Radio-sensitizing effect of MEK inhibition in glioblastoma in vitro and in vivo.

INTRODUCTION: Glioblastoma (GBM) is an incurable cancer type. New therapeutic options are investigated, including targeting the mitogen-activated protein kinase (MAPK) pathway using MEK inhibitors as radio-sensitizers. In this study, we investigated whether MEK inhibition via PD0325901 leads to radio-sensitization in experimental in vitro and in vivo models of GBM. MATERIALS AND METHODS: In vitro, GBM8 multicellular spheroids were irradiated with 3 fractions of 2 Gy, during 5 consecutive days of incubation with either PD0325901 or MEK-162. In vivo, we combined PD0325901 with radiotherapy in the GBM8 orthotopic mouse model, tumor growth was measured weekly by bioluminescence imaging and overall survival and toxicity were assessed. RESULTS: Regrowth and viability of spheroids monitored until day 18, showed that both MEK inhibitors had an in vitro radio-sensitizing effect. In vivo, PD0325901 concentrations were relatively constant throughout multiple brain areas and temporal PD0325901-related adverse events such as dermatitis were observed in 4 out of 14 mice (29%). Mice that were treated with radiation alone or combined with PD0325901 had significantly better survival compared to vehicle (both P < 0.005), however, no significant interaction between PD0325901 MEK inhibition and irradiation was observed. CONCLUSION: The difference between the radiotherapy-enhancing effect of PD0325901 in vitro and in vivo urges further pharmacodynamic/pharmacokinetic investigation of PD0325901 and possibly other candidate MEK inhibitors.

Single Coronary Artery from Right Sinus of Valsalva: A Single Center Experience of Seven Cases.

Background: Single coronary artery (SCA) is a rare anomaly with a prevalence of 0.024-0.066%. Some anomalies are merely benign anatomical variants, whereas some can result in myocardial ischemia or life-threatening arrhythmia. Case Presentation. We described seven cases in which all three major coronaries emerged from the right sinus of Valsalva via a single ostium and supplied the vast majority of the myocardium. A smaller branch arising from the left sinus supplied a modest quantity of myocardium in some of those few cases. These SCA variations do not exactly fit into any existing classification. It is unclear whether we need to modify previous classification systems or newer classification systems. Conclusions: SCA is divided based on its anomalous course and is usually a benign condition but it may present with cardiovascular complications. Clinicians should be aware of this entity along with the role of CT angiogram in its diagnosis and management.