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)

Oncolytic virotherapy represents an emerging field with tremendous promise for harnessing the replicative capabilities of viruses against rapidly proliferating cancer cells. Among the different replicating virus technologies being tested, replication-competent retrovirus (RCR) vectors based on murine leukemia virus (MLV) exhibit unique characteristics. MLV exhibits intrinsic tumor selectivity due to its inability to infect quiescent cells, and can achieve highly selective and stable gene transfer throughout entire solid tumors in vivo at efficiencies of up to >99%, even after initial inoculation at MOIs as low as 0.01. RCR vectors with suicide genes mediate synchronized cell killing after prodrug administration, and due to their ability to undergo stable integration, residual cancer cells serve as a reservoir for long-term viral persistence even as they migrate to new sites, enabling multiple cycles of prodrug to achieve prolonged survival benefit. Further testing in various tumor models, new vector targeting and delivery strategies, and development of GMP manufacturing, are being pursued through a multi-national consortium, and preparations are now being undertaken for clinical trials using RCR vectors in glioblastoma.
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PMID:Replication-competent retrovirus vectors for cancer gene therapy. 1798 78

To improve activity of a recombinant IL-13 cytotoxin (CT) comprised of IL-13 spliced to truncated diphtheria toxin (DT(390)), epidermal growth factor (EGF) was added to the same single chain protein. This new recombinant bispecific CT, called DTEGF13, enhanced the killing potency against the human glioblastoma lines, U87MG (0.015 nM) and U118MG (0.02 nM). A similar enhancement was observed against the lung carcinoma cell line, Calu-3 (0.0018 nM). Enhanced activity could not be explained by an increased number of cytokines available for binding since a combination of monospecific DTEGF and DTIL13 did not cause the same enhanced activity. Enhanced activity was dependent on the presence of both cytokines on the same single chain molecule and killing was receptor specific since target receptor negative leukemia cells were unaffected by the highly selective DTEGF13 and cytotoxicity could be blocked with anti-EGFR and anti-IL-13 antibodies. In a xenograft flank tumor model, intratumoral injection of DTEGF13, but not monospecific DTEGF or DTIL13, significantly inhibited the growth of established U87 tumors in nude mice (P < 0.04). In this model, the human EGF and IL-13 components of DTEGF13 are reactive with mouse EGFR and IL-13R, respectively. These studies show that a new co-targeting agent that simultaneously recognizes EGFR and IL-13R is more effective than its monospecific counterparts and that DTEGF13 has therapeutic advantages for glioblastoma.
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PMID:Anti-glioblastoma effect of a recombinant bispecific cytotoxin cotargeting human IL-13 and EGF receptors in a mouse xenograft model. 1808 21

Balanites aegyptiaca is a widely distributed African plant of medicinal interest containing a number of cytotoxic and cytostatic compounds. The studies reported here have attempted to further characterize the anti-cancer activity of a mixture of steroidal saponins: balanitin-6 (28%) and balanitin-7 (72%) isolated from Balanites aegyptiaca kernels. The balanitin-6 and -7 mixture (henceforth referred to as bal6/7) has demonstrated appreciable anti-cancer effects in human cancer cell lines in vitro. Bal6/7 displayed higher anti-proliferative activity than etoposide and oxaliplatin, although the mixture was appreciably less active than SN38 and markedly less active than taxol. Bal6/7 demonstrated highest activity against A549 non-small cell lung cancer (NSCLC) (IC(50), 0.3 microM) and U373 glioblastoma (IC(50), 0.5 microM) cell lines. The current study has further indicated that bal6/7 is more a cytotoxic compound than a cytostatic one. However, Bal6/7 does not appear to mediate its anti-proliferative effects by inducing apoptotic cell death. Computer-assisted cellular imaging has revealed that bal6/7 does not induce detergent-like effects in A549 NSCLC and U373 glioblastoma unlike certain saponins. Furthermore there is indication that its in vitro anti-cancer activities result at least partly from depletion of [ATP]i, leading in turn to major disorganization of actin cytoskeleton, ultimately resulting in the impairment of cancer cell proliferation and migration. In contrast to a number of natural products acting as anti-cancer agents, bal6/7 does not induce an increase in intra-cellular reactive oxygen species. In vivo, bal6/7 increased the survival time of mice bearing murine L1210 leukemia grafts to the same extent reported for vincristine. These preliminary in vivo data suggest that it may be possible to generate novel hemi-synthetic derivatives of balanitin-6 and -7 with potentially improved in vitro and in vivo anti-cancer activity and reduced in vivo toxicity, thus markedly improving the therapeutic ratio.
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PMID:Balanitin-6 and -7: diosgenyl saponins isolated from Balanites aegyptiaca Del. display significant anti-tumor activity in vitro and in vivo. 1809 38

