Preliminary data around the systemic administration of KCN1 in LN229 glioma xenograft bearing mice suggest that intratumoral ranges of HIF 1A are diminished in contrast with controls, and this reduction correlates with elevated necrosis in taken care of tumors. We are at present identifying the pharmacokinetic characteristics of KCN1 to define the most effective administration route and ” selleck chemical Quizartinib “ dosing to evaluate its anti tumor results in glioma models. ET 05. POLYNUCLEAR PLATINUM CHEMOTHERAPEUTICS From the Remedy OF GLIOMA Vaibhav Chumbalkar,1 Yeo Hyeon Huang,1 Ho Shin Gwak,one Wei Zhang,2 Yasuko Kondo,one Nicholas P. Farrell,3 and Oliver Bogler1, Departments of 1Neurosurgery, Brain Tumor Center and 2Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA, and 3Department of Chemistry, Virginia Commonwealth University, Richmond, VA, USA Polynuclear platinum chemotherapeutics BBR3464, BBR3571, and BBR3610 are potent agents towards glioma cells in cultures and ani mal versions, hence, we established their mechanism of action at the cellular level.
BBR3610, essentially the most potent compound, had BI-2536 an IC90 dose 250 times reduced than cisplatin for glioma cells and significantly extended survival in mice with U87 intracranial tumors. An evaluation of apoptosis and cell cycle distribution showed that PPCs induced G2/M arrest while in the absence of cell death, whereas cisplatin predominantly induced apoptosis. The cell cycle arrest induced by PPCs was accompanied by hallmarks of autophagy, like vacuole acidification and LC3 clustering and processing. Each PPCs and cisplatin induced ERK1/2 phosphorylation, and inhibition of this pathway with the level of MEK antagonized the induction of G2/M arrest or apoptosis, respectively. An evaluation of Chk1, Chk2, and survivin did not reveal what underlies the various response.
This prompted a

broader molecular examination, undertaken on the mRNA and protein ranges. Using Agi lent microarray based gene expression analysis in glioma cells, we identified genes that were specifically suppressed by therapy with cisplatin but not BBR3610. Knockdown by siRNA of these genes is being evaluated as a strategy to enhance the apoptosis seen in response to PPCs. We have also used two dimensional liquid chromatography for the PF2D platform to profile the proteome in PPC handled cells. This approach led to the isolation of 39 peaks specifically associated with BBR3610 therapy, and we are identify ing the proteins using LC MS/MS to elucidate PPCs mechanism of action and develop biomarkers indicative of response. ET 06. shRNA KNOCKDOWN OF AMPA RECEPTORS INHIBITS GLIOMA PROLIFERATION John F. de Groot,1 Li Lu,1 Ta Jen Liu,1 Gregory Fuller,two W. K. Alfred Yung1, Brain Tumor Center, Departments of 1Neuro Oncology and 2 Neuropathology, The University of Texas M.