Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant gliomas represent the most common primary brain tumor: more than 50% of them are glioblastoma multiforme (GBM). Photodynamic therapy may offer a very good chance of targeted destruction of infiltrating GBM cells, thus increasing the survival time and recurrence-free interval of GBM patients. Among photosensitizing agents, meta-tetrahydroxyphenylchlorin (m-THPC) is promising for the treatment of brain tumors. In previous studies, we investigated the transfection activity of dimyristoyl-sn-glycero-phosphatidylcholine (DMPC) liposomes, containing a cationic gemini surfactant, loaded with m-THPC on human colon adenocarcinoma and glioblastoma cell lines. In this paper, the uptake and the intracellular distribution of m-THPC, loaded in several formulations of cationic liposomes, were analyzed, by making a comparison with those obtained using the same chlorin in the pharmaceutical form (Foscan(R)). Moreover, by cloning efficiency assay the potential therapeutic efficiency of chlorin delivered by liposome formulations was compared with that of the pharmaceutical compound, before and after irradiation with laser light at 652 nm. The obtained results indicated that cationic liposomes (i) transferred m-THPC in glioblastoma cells more efficiently than pharmaceutical formulation; (ii) significantly (p < 0.001) increased the m-THPC cytotoxic effect after laser irradiation; (iii) seemed to exert their cytotoxic action in the early phase of interaction with the cells, during adhesion to the plasma membrane.
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PMID:m-THPC-mediated photodynamic therapy of malignant gliomas: assessment of a new transfection strategy. 1747 62

A range of amines was reacted with norcantharidin (2) to provide the corresponding norcantharimides (9-43). Treatment of norcantharidin with allylamine afforded the corresponding allyl-norcantharimide (20) which was amenable to epoxidation (mCPBA, 22) and subsequent ring opening (MeOH/H(+); 23) or alternatively, osmylation (OsO(4)/NMO; 24). These simple synthetic modifications of 2 facilitated the development of a novel series of norcantharimides displaying modest to good broad spectrum cytotoxicity against HT29 and SW480 (colorectal carcinoma); MCF-7 (breast adenocarcinoma); A2780 (ovarian carcinoma); H460 (lung carcinoma); A431 (epidermoid carcinoma); DU145 (prostate carcinoma); BE2-C (neuroblastoma); and SJ-G2 (glioblastoma). Analogues possessing a C(10), C(12) or C(14) alkyl chain or a C(12) linked bis-norcantharimide displayed the highest levels of cytotoxicity.
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PMID:Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation. 1760 77

Novel bis-heterocyclic bisphosphonates/phosphonamidates were synthesized utilizing the Pudovick reaction. The employment of Nb(2)O(5) as catalyst was found to increase the yields and purity of the bisbenzoxazaphosphine derivatives (13a-h). Their anticancer activity studies in vitro, on three human tumor cell lines NCI-H460 (lung large cell), MCF-7 (breast adenocarcinoma), and SF-268 (central nervous system glioblastoma), showed that bis-[3-(3-chloro-4-fluorophenyl)-2-oxo-3,4-dihydro-2H-2lambda(5)-benzo[e][1,3,2]oxazaphosphinin-2-yl]arylmethanes (13a-h) and [(4-chlorophenyl)-(hydroxyamidophosphinoyl)-methyl]phosphonic acid (14) exhibited significant anticancer activity.
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PMID:Synthesis and anticancer activity of new class of bisphosphonates/phosphanamidates. 1764 Jul 73

Bone marrow-derived stem cells have been shown to participate in solid organ repair after tissue injury. Animal models suggest that epithelial malignancies may arise as aberrant stem cell differentiation during tissue repair. We hypothesized that if bone marrow stem cells participate in human neoplasia, then solid organ cancers developing after allogeneic bone marrow transplantation (ABMT) might include malignant cells of donor origin. We identified four male patients who developed solid organ cancers (lung adenocarcinoma, laryngeal squamous cell carcinoma, glioblastoma, and Kaposi sarcoma) after myeloablation, total body irradiation, and ABMT from female donors. Donor-derived malignant cells comprised 2.5%-6% of the tumor cellularity The presence of donor-derived malignant cells in solid organ cancers suggests that human bone marrow-derived stem cells have a role in solid organ cancer's carcinogenesis. However, the nature of this role is yet to be defined.
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PMID:Donor-derived human bone marrow cells contribute to solid organ cancers developing after bone marrow transplantation. 1769 Jan 78