A novel peptide combination consisting of four synthetic neuropeptide analogs of Vasoactive Intestinal Peptide (VIP), Bombesin, Substance P and Somatostatin has been found to have potent anticancer activity in vitro and in vivo. The receptors of these four neuropeptides are known to be over expressed in various cancers. We have found the presence of native neuropeptides in the culture supernatant of the primary tumor cells of human colon adenocarcinomas. It was further demonstrated by receptor-ligand assays that not only do these tumor cells synthesize and secrete four peptide hormones but also possess specific high affinity receptors on their surface. Screening a large panel of analogs to the four peptide hormones on tumor cell proliferation led to the identification of four cytotoxic analogs, the combination of which was code-named DRF7295. The design and synthesis of the peptide analogs have been described in this paper. In vitro anticancer activity of DRF7295 was studied in a large panel of human tumor cells. Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to be most sensitive to DRF7295 with moderate activity seen in glioblastoma, prostate, leukemia and those of oral cancer cells. Efficacy studies in xenograft models of colon and duodenum resulted in T/C% of less than 40%, which is indicative of strong tumor regressing potential of DRF7295 in gastrointestinal cancers. Acute and long-term toxicity studies as well as safety pharmacology studies conducted indicate the safety of the drug upon systemic administration with no significant adverse pharmacological effects.
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PMID:Anticancer activity of a peptide combination in gastrointestinal cancers targeting multiple neuropeptide receptors. 1821 5

Wilms' tumor gene WT1 is overexpressed in leukemia and various types of solid tumors and plays an important role in leukemogenesis and tumorigenesis. We tested apoptosis-inducing ability of short hairpin RNAs targeting exon 5 (shWTE5), exon10 (shWTE10) and 3'UTR (shWT3U) of the WT1 gene. Among the three WT1-shRNAs, since shWTE5 most effectively induced apoptosis, its ability as an apoptosis-inducing agent was intensively examined. shWTE5 induced mitochondrial damage and resultant apoptosis in five WT1-expressing solid cancer cells originated from gastric (AZ-521), lung (LU99B), ovarian (TYKnuCPr) cancers, fibrosarcoma (HT-1080) and glioblastoma (A172). Moreover, shWTE5 significantly enhanced apoptosis induced by chemotherapeutic agents, doxorubicin (DOX) and etoposide (ETP), or by death ligand TRAIL in all of the four solid tumor cells examined (HT-1080, LU99B, TYK and A172). Transduction of one each of WT1 isoforms with exon 5 [17AA(+)KTS(+) and 17AA(+)KTS(-)] prevented mitochondrial damage induced by ETP or TRAIL and inhibited apoptosis. These results showed that shWTE5 induced apoptosis through the suppression of the WT1 isoform with exon 5. Furthermore, shWTE5 increased expression of proapoptotic Bak and Bax proteins and decreased antiapoptotic Bcl-xL and Bcl-2 proteins in WT1-expressing HT-1080 cells, indicating that WT1 isoforms with exon 5 might play an antiapoptotic role through regulation of Bcl-2 family genes in solid tumor cells. The results presented here demonstrated that WT1-shRNA targeting exon 5 should serve as a potent anti-cancer agent for various types of solid tumors.
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PMID:Wilms' tumor gene WT1-shRNA as a potent apoptosis-inducing agent for solid tumors. 1829 48

IMP preferring cytosolic 5'-nucleotidase (cN-II) is an ubiquitous nucleotide hydrolysing enzyme. The enzyme is widely distributed and its amino acid sequence is highly conserved among vertebrates. Fluctuations of cN-II activity have been associated with the pathogenesis of neurological disorders. The enzyme appears to be involved in the regulation of the intracellular availability of the purine precursor IMP and also of GMP and AMP, but the contribution of this activity and of its regulation to cell metabolism and to CNS cell functions remains uncertain. To address this issue, we used a vector based short hairpin RNA (shRNA) strategy to knockdown cN-II activity in human astrocytoma cells. Our results demonstrated that 53 h after transduction, cN-II mRNA was reduced to 17.9+/-0.03% of control cells. 19 h later enzyme activity was decreased from 0.7+/-0.026 mU/mg in control ADF cells to 0.45+/-0.046 mU/mg, while cell viability (evaluated by the MTT reduction assay) decreased up to 0.59+/-0.01 (fold vs control) and caspase 3 activity increased from 136+/-5.8 pmol min(-1) mg(-1) in control cells to 639+/-37.5 pmol min(-1) mg(-1) in silenced cells, thus demonstrating that cN-II is essential for cell survival. The decrease of enzyme activity causes apoptosis of the cultured cells without altering intracellular nucleotide and nucleoside concentration or energy charge. Since cN-II is highly expressed in tumour cells, our finding offers a new possible therapeutical approach especially against primary brain tumours such as glioblastoma, and to ameliorate chemotherapy against leukemia.
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PMID:Knockdown of cytosolic 5'-nucleotidase II (cN-II) reveals that its activity is essential for survival in astrocytoma cells. 1844 85

