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Gamma secretase is a mult subunit protease complex

The network of tumor blood vessels that perfuse a solid tumor plays a fundamental role in its growth and survival. Not only do the blood vessels feed the Gamma Secretase tumor with oxygen and nutrients through the blood, they also allow for the subsequent removal of cellular waste products. Vasculardisrupting agents (VDAs) are a class of cancer therapeutics that cause a rapid and selective shutdown of established tumor blood vessels. Subsequently, the blood supply that feeds the tumor is diminished, and the tumor tissue becomes necrotic due to prolonged ischemia [1,2]. It is JAK Signaling Pathway hypothesized that VDAs cause a selective shutdown of tumor blood flow by targeting and destroying the endothelial cells of tumor blood vessels [2]. The selectivity of VDAs for the tumor vasculature is thought to be due to the exaggerated proliferation rate of tumor blood vessel endothelial cells, which is much more rapid than that of normal quiescent endothelial cells [3]. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a lowmolecular- weight VDA that has completed phase I single-agent trials and is now in phase II trials, in combination with chemotherapy, for the treatment of various cancers [2].

There is often no visible tumor shrinkage in response to DMXAA or other VDA treatment, but tumor growth after treatment may be delayed. This is because VDAs typically induce central necrosis but leave a viable rim of cells at the TNF-Alpha Signaling Pathway periphery of the tumor, which eventually causes tumor cell repopulation [1,2]. Due to the nature of its antitumor action, the clinical development of DMXAA requires biomarkers associated with its vascular-disrupting activity. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive technique commonly used in both preclinical and clinical oncology to assess the action of anticancer therapies in vivo. DCE-MRI reveals the kinetics of intravenously administered contrast agent "wash-in" and "wash-out" to give information on tumor perfusion and blood vessel permeability. The two recommended primary DCEAddress MRI?Cderived biomarkers for the assessment of antivascular therapeutics are Ktrans (min_1) and the integrated area under the gadolinium time curve (IAUGC) (mM Gd min) [4]. Because DCE-MRI can provide bcr-abl physiological information that is directly related to the tumor vasculature, it is an ideal method for monitoring the effectiveness of DMXAA and other VDAs as they target tumor blood vessels [4].
In addition to using DCE-MRI, the antivascular effects of DMXAA were also monitored by measuring the change in the plasma concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) following treatment. The rationale for using plasma 5-HIAA levels as a surrogate marker of antivascular effects arises from preclinical studies in mice in which the release of serotonin into the plasma appears to be a feature associated with the antivascular action of DMXAA [5]. It is most likely that this occurs as a consequence of an accumulation of aggregated platelets at the sites of vascular damage, releasing the vasoactive amine serotonin. Measurements of plasma 5-HIAA concentration have also been used in phase I clinical trials of DMXAA to Topoisomerase monitor its antitumor activity in patients [6]. The aim of this study was to further investigate the dose response of tumors to DMXAA using DCE-MRI and the quantitation of 5-HIAA levels after treatment in a rat tumor model. A rat model was chosen because rats, like humans, can tolerate far greater doses of DMXAA than mice, which appear to be very sensitive to the drug [7,8].
DCE-MRI data were analyzed using K trans and IAUGC as response biomarkers to changes in tumor blood flow and permeability following treatment [4]. A 24-hour posttreatment time point was used for all doses in the study. An additional cohort of tumor-bearing rats was investigated prior to treatment (pretreatment) and 4 hours posttreatment with 200 mg/kg DMXAA. This decision was in support of the current phase II clinical trials in which patients are administered 1200 mg/m2 DMXAA (a dose approximately equating to 200 mg/kg in rats) [9] and any antivascular effect is evaluated 4 hours posttreatment. In addition, the degree of tumor necrosis induced by DMXAA was also assessed by grading hematoxylin and eosin?Cstained sections cut from the same tumors used in the study.

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S1575 RO4929097 RO4929097 is a γ secretase inhibitor with IC50 of 4 nM in a cell-free assay, inhibiting cellular processing of Aβ40 and Notch with EC50 of 14 nM and 5 nM, respectively. Phase 2. (92) (7)

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