoms responding to treatment included persistent headache, abdominal pain, muscle weakness, and stroke-like episodes. In contrast, no improvements in mental status, deafness, short stature, or neuroelectrophysiological findings were observed. Adverse effects included mild liver dysfunction in all patients, hypocalcemia in three and peripheral neuropathy in one. None of these adverse events was severe enough to require discontinuation of treatment. To determine suitable indications for DCA therapy, analysis of many more patients who have undergone DCA administration is required. Department of Pediatrics, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi, Tochigi 329-0498, Japan. morim@jichi.ac.jp http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15351081
    10. Pereira MA, Wang W, Kramer PM and Tao L (2004). Prevention by methionine of dichloroacetic acid-induced liver cancer and DNA hypomethylation in mice. Toxicol Sci 77: 243-8. Dichloroacetic acid (DCA) is a liver carcinogen that induces DNA hypomethylation in mouse liver. To test the involvement of DNA hypomethylation in the carcinogenic activity of DCA, we determined the effect of methionine on both activities. Female B6C3F1 mice were administered 3.2 g/l DCA in their drinking water and 0, 4.0, and 8.0 g/kg methionine in their diet. Mice were sacrificed after 8 and 44 weeks of exposure. After 8 weeks of exposure, DCA increased the liver/body weight ratio and caused DNA hypomethylation, glycogen accumulation, and peroxisome proliferation. Methionine prevented completely the DNA hypomethylation, reduced by only 25% the glycogen accumulation, and did not alter the increased liver/body weight ratio and the proliferation of peroxisomes induced by DCA. After 44 weeks of exposure, DCA induced foci of altered hepatocytes and hepatocellular adenomas. The multiplicity of foci of altered hepatocytes/mouse was increased from 2.41 +/- 0.38 to 3.40 +/- 0.46 by 4.0 g/kg methionine and decreased to 0.94 +/- 0.24 by 8.0 g/kg methionine, suggesting that methionine slowed the progression of foci to tumors. The low and high concentrations of methionine reduced the multiplicity of liver tumors/mouse from 1.28 +/- 0.31 to 0.167 +/- 0.093 and 0.028 +/- 0.028 (i.e., by 87 and 98%, respectively). Thus, the prevention of liver tumors by methionine was associated with its prevention of DNA hypomethylation, indicating that DNA hypomethylation was critical for the carcinogenic activity of DCA. Department of Pathology, Medical College of Ohio, Toledo, Ohio 43614, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=14657517
    11. Spruijt L, Naviaux RK, McGowan KA, Nyhan WL, Sheean G, Haas RH and Barshop BA (2001). Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate. Muscle Nerve 24: 916-24. Serial measurements of nerve conduction velocities and amplitudes were performed in 27 patients with congenital lactic acidemia over 1 year of sodium dichloroacetate (DCA) administration. Patients were treated with oral thiamine (100 mg) and DCA (initial dose of 50 mg/kg) daily. Nerve conduction velocity and response amplitude were measured in the median, radial, tibial, and sural nerves at 0, 3, 6, and 12 months, and plasma DCA pharmacokinetics were measured at 3 and 12 months. Baseline electrophysiologic parameters in this population were generally below normal but as a group were within 2 standard deviations of normal means. Although symptoms of neuropathy were reported by only three patients or their families, nerve conduction declined in 12 patients with normal baseline studies, and worsening of nerve conduction occurred in the two who had abnormalities at baseline. Peripheral neuropathy appears to be a common side effect during chronic DCA treatment, even with coadministration of oral thiamine. Nerve conduction should be monitored during DCA treatment. Department of Pediatrics, 0830, Division of Biochemical Genetics, UCSD School of Medicine, La Jolla, California 92093, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=11410919
