funding of medical research vs. public, and difficulty funding research into orphan drugs, is very real, although I think the problem is less that Rx companies are spending more money on research (why would this be a problem) than that the government share of research money is stagnant (increased less than inflation this last year).
The points you bring up are good. Because one guy published one study, people seem to have taken leave of any skepticism: "It's the cure for cancer!" How many of THOSE have we had over the last few decades, whether it's antiangiogenesis drugs, immune modulating drugs, monoclonal antibodies and many more, all of which showed promise, none of which are "the cure for cancer" (which there will never be ONE because it's such a wide group of different diseases).
Because dichloroacetate has actually already undergone clinical trials in humans for treatment of mitochondrial disorders, some of the initial barriers to study of this drug are already crossed.
In my other thread which I linked elsewhere in this thread, there are examples of some of the trials, in humans, that have been done on DCA for mitochondrial diseases. They definitely show toxicity to the nerves, one of the pediatric studies was terminated due to nerve toxicity issues.
Of interest, DCA is actually known to be carcinogenic to the liver, at least in mice. Apparently the mouse exposure causing liver cancer is at higher levels than have been used in the clinical trials of DCA in humans:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15036762&query_hl=1&itool=pubmed_docsum 1: Toxicology. 2004 Mar 1;196(1-2):127-36.Click here to read Links
Hypomethylation of DNA and the insulin-like growth factor-II gene in dichloroacetic and trichloroacetic acid-promoted mouse liver tumors.
* Tao L,
* Li Y,
* Kramer PM,
* Wang W,
* Pereira MA.
Department of Pathology, Medical College of Ohio, 3055 Arlington Avenue, Toledo, OH 43614-5806, USA.
[email protected] 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.
PMID: 15036762
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10807555&query_hl=1&itool=pubmed_DocSum1: Environ Health Perspect. 2000 May;108 Suppl 2:241-59.Click here to read Links
Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate.
* Bull RJ.
Pacific Northwest National Laboratory, U.S. Department of Energy, Richland, WA 99352-0999, USA.
[email protected] Trichloroethylene (TCE) induces liver cancer in mice but not in rats. Three metabolites of TCE may contribute--chloral hydrate (CH), dichloroacetate (DCA), and trichloroacetate (TCA). CH and TCA appear capable of only inducing liver tumors in mice, but DCA is active in rats as well. The concentrations of TCA in blood required to induce liver cancer approach the mM range. Concentrations of DCA in blood associated with carcinogenesis are in the sub-microM range. The carcinogenic activity of CH is largely dependent on its conversion to TCA and/or DCA. TCA is a peroxisome proliferator in the same dose range that induces liver cancer. Mice with targeted disruptions of the peroxisome proliferator-activated receptor alpha (PPAR-alpha) are insensitive to the liver cancer-inducing properties of other peroxisome proliferators. Human cells do not display the responses associated with PPAR-alpha that are observed in rodents. This may be attributed to lower levels of expressed PPAR-alpha in human liver. DCA treatment produces liver tumors with a different phenotype than TCA. Its tumorigenic effects are closely associated with differential effects on cell replication rates in tumors, normal hepatocytes, and suppression of apoptosis. Growth of DCA-induced tumors has been shown to arrest after cessation of treatment. The DCA and TCA adequately account for the hepatocarcinogenic responses to TCE. Low-level exposure to TCE is not likely to induce liver cancer in humans. Higher exposures to TCE could affect sensitive populations. Sensitivity could be based on different metabolic capacities for TCE or its metabolites or result from certain chronic diseases that have a genetic basis.
PMID: 10807555
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10771136&query_hl=1&itool=pubmed_DocSum 1: Toxicology. 2000 Apr 14;145(2-3):115-25.Click here to read Links
In vivo MRI measurements of tumor growth induced by dichloroacetate: implications for mode of action.
* Miller JH,
* Minard K,
* Wind RA,
* Orner GA,
* Sasser LB,
* Bull RJ.
Pacific Northwest National Laboratory, Molecular Biosciences, PO Box 999-P7-56, Richland, WA 99352, USA.
