For 80 years it has been noted that cancer cells exhibit increased glycolysis and pentose phosphate cycle activity, while demonstrating only slightly reduced rates of respiration. These metabolic differences were thought to arise as a result of "damage" to the respiratory mechanism and tumor cells were thought to compensate for this defect by increasing glycolysis (Science 132:309). In the last 10 years, glucose deprivation-induced oxidative stress has been shown to cause cytotoxicity, activation of signal transduction (i.e., ERK1, ERK2, JNK, and Lyn kinase), and increased expression of genes associated with malignancy (i.e., bFGF and c-Myc) in MCF-7/ADR human breast cancer cells (J. Biol. Chem. 273:5294; Free Radic. Biol. Med. 26:419). These results have lead to the proposal that intracellular oxidation/reduction reactions involving hydroperoxides and thiols may provide a mechanistic link between metabolism, signal transduction, and gene expression in human cancer cells during glucose deprivation (Ann. NY Acad. Sci. 899:349). Further studies have shown that several other transformed human cell types appear to be more susceptible to glucose deprivation-induced cytotoxicity and oxidative stress than untransformed human cell types (Free Radic. Biol. Med. 26:419; Ann. NY Acad. Sci. 899:349; Biochem J. 418:29). Studies with mitochondrial electron transport chain blockers that increase superoxide and hydrogen peroxide production have shown that glucose deprivation-induced oxidative stress and cytotoxicity can be greatly enhanced in human cancer cells, relative to normal cells (J. Biol. Chem. 280:4254; Biochem J. 418:29). Finally, CHO cells carrying mutations in mitochondrial electron transport chain proteins (succinate dehydrogenase subunits C and D) that are associated with human cancers demonstrate increased production of reactive oxygen species, increased glucose consumption, increased genomic instability, and increased sensitivity to glucose deprivation-induced cytotoxicity that can be reversed by over expressing cellular antioxidants. Overall, these results support the working hypothesis that transformed cells may have dysfunctional mitochondrial respiration leading to increased steady-state levels of reactive oxygen species and glucose metabolism may be increased to provide reducing equivalents to compensate for this defect. This theorectical construct is being utilized by Dr. Spitz's lab in basic science studies of cancer vs. normal cell mitochondria metabolism to determine the role that damage to genes coding for mitochondrial electron transport chain proteins may play in cancer and aging. This theorectical construct is also being used to develop novel strategies for treating cancers with combined therapies utilizing inhibitors of glucose and hydroperoxide metabolism together with agents that increase respiratory dependent damage caused by reactive oxygen species. Finally, Dr. Spitz's laboratory is also using these principals in preclinical translational studies to develop strategies for imaging glucose utilization and alterations in mitochondrial metabolism in cancer cells for the purpose of predicting which patients may respond to therapies base on taking advantage of fundamental defects in oxidative metabolism.