As demonstrated recently, ionizing radiation (IR) can mediate phosphorylation of DNA-PKcs in human tumor cells through stimulation of the PI3K/Akt pathway. It is also known that DNA-PKcs directly interacts the X-ray repair cross-complementing group 1 protein (XRCC1) involved in base excision repair (BER). Therefore, in the present study we investigated the role of PI3K/Akt activity and DNA-PKcs on XRCC1 expression/stabilization. In contrast to the DNA-PKcs-deficient glioblastoma cell line MO59J, the DNA-PKcs-proficient counterpart MO59K as well as human lung adenocarcinoma A549 cells presented a high basal level of XRCC1 expression. Radiation doses of 3-12Gy did not stimulate a further enhanced expression of XRCC1 in DNA-PKcs-proficient cells (MO59K and A549) within 180min post-irradiation. However, a marked induction of XRCC1 expression was apparent in DNA-PKcs-deficient MO59J cells. Targeting of DNA-PKcs as well as PI3K/Akt pathway by specific kinase inhibitors and/or siRNA reduced basal XRCC1 expression in un-irradiated DNA-PKcs-proficient cells to the level observed in DNA-PKcs-deficient cells. Reduction of basal expression of XRCC1 by XRCC1-siRNA, AKT-siRNA as well as DNA-PKcs inhibitor facilitated IR-induced XRCC1 expression. XRCC1 expression induced by irradiation, however, was independent of PI3K/Akt signaling, but dependent of MAPK-ERK1/2. By immuno-precipitation experiments and confocal microscopy a complex formation of XRCC1 and DNA-PKcs was shown. Applying gamma-H2AX foci analysis it was shown that basal expression of XRCC1 is important for the repair of IR-induced DNA-double strand breaks (DNA-DSBs). These data indicate that IR-induced XRCC1 expression is dependent on the expression level of DNA-PKcs and basal activity status of PI3K/Akt signaling. Likewise, potential of IR-induced XRCC1 expression depends on its basal expression level.
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PMID:PI3K-Akt signaling regulates basal, but MAP-kinase signaling regulates radiation-induced XRCC1 expression in human tumor cells in vitro. 1867 86

Radiotherapy combined with chemotherapy is the treatment of choice for glioblastoma and locally advanced lung cancer, but radioresistance of these two types of cancer remains a significant therapeutic hindrance. To identify molecular target(s) for radiosensitization, we screened a small interfering RNA (siRNA) library targeting all protein kinases and E3 ubiquitin ligases in the human genome and identified tumor necrosis factor receptor-associated factor 2 (TRAF2). Silencing of TRAF2 using siRNA caused a significant growth suppression of glioblastoma U251 cells and moderately sensitized these radioresistant cells to radiation. Overexpression of a really interesting new gene (RING)-deleted dominant-negative TRAF2 mutant also conferred radiosensitivity, whereas overexpression of wild-type (WT) TRAF2 significantly protected cells from radiation-induced killing. Likewise, siRNA silencing of TRAF2 in radioresistant lung cancer H1299 cells caused growth suppression and radiosensitization, whereas overexpression of WT TRAF2 enhanced radioresistance in a RING ligase-dependent manner. Moreover, siRNA silencing of TRAF2 in UM-SCC-1 head and neck cancer cells also conferred radiosensitization. Further support for the role of TRAF2 in cancer comes from the observations that TRAF2 is overexpressed in both lung adenocarcinoma tissues and multiple lung cancer cell lines. Importantly, TRAF2 expression was very low in normal bronchial epithelial NL20 cells, and TRAF2 silencing had a minimal effect on NL20 growth and radiation sensitivity. Mechanistically, TRAF2 silencing blocks the activation of the nuclear factor-kappaB signaling pathway and down-regulates several G(2)-M cell cycle control proteins, resulting in enhanced G(2)-M arrest, growth suppression, and radiosensitization. Our studies suggest that TRAF2 is an attractive drug target for anticancer therapy and radiosensitization.
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PMID:Growth inhibition and radiosensitization of glioblastoma and lung cancer cells by small interfering RNA silencing of tumor necrosis factor receptor-associated factor 2. 1879 45

Fluorine-18-fluorodeoxyglucose positron emission tomography ([18F]FDG PET) was assessed as a method for providing information about the malignancy of orbital tumors. Twelve patients with 13 orbital tumors underwent [18F]FDG PET followed by biopsy or tumor removal via a transcranial approach. The accumulation ratio between the tumor and the contralateral normal tissue (T/N ratio) was calculated for 10 of the 13 lesions. The T/N ratio in benign lesions was compared with that in malignant tumors. Histological examination identified 7 lesions as malignant: anaplastic astrocytoma of the optic nerve in 1 patient, which recurred as glioblastoma of the optic nerve, malignant lymphoma of mucosa-associated lymphoid tissue type in 1 patient, malignant melanoma in 1 patient, adenoid cystic carcinoma in 2 patients, and adenocarcinoma (unknown origin) in 1 patient. The T/N ratio was 1.06 +/- 0.03 (mean +/- standard deviation) in benign tumors, and significantly higher at 1.81 +/- 0.27 in malignant tumors (p = 0.0027). Both patterns of high and iso uptake of [18F]FDG were found in orbital pseudotumor. [18F]FDG PET can determine the malignancy of orbital tumors, but cannot distinguish malignant tumor from inflammatory disease such as pseudotumor.
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PMID:Usefulness and limitations of fluorine-18-fluorodeoxyglucose positron emission tomography for the detection of malignancy of orbital tumors. 1902 76