    12. Tao L, Li Y, Kramer PM, Wang W and Pereira MA (2004). Hypomethylation of DNA and the insulin-like growth factor-II gene in dichloroacetic and trichloroacetic acid-promoted mouse liver tumors. Toxicology 196: 127-36. Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are mouse liver carcinogens. DNA hypomethylation is a common molecular event in cancer that is induced by DCA and TCA. Hypomethylation of DNA and the insulin-like growth factor-II (IGF-II) gene was determined in DCA- and TCA-promoted liver tumors. Mouse liver tumors were initiated by N-methyl-N-nitrosourea and promoted by either DCA or TCA. By dot-blot analysis using an antibody for 5-methylcytosine, the DNA in DCA- and TCA-promoted tumors was demonstrated to be hypomethylated. The methylation status of 28 CpG sites in the differentially methylated region-2 (DMR-2) of mouse IGF-II gene was determined. In liver, 79.3 +/- 1.7% of the sites were methylated, while in DCA- and TCA-treated mice, only 46.4 +/- 2.1% and 58.0 +/- 1.7% of them were methylated and 8.7 +/- 2.6% and 10.7 +/- 7.4% were methylated in tumors. The decreased methylation found in liver from mice exposed to DCA or TCA occurred only in the upstream region of DMR-2, while in tumors it occurred throughout the probed region. mRNA expression of the IGF-II gene was increased in DCA- and TCA-promoted liver tumors but not in non-involved liver from DCA- and TCA-exposed mice. The results support the hypothesis that DNA hypomethylation is involved in the mechanism for the tumorigenicity of DCA and TCA. Department of Pathology, Medical College of Ohio, 3055 Arlington Avenue, Toledo, OH 43614-5806, USA. tao.31@osu.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15036762
    13. Tao L, Yang S, Xie M, Kramer PM and Pereira MA (2000). Hypomethylation and overexpression of c-jun and c-myc protooncogenes and increased DNA methyltransferase activity in dichloroacetic and trichloroacetic acid-promoted mouse liver tumors. Cancer Lett 158: 185-93. Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are mouse liver carcinogens. Methylation of the c-jun and c-myc genes, expression of both genes and DNA methyltransferase (DNA MTase) activity were determined in liver tumors initiated by N-methyl-N-nitrosourea and promoted by DCA and TCA in female B6C3F1 mice. Hypomethylated and over-expression of c-jun and c-myc genes were found in DCA- and TCA-promoted liver tumors. DNA MTase activity was increased in tumors while decreased in non-involved liver. Thus, DCA- and TCA-promoted carcinogenesis appears to include decreased methylation and increased expression of c-jun and c-myc genes in the presence of increased DNA MTase activity. Department of Pathology, Medical College of Ohio, Health Education Building, 3055 Arlington Ave., Toledo, OH 43614-5806, USA. ltao@mco.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=10960769
    14. Thai SF, Allen JW, DeAngelo AB, George MH and Fuscoe JC (2001). Detection of early gene expression changes by differential display in the livers of mice exposed to dichloroacetic acid. Carcinogenesis 22: 1317-22. Dichloroacetic acid (DCA) is a major by-product of water disinfection by chlorination. Several studies have demonstrated the hepatocarcinogenicity of DCA in mice when administered in drinking water. The mechanism of DCA carcinogenicity is not clear and we speculate that changes in gene expression may be important. In order to analyze early changes in gene expression induced by DCA treatment we used the differential display method. Mice were treated with 2 g/l DCA in drinking water for 4 weeks. Total RNAs were obtained from livers of both control and treated mice for analysis. Of approximately 48 000 bands on the differential display gels representing an estimated 96% of RNA species, 381 showed differences in intensity. After cloning and confirmation by both reverse-northern and northern analyses, six differentially expressed genes were found. The expression of five of these genes was suppressed in the DCA-treated mice while one was induced. After sequencing, four genes were identified and two were matched to expressed sequence tags through the BLAST program. These genes are alpha-1 protease inhibitor, cytochrome b5, stearoyl-CoA desaturase and carboxylesterase. Stearoyl-CoA desaturase was induced approximately 3-fold in the livers of DCA-treated mice and the other three genes were suppressed approximately 3-fold. Stearoyl-CoA desaturase, cytochrome b5 and carboxylesterase are endoplasmic reticulum membrane-bound enzymes involved in fatty acid metabolism. The expression pattern of four of these genes was similar in DCA-induced hepatocellular carcinomas and the 4 week DCA-treated mouse livers. The expression of stearoyl-CoA desaturase and one of the unidentified genes returned to control levels in the carcinomas. Understanding the roles and interactions between these genes may shed light on the mechanism of DCA carcinogenesis. National Health and Environmental Effects Research Laboratory, Environmental Carcinogenesis Division, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=11470764
    Last edited by Wise Young; 02-23-2007 at 10:01 PM.