Dichloroacetate (DCA) is an important by-product of the chlorination of drinking water that produces liver cancer in rodents. Assessment of the risk that results from concentrations that occur in drinking water will be dependent upon the mode of action held responsible for these tumors. A study by Stauber and Bull
in mice treated with DCA demonstrated a lesion distribution that was skewed towards many small, altered foci of cells that are assumed to be precursor lesions . The present study was designed to determine the extent to which the tumorigenic effects of DCA could be explained by its effect on tumor growth rates (i.e. tumor promoting activity). In vivo magnetic resonance imaging (MRI) allowed accurate determination of growth rates of individual lesions in mice that had been treated with DCA in drinking water at 2 g/l. Out of thirty treated mice, ten were found to have hepatic tumors detectable by MRI at 48 weeks of treatment. These tumor-bearing animals were assigned to two groups matched on the size of lesions observed by in vivo MR1. Treatment with DCA continued in one group of five mice and was stopped in the other. For both groups, tumor growth rates were determined by measuring changes in size of all lesions greater than 1 mm(3) in volume during a 14-day period. Removal of DCA treatment resulted in growth rates that could not be distinguished from zero across all lesion sizes represented in the sample. These data are in agreement with previous observations of DCAs effects on replication rates within tumors (Stauber and Bull, (1997)). Tumor growth rates observed in animals maintained on treatment decreased with lesion volume in a manner that is consistent with a stochastic Gompertz birth-death process proposed by Tan . Parameters of this model obtained by fitting measured growth rates were used to predict the lesion-size distribution expected after one year of DCA treatment. The shape of the predicted lesion-size distribution was similar to that observed by Stauber and Bull (Stauber and Bull, (1997)) in mice sacrificed after 40 weeks of DCA treatment. We conclude that the effects of DCA on the division and/or death rates of spontaneously initiated cells can account for the predominance of small lesions in DCA-treated animals.
PMID: 10771136
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10632141&query_hl=1&itool=pubmed_DocSum1: J Toxicol Environ Health A. 1999 Dec 24;58(8):485-507. Links
Hepatocarcinogenicity in the male B6C3F1 mouse following a lifetime exposure to dichloroacetic acid in the drinking water: dose-response determination and modes of action.
* DeAngelo AB,
* George MH,
* House DE.
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
[email protected] Male B6C3F, mice were exposed to dichloroacetic acid (DCA) in the drinking water in order to establish a dose response for the induction of hepatocellular cancer and to examine several modes of action for the carcinogenic process. Groups of animals were exposed to control, 0.05, 0.5, 1, 2, or 3.5 g/L DCA in the drinking water for 90-100 wk. Mean daily doses (MDD) of 8, 84, 168, 315, and 429 mg/kg/d of DCA were calculated. The prevalence (percent of animals) with hepatocellular carcinoma (HC) was significantly increased in the 1-g/L (71%), 2-g/L (95%), and 3.5-g/L (100%) treatment groups when compared to the control (26%). HC multiplicity (tumors/animal) was significantly increased by all DCA treatments-0.05 g/L (0.58), 0.5 g/L (0.68), 1 g/L (1.29), 2 g/L (2.47), and 3.5 g/L (2.90)-compared to the control group (0.28). Based upon HC multiplicity, a no-observed-effect level (NOEL) for hepatocarcinogenicity could not be determined. Hepatic peroxisome proliferation was significantly increased only for 3.5 g/L DCA treatment at 26 wk. and did not correlate with the liver tumor response. The severity of hepatotoxicity increased with DCA concentration. Below 1 g/L, hepatotoxicity was mild and transient as demonstrated by the severity indices and serum lactate dehydrogenase activity. An analysis of generalized hepatocyte proliferation reflected the mild hepatotoxicity and demonstrated no significant treatment effects on the labeling index of hepatocytes outside proliferative lesions. Consequently, the induction of liver cancer by DCA does not appear to be conditional upon peroxisome induction or chemically sustained cell proliferation. Hepatotoxicity, especially at the higher doses, may exert an important influence on the carcinogenic process.
PMID: 10632141
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9703483&query_hl=1&itool=pubmed_DocSum 1: Environ Health Perspect. 1998 Aug;106 Suppl 4:989-94.Click here to read Links
Clinical pharmacology and toxicology of dichloroacetate.
* Stacpoole PW,
* Henderson GN,
* Yan Z,
* James MO.
Department of Medicine, College of Medicine, University of Florida, Gainesville, USA.
[email protected] 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.
PMID: 9703483
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8980710&query_hl=1&itool=pubmed_DocSum1: Toxicology. 1996 Dec 18;114(3):207-21.Click here to read Links
The carcinogenicity of dichloroacetic acid in the male Fischer 344 rat.
* DeAngelo AB,
* Daniel FB,
* Most BM,
* Olson GR.
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
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).
PMID: 8980710