Genome structural variation includes segmental duplications, deletions, and other rearrangements, and array-based comparative genomic hybridization (array-CGH) is a popular technology for determining this. Drawing relevant conclusions from array-CGH requires computational methods for partitioning the chromosome into segments of elevated, reduced, or unchanged copy number. Several approaches have been described, most of which attempt to explicitly model the underlying distribution of data based on particular assumptions. Often, they optimize likelihood functions for estimating model parameters, by expectation maximization or related approaches; however, this requires good parameter initialization through prespecifying the number of segments. Moreover, convergence is difficult to achieve, since many parameters are required to characterize an experiment. To overcome these limitations, we propose a nonparametric method without a global criterion to be optimized. Our method involves mean-shift-based (MSB) procedures; it considers the observed array-CGH signal as sampling from a probability-density function, uses a kernel-based approach to estimate local gradients for this function, and iteratively follows them to determine local modes of the signal. Overall, our method achieves robust discontinuity-preserving smoothing, thus accurately segmenting chromosomes into regions of duplication and deletion. It does not require the number of segments as input, nor does its convergence depend on this. We successfully applied our method to both simulated data and array-CGH experiments on glioblastoma and adenocarcinoma. We show that it performs at least as well as, and often better than, 10 previously published algorithms. Finally, we show that our approach can be extended to segmenting the signal resulting from the depth-of-coverage of mapped reads from next-generation sequencing.
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PMID:MSB: a mean-shift-based approach for the analysis of structural variation in the genome. 1903 15

The goal of our study was two-fold: (i) develop a robust 3D colony assay methodology to interrogate drug combinations using GelCount and (ii) to develop 2-drug combinations that might be useful in the clinic for the treatment of high-grade gliomas. We used three glioma cell lines (U251MG, SNB19, and LNZ308) and two adenocarcinoma cell lines (MiaPaCa and SW480) grown as colonies in a two-tiered agarose cultures. We evaluated two-drug combinations of difluoromethylornithine (DFMO), carboplatin, vorinostat (SAHA), and docetaxel. To analyze for antitumor efficacy we used GelCount to measure the area under the curve for tumor colony volumes (microm(2) x OD) in each plate. The non-linear dose-response E(max) model and the interaction index based on the Loewe additivity are applied to calculate two-drug synergy, additive, and antagonistic interactions. For glioblastoma cell lines, (i) carboplatin followed by DFMO was synergistic or additive in 2/3 cell lines, (ii) carboplatin before SAHA was synergistic in 1 cell line, (iii) carboplatin before docetaxel was synergistic in 2/3 cell lines and partially additive in the third, (iv) SAHA before docetaxel was synergistic in 1/3 cell lines, (v) docetaxel before DFMO was additive or partially active in 3/3 cell lines, and (vi) DFMO plus SAHA was inactive regardless of order. In the MiaPaCA cell line, synergy occurred when DFMO followed carboplatin and, at short exposure times, when SAHA was combined with carboplatin (regardless of order). In the SW480 cell line synergy occurred only in short exposures for carboplatin followed by docetaxel; additive and mixed partial effects were also seen with DFMO plus carboplatin or docetaxel (regardless of order), carboplatin before DFMO, carboplatin before SAHA, and docetaxel before carboplatin. In conclusion, by applying the Gelcount automated counting and sizing of colonies and the use of E(max) and Loewe models to define drug interactions, we can reliably define drug combination efficacy as a function of log dose and duration of drug exposure.
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PMID:Melding a New 3-Dimensional Agarose Colony Assay with the E(max) Model to Determine the Effects of Drug Combinations on Cancer Cells. 1933 98

For cancer-targeting gene delivery, we applied a protein kinase C (PKC)alpha-responsive polymeric carrier to human cancers (U-87 MG [human glioblastoma-astrocytoma, epithelial-like cell line] and A549 [human lung adenocarcinoma epithelial cell line]). Two polymers, one a PKCalpha-responsive polymer (PPC[S]) containing the phosphorylation site serine, and the other a negative control polymer (PPC[A]), in which the serine was substituted with alanine, were synthesized. No cytotoxicity of the polymer was identified. When the complexes were transfected into cancer cells or tissues in which PKCalpha was hyper-activated, the luciferase expression from the PPC(S)/plasmid (pDNA) complex was higher than that from the PPC(A)/pDNA complex. These results show that the phosphorylation of complex by PKCalpha in cancer cells leads to high gene expression and that our system can be used as a human cancer cell-targeting gene delivery system.
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PMID:Protein kinase Calpha-responsive polymeric carrier: its application for gene delivery into human cancers. 1945 55


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