  7. #7
    Senior Member Myc0's Avatar
    Join Date
    Jul 2005
    Location
    Twilight in the Garden of Good and Evil
    Posts
    1,891
    Bummer, my grandmother's breast cancer just returned. I was hoping that the miracle cure showed up at the perfect time. Damn. Well, thanks for shedding some light on this Wise, even if the light is kinda dark.
    De Omnibus Dubitandum

  8. #8
    Senior Member Mike C's Avatar
    Join Date
    Jul 2001
    Location
    Deutschland
    Posts
    4,892
    Yeah, it´s a bummer allright. I figured that New Scientist would have screened the claim for hype more extensively, but they must be getting huge traffic from this story. The link fowarding people towards the Uni of Alberta gives the impression that all that is needed is money.
    "So I have stayed as I am, without regret, seperated from the normal human condition." Guy Sajer

  9. #9
    Quote Originally Posted by Mike C
    Yeah, it´s a bummer allright. I figured that New Scientist would have screened the claim for hype more extensively, but they must be getting huge traffic from this story. The link fowarding people towards the Uni of Alberta gives the impression that all that is needed is money.
    The New Scientist has become more sensationalistic. They have been publishing a bunch of crackpot stuff recently, as the following comment and response from the editors show:
    http://golem.ph.utexas.edu/category/...st_reacts.html
    New Scientist Reacts!


    Posted by John Baez


    MathML-enabled post (click for more details).

    You may recall Greg Egan’s plea to save the magazine New Scientist from a rising tide of crackpottery after it published a glowing article about a propulsion system called the EmDrive. According to its inventor, Roger Shawyer, this drive can push a rocket forwards by bouncing microwaves back and forth in a box. The article didn’t mention that this violates conservation of momentum.


    A bunch of us wrote emails to the magazine, with no apparent reaction.


    Now they’ve reacted! New Scientist now has a blog thread on the Shawyer article. It starts with a statement by the editor defending the article - see below.


    I urge folks who sent email to New Scientist or comments on this blog to post them on
    the New Scientist blog. That way, your opinions will be publicly visible. But please: be polite, rational, and crystal-clear. There’s nothing to be gained by rudeness.



    MathML-enabled post (click for more details).

    The New Scientist’s blog thread on the Shawyer article starts with this statement by the editor:




    Editor’s note


    It is a fair criticism that New Scientist did not make clear enough how controversial Roger Shawyer’s engine is. We should have made more explicit where it apparently contravenes the laws of nature and reported that several physicists declined to comment on the device because they thought it too contentious.


    But should New Scientist should have covered this story at all? The answer is a resounding yes: it is, after all, an ideas magazine. That means writing about hypotheses as well as theories.


    And let’s not forget that Shawyer has experimental data that has convinced peer reviewers that he is onto something. He believes he can explain his machine’s behaviour in terms of existing physical laws, which is what the theorists contest.


    The great thing is that Shawyer’s ideas are testable. If he succeeds in getting his machine flown in space, we will know soon enough if it is ground-breaking device or a mere flight of fancy.


    Jeremy Webb, Editor, New Scientist


    Posted at October 5, 2006 4:15 PM UTC
    It already tells you that the editor of New Scientist does not think that it is necessary to review the science underlying an article before they publish it.

    Wise.

  10. #10

    Confusing "DCA"

    Wise - you seem to be confusing the definition of DCA. In several of the references you provide, they refer to dichloracetic acid (defined as DCA), while in the study they used the salt (dichloroacetate, also defined as DCA). The two are quite different.

    The side effects you suggest seem only to linked to the dichloracetic acid?

    As for the nerve toxisity, this is temporary and can be reduced by temporarily stopping usage until the effects disappear.

Similar Threads

  1. Replies: 77
    Last Post: 12-15-2016, 12:10 PM
  2. BLIND GIRL RAPED IN NYC SUBWAY..
    By michaelm in forum General News
    Replies: 2
    Last Post: 03-19-2005, 09:43 PM
  3. Replies: 3
    Last Post: 06-15-2002, 06:56 PM

Posting Permissions

  • You may not post new threads
  • You may not post replies
  • You may not post attachments
  • You may not edit your posts
  •