Metabolic modulation of glioblastoma with dichloroacetate.

Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133(+), nestin(+) cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma.

Patient-controlled epidural analgesia after thoracotomy: a comparison of meperidine with and without bupivacaine.

The purpose of this study was to compare meperidine to meperidine with bupivacaine when used for patient-controlled epidural analgesia (PCEA) after thoracotomy. For 3 days after thoracotomy patients received thoracic PCEA with meperidine 0.1% plain or with added bupivacaine 0.1% or 0.01%. No background infusion was used. All patients received indomethacin postoperatively for the duration of the study. Patients were assessed with respect to meperidine consumption, analgesia, and side effects. Sixty-six patients participated. Patients in all three groups obtained effective analgesia with median meperidine consumption of 5-6 mg/h. There were no significant differences between groups in meperidine consumption or pain scores at rest or with coughing. The addition of bupivacaine 0.1% reduced the incidence of pruritus (P = 0.036), but 5 of 23 patients in this group were with-drawn from the study because of significant hypotension, oliguria, and/or motor or sensory block (P = 0.006). We conclude that the addition of bupivacaine 0.1% or 0.01% to thoracic PCEA meperidine 0.1% does not affect meperidine requirements or analgesia after thoracotomy. The addition of bupivacaine 0.1% may reduce pruritus, but is associated with signs of excessive sensory, motor, or autonomic blockade in a significant number of patients.