Besides the role of normal stem cells in organogenesis, cancer stem cells are thought to be crucial for tumorigenesis. Most current research on human tumors is focused on molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and, more recently, in solid tumors suggests that the tumor cell population is heterogeneous. In recent years, several groups have described the existence of a cancer stem cell population in different brain tumors. These neural cancer stem cells (NCSC) can be isolated by cell sorting of dissociated suspensions of tumor cells for the neural stem cell marker CD133. These CD133+ cells -which also express nestin, an intermediate filament that is another neural stem cell marker- represent a small fraction of the entire brain tumor population. The stem-like cancer cells appear to be solely responsible for propagating the disease in laboratory models. A promising new approach to treating glioblastoma proposes targeting cancer stem cells. Here, we summarize progress in delineating NCSC and the implications of the discovery of this cell population in human brain tumors.
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PMID:Cancer stem cells and brain tumors. 1849 Feb 42

Forkhead box protein P3 (FOXP3) contributes to a unique transcriptional signature and serves as a functional marker of CD4(+)CD25(+) natural regulatory T cells. Dysfunction of FOXP3 in human is associated with fatal autoimmune disease known as immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) or X-linked autoimmunity-allergic disregulation syndrome (XLAAD). FOXP3 also can act as a breast tumor suppressor of the v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (neuro/glioblastoma derived oncogene homolog (avian)) (Her2/neu) gene. While the suppressive functions of FOXP3 in maintaining the immune balance between tolerance and autoimmunity are obvious, the underlying molecular mechanism remains almost entirely undefined. Recent studies indicate that FOXP3 may form a dynamic superamolecular complex with a variety of molecular partners including transcription factors and enzymatic proteins to regulate transcription. How the FOXP3 ensemble changes in response to T-cell receptor signals and/or proinflammatory signal remains unclear although work from this laboratory has revealed its complexity. Structural information on FOXP3 complex may offer novel functional insights, as well as facilitate the development of rational means to modulate regulatory T-cell function in various human diseases.
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PMID:FOXP3 and its partners: structural and biochemical insights into the regulation of FOXP3 activity. 1862 75

Sasa senanensis Rehder extract (SE) showed slightly higher cytotoxicity against human squamous cell carcinoma cell lines and human glioblastoma cell lines, as compared with human oral normal cells (gingival fibroblast, pulp cell, periodontal ligament fibroblast), and was more cytotoxic to human myelogenous and T-cell leukemia cell lines. SE showed a bacteriostatic effect on Fusobacterium nucleatum and Prevotella intermedia, but almost completely eliminated hydrogen sulfide (H2S) and methyl mercaptan (CH3SH) produced by these bacteria. SE protected human T-cell leukemia MT-4 cells from the cytopathic effect of human immunodeficiency virus (HIV) infection, and its anti-HIV activity was much higher than that of tannins and flavonoids, comparable with that of natural and synthetic lignins. SE also protected the MDCK cells from the cytopathic effect of influenza virus infection. SE synergistically enhanced the superoxide anion and hydroxyl radical-scavenging activity of vitamin C. The present study suggests the functionality of SE as a complementary alternative medicine.
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PMID:Antiviral, antibacterial and vitamin C-synergized radical-scavenging activity of Sasa senanensis Rehder extract. 1871 74

The insulin-like growth factor 1 receptor (IGF-1R) and its associated signalling system has provoked considerable interest over recent years as a novel therapeutic target in cancer. A brief outline of the IGF-1R signalling system and the rationale for its use in cancer medicine is given. This is followed by a discussion of the different possible targets within the IGF-1R system, and drugs developed to interact at each target. A systems-based approach is then used to review the in vitro and in vivo data in the published literature of the following compounds targeting IGF-1R components using specific examples: growth hormone releasing hormone antagonists (e.g. JV-1-38), growth hormone receptor antagonists (e.g. pegvisomant), IGF-1R antibodies (e.g. CP-751,871, AVE1642/EM164, IMC-A12, SCH-717454, BIIB022, AMG 479, MK-0646/h7C10), and IGF-1R tyrosine kinase inhibitors (e.g. BMS-536942, BMS-554417, NVP-AEW541, NVP-ADW742, AG1024, potent quinolinyl-derived imidazo (1,5-a)pyrazine PQIP, picropodophyllin PPP, Nordihydroguaiaretic acid Insm-18/NDGA). The following tumour types are specifically discussed: lung, breast, colorectal, pancreatic, NETs, sarcoma, prostate, leukaemia, multiple myeloma. Other tumour types are mentioned briefly: squamous cell carcinoma of the head and neck, melanoma, glioblastoma, ovary, gastric and mesothelioma. Results of early stage clinical trials, involving recently patented drugs. are included where appropriate. We then outline the current understanding of toxicity related to IGF-1R targeted therapy, and finally outline areas for further research.
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PMID:Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine. 1914 88


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