Summary Background Recurrent malignant brain tumors (RMBTs) carry a poor prognosis. Dichloroacetate (DCA) activates mitochondrial oxidative metabolism and has shown activity against several human cancers. Design We conducted an open-label study of oral DCA in 15 adults with recurrent WHO grade III – IV gliomas or metastases from a primary cancer outside the central nervous system. The primary objective was detection of a dose limiting toxicity for RMBTs at 4 weeks of treatment, defined as any grade 4 or 5 toxicity, or grade 3 toxicity directly attributable to DCA, based on the National Cancer Institute’s Common Toxicity Criteria for Adverse Events, version 4.0. Secondary objectives involved safety, tolerability and hypothesis-generating data on disease status. Dosing was based on haplotype variation in glutathione transferase zeta 1/maleylacetoacetate isomerase (GSTZ1/MAAI), which participates in DCA and tyrosine catabolism. Results Eight patients completed at least 1 four week cycle. During this time, no dose-limiting toxicities occurred. No patient withdrew because of lack of tolerance to DCA, although 2 subjects experienced grade 0–1 distal parasthesias that led to elective withdrawal and/or dose-adjustment. All subjects completing at least 1 four week cycle remained clinically stable during this time and remained on DCA for an average of 75.5 days (range 26–312). Conclusions Chronic, oral DCA is feasible and well-tolerated in patients with recurrent malignant gliomas and other tumors metastatic to the brain using the dose range established for metabolic diseases. The importance of genetic-based dosing is confirmed and should be incorporated into future trials of chronic DCA administration.

, respectively). However, the rate of overall homocysteine remethylation (ϳ8 mol⅐kg Ϫ1 ⅐h Ϫ1) was twice that of previous reports, which suggests a larger role for homocysteine remethylation in methionine metabolism than previously thought. By use of estimates of intracellular [3-13 C]serine enrichment based on a conservative correction of plasma [3-13 C]serine enrichment, serine was calculated to contribute ϳ100% of the methyl groups used for total body homocysteine remethylation under the conditions of this protocol. This contribution represented only a small fraction (ϳ2.8%) of total serine flux. Our dual-tracer procedure is well suited to measure the effects of nutrient deficiencies, genetic polymorphisms, and other metabolic perturbations on homocysteine synthesis and total and folate-dependent homocysteine remethylation. methionine; methylation cycle; cystathionine ELEVATED PLASMA HOMOCYSTEINE CONCENTRATION is considered an independent risk factor for the development of cardiovascular disease (5,30,32). Accordingly, many investigators have sought to define the genetic and environmental factors that affect plasma homocysteine concentration. Associations exist between plasma homocysteine concentrations and gene polymorphisms, as well as lifestyle and other environmental factors (5). Strong evidence implicates nutritional deficiencies of folate, vitamins B 6 and B 12 , and the methylenetetrahydrofolate reductase (MTHFR) 677C 3 T polymorphism as causes of elevated plasma homocysteine concentration (12, 25). Folate and vitamin B 6 deficiencies and the MTHFR 677C 3 T polymorphism are thought to increase circulating homocysteine concentrations by decreasing the availability of 5-methyltetrahydrofolate (5-CH 3 THF) and thereby inhibiting homocysteine remethylation (24). However, a causal relationship between reduced homocysteine remethylation and hyperhomocysteinemia under these conditions has not been confirmed in humans in vivo.Steady-state plasma homocysteine concentration is not solely a function of the rate of its removal by remethylation but is also affected by the rates of homocysteine production, catabolism through transsulfuration, and loss in renal excretion (24). Specific measurements of homocysteine metabolism through these individual pathways are needed to clarify why homocysteine concentration is elevated by particular genetic variations as well as by nutritional and other environmental conditions. To test the hypothesis that homocysteine remethylation is compromised when 5-CH 3 THF availability is reduced, homocysteine remethylation rates must be measured in individuals affected by these homocysteineelevating factors.Remethylation rates have been measured in humans in vivo by use of methionine tracers labeled with stable isotopes at both the carboxyl and methyl groups or else by measurements of separate methyl-and carboxyl-labeled methionine tracers in primed constant infusion experiments (18,26). By use of these methodologies, the effects of dietary sulfur amino acid intake, sex, age, prandial statu...

Moderate vitamin B-6 deficiency does not significantly alter the rates of homocysteine remethylation or synthesis in healthy young adults in the absence of dietary methionine intake.

Dichloroacetate (DCA), a chemical relevant to environmental science and allopathic medicine, is dehalogenated by the bifunctional enzyme glutathione transferase zeta (GSTz1) maleylacetoacetate isomerase (MAAI), the penultimate enzyme in the phenylalanine/tyrosine catabolic pathway. The authors postulated that polymorphisms in GSTz1/MAAI modify the toxicokinetics of DCA. GSTz1/MAAI haplotype significantly affected the kinetics and biotransformation of 1,2-13C-DCA when it was administered at either environmentally (μg/kg/d) or clinically (mg/kg/d) relevant doses. GSTz1/MAAI haplotype also influenced the urinary accumulation of potentially toxic tyrosine metabolites. Atomic modeling revealed that GSTz1/MAAI variants associated with the slowest rates of DCA metabolism induced structural changes in the enzyme homodimer, predicting protein instability or abnormal protein-protein interactions. Knowledge of the GSTz1/MAAI haplotype can be used prospectively to identify individuals at potential risk of DCA’s adverse side effects from environmental or clinical exposure or who may exhibit aberrant amino acid metabolism in response to dietary protein.

We followed 8 patients (4 males) with biochemically and/or molecular genetically proven deficiencies of the E1α subunit of the pyruvate dehydrogenase complex (PDC; 3 patients) or respiratory chain complexes I (1 patient), IV (3 patients) or I+IV (1 patient) who received oral dichloroacetate (DCA; 12.5 mg/kg/12 hours) for 9.7 to 16.5 years. All subjects originally participated in randomized controlled trials of DCA and were continued on an open-label chronic safety study. Patients (1 adult) ranged in age from 3.5 to 40.2 years at the start of DCA administration and are currently aged 16.9 to 49.9 years (mean ± SD: 23.5 ± 10.9 years). Subjects were either normal or below normal body weight for age and gender. The 3 PDC deficient patients did not consume high fat (ketogenic) diets. DCA maintained normal blood lactate concentrations, even in PDC deficient children on essentially unrestricted diets. Hematological, electrolyte, renal and hepatic status remained stable. Nerve conduction either did not change or decreased modestly and led to reduction or temporary discontinuation of DCA in 3 patients, although symptomatic worsening of peripheral neuropathy did not occur. We conclude that chronic DCA administration is generally well-tolerated in patients with congenital causes of lactic acidosis and is effective in maintaining normal blood lactate levels, even in PDC-deficient children not consuming strict ketogenic diets.