Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres.
ABSTRACT Object The aim of this study was to demonstrate that paclitaxel could function as a radiosensitizer for malignant glioma in vitro and in vivo. Methods The radiosensitizing effect of paclitaxel was tested in vitro using the human U373MG and rat 9L glioma cell lines. Cell cycle arrest in response to paclitaxel exposure was quantified by flow cytometry. Cells were subsequently irradiated, and toxicity was measured using the clonogenic assay. In vivo studies were performed in Fischer 344 rats implanted with intracranial 9L gliosarcoma. Rats were treated with control polymer implants, paclitaxel controlled-release polymers, radiotherapy, or a combination of the 2 treatments. The study end point was survival. Results Flow cytometry demonstrated G2-M arrest in both U373MG and 9L cells following 6-12 hours of paclitaxel exposure. The order in which the combination treatment was administered was significant. Exposure to radiation treatment (XRT) during the 6-12 hours after paclitaxel treatment resulted in a synergistic reduction in colony formation. This effect was greater than the effect from either treatment alone and was also greater than the effect of radiation exposure followed by paclitaxel. Rats bearing 9L gliosarcoma tumors treated with paclitaxel polymer administration followed by single-fraction radiotherapy demonstrated a synergistic improvement in survival compared with any other treatment, including radiotherapy followed by paclitaxel treatment. Median survival for control animals was 13 days; for those treated with paclitaxel alone, 21 days; for those treated with XRT alone, 21 days; for those treated with XRT followed by paclitaxel, 45 days; and for those treated with paclitaxel followed by XRT, more than 150 days (p < 0.0001). Conclusions These results indicate that paclitaxel is an effective radiosensitizer for malignant gliomas because it renders glioma cells more sensitive to ionizing radiation by causing G2-M arrest, and induces a synergistic response to chemoradiotherapy.
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ABSTRACT: Glioblastomas (GBM) are the most common primary malignant brain tumors with a high invasiveness and resistance to radiation and other treatments. The need for the development of new therapeutic agents for GBM is urgent. Here, we aimed to explore the metabolic mechanism of GBM and identified potential novel drugs for GBM by a sub-pathway-based method. By using the GBM microarray data from "The Cancer Genome Atlas" database, we first identified the 274 differentially expressed genes between GBM and normal samples. Then, we identified 18 significant enriched metabolic sub-pathways that may involve in the development of GBM. Finally, by an integrated analysis of GBM-involved sub-pathways and drug-affected sub-pathways, we identified 66 novel small-molecular drugs capable to target the GBM-involved sub-pathways. Our method could not only identify existing drug (paclitaxel) for GBM, but also predict potentially novel agents (pergolide) that might have therapeutic effects. We also experimentally verified that pergolide could induce GBM cell death. These candidate small-molecular drugs identified by our approach may provide insights into a novel therapy approach for GBM.Medical Oncology 09/2014; 31(9):182. DOI:10.1007/s12032-014-0182-6 · 2.06 Impact Factor
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ABSTRACT: 6"-O-Acetylginsenoside Rb-1 (ac-Rb-1) isolated from North American ginseng was encapsulated within biodegradable poly(DL-lactide-co-glycolide) (PLGA) microspheres. Both a conventional double emulsion and a microfluidic technique were examined for microsphere formation. The ac-Rb-1 encapsulation within PLGA microspheres was characterized by various physicochemical techniques including FTIR, DSC, and XRD. The experimental data showed that the PLGA microspheres produced from the microfluidic technique were uniform with tunable mean diameters from 7 to 59 mu m and standard deviations less than 10%. The size was independent of the capillary number and could be tuned by altering the continuous and disperse phase flow rate ratios. Release profiles from the uniform microspheres were investigated, showing controlled release of ac-Rb-1 which followed a Fickian diffusion while retaining potency toward immunosuppressive activity using macrophages in vitro. This study shows that ac-Rb-1 encapsulated PLGA microspheres obtained using the microfluidic approach are promising for the development of next-generation biomedical agents.Industrial & Engineering Chemistry Research 06/2014; 53(28):11333−11344. DOI:10.1021/ie501118u · 2.24 Impact Factor