This randomized, open-label, active-controlled, dose-finding phase IIb study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 µM or standard chemotherapy (temozolomide or procarbazine/lomustine/vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 µM trabedersen vs chemotherapy (p= .0032). The 2-year survival rate had a trend for superiority for 10 µM trabedersen vs chemotherapy (p = .10). Median survival for 10 µM trabedersen was 39.1 months compared with 35.2 months for 80 µM trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged ≤55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 µM trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 µM trabedersen (43%) and 10 µM trabedersen (27%). Superior efficacy and safety for 10 µM trabedersen over 80 µM trabedersen and chemotherapy and positive risk–benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma.

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Aims/hypothesis: Obesity is an independent risk factor for heart diseases but the underlying mechanism is not clear. This study examined cardiac contraction, oxidative stress, oxidative modification of sarco(endo) plasmic reticulum Ca 2+ -ATPase (SERCA) and the myosin heavy chain (MHC) isoform switch in obese mice. Methods: Mechanical properties were evaluated in ventricular myocytes from C57BL/6J lean and Lep/Lep obese mice (formerly known as ob/ob mice), including peak shortening (PS), time to 50 or 90% PS, time to 50 or 90% relengthening (TR 50 , TR 90 ), maximal velocity of shortening/relengthening (±dL/dt), intracellular Ca 2+ and its decay (τ). Oxidative stress, lipid peroxidation, protein damage and SERCA activity were assessed by glutathione/glutathione disulfide, malondialdehyde, protein carbonyl and 45 Ca 2+ uptake, respectively. NADPH oxidase was determined by immunoblotting. Results: Myocytes from Lep/Lep mice displayed depressed PS and ± dL/dt, prolonged TR 50 , TR 90 , elevated resting [Ca 2+ ] i , prolonged τ, reduced contractile capacity at high stimulus frequencies and diminished responsiveness to extracellular Ca 2+ compared with lean controls. Cardiac glutathione/glutathione disulfide was decreased whereas malondialdehyde, protein carbonyl, membrane p47 phox and membrane gp91 phox were increased in the Lep/Lep group. SERCA isoenzyme 2a was markedly modified by oxidation in Lep/ Lep hearts and associated with decreased 45 Ca 2+ uptake. The MHC isozyme displayed a shift from the α to the β isoform in Lep/Lep hearts. Short-term incubation of angiotensin II with myocytes mimicked the mechanical defects, SERCA oxidation and 45 Ca 2+ uptake seen in Lep/ Lep myocytes. Incubation of the NADPH oxidase inhibitor apocynin with Lep/Lep myocytes alleviated contractile defects without reversing SERCA oxidation or activity. Conclusions/interpretation: These data indicate that obesity-related cardiac defects may be related to NADPH oxidase activation, oxidative damage to SERCA and the MHC isozyme switch.

γ-tocopherol (γ-T) alone or in combination with α-tocopherol has been shown to suppress biomarkers of oxidative stress in asthamatics and human subjects with metabolic syndrome. Oxidative stress has been implicated as a key event in prostate carcinogenesis. Hence, the purpose of this study was to examine the effects of γ-tocopherol-enriched mixed tocopherol diet on prostate carcinogenesis in a murine prostate cancer model (TRAMP). 8 week old TRAMP males were fed 0.1% γ -T-enriched mixed tocopherol diet that contained 20-fold higher levels of γ-tocopherol, and roughly 3-fold higher levels of α-tocopherol. The effect of such diet on tumor and PIN development was observed. The expression of phase II detoxifying, antioxidant enzymes and Nrf2 mRNA and protein were determined by RT-PCR, immunohistochemistry and western blotting techniques. Treatment with γ-T-enriched mixed tocopherols significantly suppressed the incidence of palpable tumor and Prostate Intraepithelial Neoplasia (PIN) development without affecting the expression of the transgene (SV-40). Tumor progression occurred with a significant suppression of antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase, heme-oxygenase-1 and phase II detoxifying enzymes. Treatment with γ-T-enriched mixed tocopherol diet upregulated the expression of most detoxifying and antioxidant enzymes. Nrf2—a redox sensitive transcription factor known to mediate the expression of phase II detoxifying enzymes, was also significantly upregulated following treatment with γ-T-enriched mixed tocopherol diet. γ-T-enriched mixed tocopherols significantly up-regulated the expression of Nrf2 and its related detoxifying and antioxidant enzymes thereby suppressing PIN and tumor development.

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