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.

Absorbed dose to very low birth weight infants from 18F-fluorodeoxyglucose.

The radiation absorbed dose to very low birth weight infants from 18F-fluorodeoxyglucose was investigated. Ten newborns undergoing clinical positron tomography lung imaging were included in this study. Two consecutive 45-min dynamic scans immediately following intravenous injection of fluorodeoxyglucose were acquired; the first was over the head, and the second was over the chest. Time-activity curves were generated for the brain, heart wall, lungs, and, when visible, the kidneys. The cumulated activity measurements obtained were for the entire organ masses; these masses were much smaller than the corresponding organ masses for the newborn mathematical model. Patient-specific dosimetry yielded average doses of 2.5 x 10(-1) mGy MBq(-1) for the brain, 6.8 x 10(-1) mGy MBq(-1) for the heart wall, 2.2 x 10(-1) mGy MBq(-1) for the kidneys, and 4.4 x 10(-1) mGy MBq(-1) for the lungs. The effective dose was estimated to be 2.1 x 10(-1) mSv MBq(-1), which is half that previously published for newborns but still an order of magnitude higher than that for adults.

Absorbed dose to the adult male and female brain from 18F-fluorodeoxyglucose.

The absorbed doses to adult male and female brains from 18F-fluorodeoxyglucose were investigated. A total of eight male and six female patients undergoing clinical positron tomography brain scans were included in this study. This patient population allowed for a comparison of the absorbed dose to the brain in men and women. For each patient, time-activity curves for the brain were generated, yielding cumulated activity measurements for the entire organ. From these cumulated activities the average residence times for both male and female subjects were calculated and then multiplied by the S-values from the MIRDOSE 3.1 software program for absorbed dose estimates. The average absorbed dose per administered activity to the adult male brain was found to be 4.2 x 10(-2) mGy MBq(-1), which is lower than that found for the adult female brain of 5.3 x 10(-2) mGy MBq(-1). Six of the male and all six female subjects were each studied on two separate occasions, allowing for an analysis of within-subject variability. The average variation in the self-dose for all 12 patients was found to be within 14%, suggesting that in most cases this method of obtaining a single dose estimate is precise.