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

Antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-alpha) (MR1) and its binding site, the epidermal growth factor receptor (EGFR) (MR2), are efficacious against the UACC 897 breast, PC-3 and LNCaP prostate, and T98G glioblastoma tumor lines in both in vitro and in vivo studies. Oligos against the anti-apoptosis protein bcl-2 (MR4) are also efficient against PC-3 and LNCaP tumors in similar in vitro experiments. To enhance activity, and also to introduce a derivative type of multifunctional oligo into this field, "bispecifics" were constructed containing two truncated complementary DNA sequences (from either MR1 or MR2) designed to bind targeted mRNA about their respective AUG initiation codons, and/or a similar sequence adjacent to the AUG site of mRNA encoding bcl-2. Tandem pairs of bispecifics were constructed: The first had complementary sequences for TGF-alpha and EGFR mRNA, but differed in 5' to 3' tandem orientation (TGF-alpha/EGFR [MR12] and EGFR/TGF-alpha [MR21] sequences); a second pair had binding sites associated with EGFR and bcl-2, also differing in orientation (EGFR/bcl-2 [MR24] and bcl-2/EGFR [MR42]). In studies targeting PC-3 and LNCaP cells, bispecifics demonstrated significant in vitro activity, and the second pair was significantly better than the original monospecifics. These studies are now extended to the MCF-7 breast cancer model in order to determine whether these particular bispecifics have similar anti-breast cancer activity and if they are significantly better than monospecific oligos from which they were derived. We conclude that bispecific oligos significantly inhibit MCF-7 growth, however, in contrast to results obtained with PC-3 and LNCaP, the monospecific oligos directed against EGFR and bcl-2 have significantly greater activity than the bispecifics targeting a combination of TGF-alpha, EGFR, or bcl-2. These data suggest that the relative activities of oligos, whether mono- or bispecific, change with tumor type. Bispecific oligos which target different proteins, possibly those which regulate estrogen utilization, may be more effective against MCF-7 cells and warrant additional investigation, particularly if co-administered with traditional chemotherapeutics.
 ...
PMID:Treatment of MCF-7 breast cancer cells employing mono- and bispecific antisense oligonucleotides having binding specificity toward proteins associated with autocrine regulated growth and BCL-2. 1797 23

Aberrant expression levels of epidermal growth factor receptor (EGFR) and its cognate ligands have been recognized as one of the causes of cancer progression. To investigate the validity of EGFR ligands as targets for cancer therapy, we examined the expression of EGFR ligands and in vitro anti-tumor effects of small interference RNA (siRNA) for EGFR ligands in various cancer cells. HB-EGF expression was dominantly elevated in ovarian, gastric, and breast cancer, melanoma and glioblastoma cells, whereas amphiregulin was primarily expressed in pancreatic, colon, and prostate cancer, renal cell carcinoma and cholangiocarcinoma cells. Transfection of siRNAs for HB-EGF or amphiregulin into these cells significantly increased the numbers of apoptotic cells with attenuation of EGFR and ERK activation. In lung cancer cells, any EGFR ligand was not recognized as a validated target for cancer therapy. These results suggest that HB-EGF and amphiregulin are promising targets for cancer therapy.
 ...
PMID:Validation of HB-EGF and amphiregulin as targets for human cancer therapy. 1802 15

Cancer is often associated with multiple and progressive genetic alterations in genes that are important for normal development. BCAS3 (Breast Cancer Amplified Sequence 3) is a gene of unknown function on human chromosome 17q23, a region associated with breakpoints of several neoplasms. The normal expression pattern of BCAS3 has not been studied, though it is implicated in breast cancer progression. Rudhira, a murine WD40 domain protein that is 98% identical to BCAS3 is expressed in embryonic stem (ES) cells, erythropoiesis and angiogenesis. This suggests that BCAS3 expression also may not be restricted to mammary tissue and may have important roles in other normal as well as malignant tissues. We show that BCAS3 is also expressed in human ES cells and during their differentiation into blood vascular precursors. We find that BCAS3 is aberrantly expressed in malignant human brain lesions. In glioblastoma, hemangiopericytoma and brain abscess we note high levels of BCAS3 expression in tumor cells and some blood vessels. BCAS3 may be associated with multiple cancerous and rapidly proliferating cells and hence the expression, function and regulation of this gene merits further investigation. We suggest that BCAS3 is mis-expressed in brain tumors and could serve as a human ES cell and tumor marker.
 ...
PMID:Human BCAS3 expression in embryonic stem cells and vascular precursors suggests a role in human embryogenesis and tumor angiogenesis. 1803 Mar 36

Many cancer cells display down-regulated major histocompatibility complex (MHC) class I antigen (MHC-I), which seems to enable them to evade immune surveillance, whereas the underlying mechanisms remain incompletely understood. Here, we demonstrate that ligand (CXCL12) stimulation of CXCR4, a major chemokine receptor expressed in many malignant cancer cells, induced MHC-I heavy chain down-regulation from the cell surface of the human epithelioid carcinoma HeLa cells, the human U251 and U87 glioblastoma cells, the human MDA-MD 231 breast cancer cells, and the human SK-N-BE (2) neuroblastoma cells. Activation of CXCR4 also induced MHC-I down-regulation in human peripheral blood mononuclear cells. The internalized MHC-I heavy chain molecules were partially co-localized with Rab7, a later endosomal marker. Activation of CXCR4 induced ubiquitination of MHC-I heavy chain, and mutation of the C-terminal two lysine residues (Lys-332, Lys-337) on one of the MHC-I alleles, HLA.B7, blocked CXCR4-evoked ubiquitination and down-regulation of HLA.B7. Moreover, purified GST-conjugated CXCR4 C terminus directly associated with the purified His-tagged beta2-microglobulin (beta2M), and MHC-I heavy chain was co-immunoprecipitated with CXCR4 in a beta2M-dependent manner. This interaction appears to be critical for CXCR4-evoked down-regulation of MHC-I heavy chain as evidenced by the data that MHC-I heavy chain down-regulation was inhibited by either truncation of the CXCR4 C terminus or knockdown of beta2M. All together, these findings shed new light on the role of CXCR4 in tumor evasion of immune surveillance via inducing MHC-I down-regulation from the cell surface.
 ...
PMID:Activation of CXCR4 triggers ubiquitination and down-regulation of major histocompatibility complex class I (MHC-I) on epithelioid carcinoma HeLa cells. 1808 6

A 43-year-old woman who had undergone breast cancer surgery 1 year previously complained of headache and nausea. Her brain computed tomography (CT) scan and magnetic resonance imaging (MRI) showed a well-circumscribed, heterogeneously enhanced tumor in the right thalamus. She underwent gross total resection of the tumor followed by radiochemotherapy, and her clinical course was uneventful after surgery. Histological examination revealed a moderate number of tumor cells with fine bipolar processes in a mucoid matrix, which suggested pilocytic astrocytoma. The tumor was associated with microvascular proliferation but did not show significant mitosis or necrosis. In some areas, it had an epithelioid appearance, with ribbon-like, cribriform, and pseudoglandular patterns involving cuboid-shaped cells showing nuclear atypia and mitotic figures. Immunohistochemically, the tumor cells were positive for glial fibrillary acidic protein (GFAP) and vimentin in the area resembling pilocytic astrocytoma, but in the epithelioid area they were negative for GFAP and vimentin as well as for breast cancer markers, including AE1/AE3. The proliferating potential, represented by the MIB-1 labeling index, was high (82.5%) in the area of epithelioid appearance, compared to only 3% in the area of pilocytic astrocytoma-like appearance. As a rare histoarchitectural variant of glioblastoma, the epithelioid pattern may represent a very primitive tumor cell phenotype. Typically, this pattern is characterized by well-circumscribed masses, although its clinical significance is unknown.
 ...
PMID:Epithelioid glioblastoma: a case report. 1809

Doxazolidine (Doxaz), a formaldehyde-doxorubicin (Dox) conjugate, exhibits markedly increased tumor toxicity with respect to Dox without a concurrent increase in toxicity to cardiomyocytes. Pentyl PABC-Doxaz (PPD) is a Doxaz carbamate prodrug that is hydrolyzed by carboxylesterases. Here, we identify human intestinal carboxylesterase (hiCE) as the agent of activation for PPD. Upon prodrug treatment, cells that express higher levels of hiCE responded with lower IC50 values for growth inhibition. Exposing MCF-7 human breast cancer cells, which respond poorly and express little hiCE, to PPD together with hiCE resulted in a dramatic decrease in the IC50, a decrease that was absent when human carboxylesterase 1 was added to prodrug treatment. Finally, U373MG glioblastoma cells overexpressing hiCE displayed approximately 100-fold reduction in the IC50 for PPD compared to cells lacking the carboxylesterase. Overall, our studies indicate that PPD is selectively hydrolyzed to the active metabolite by hiCE.
 ...
PMID:Identification of human intestinal carboxylesterase as the primary enzyme for activation of a doxazolidine carbamate prodrug. 1817 33

beta-Catenin/Tcf and NF-kappaB pathways play an important role in biological functions. We determined the underlying mechanisms of differential interaction between two pathways in various human cancer cell lines. NF-kappaB positively regulated beta-catenin/Tcf pathways in human glioblastoma, whereas it has an opposite effect on beta-catenin/Tcf pathways in colon, liver, and breast cancer cells. Expression of lucine zipper tumor suppressor 2 (lzts2) was positively regulated by NF-kappaB activity in colon, liver, and breast cancer cells, whereas negatively regulated in glioma cells. Downregulation of lzts2 increased the beta-catenin/Tcf promoter activity and inhibited NF-kappaB-induced modulation of the nuclear translocation of beta-catenin. These data indicate that the differential crosstalk between beta-catenin/Tcf and NF-kappaB pathway in various cancer cells is resulted from the differences in the regulation of NF-kappaB-induced lzts2 expression.
 ...
PMID:Differential effect of NF-kappaB activity on beta-catenin/Tcf pathway in various cancer cells. 1824 84

The role of response gene to complement (RGC)-32 as a cell cycle regulator has been attributed to its ability to activate cdc2 kinases and to induce S-phase entry and mitosis. However, recent studies revealed novel functions for RGC-32 in diverse processes such as cellular differentiation, inflammation, and fibrosis. Besides responding to C5b-9 stimulation, RGC-32 expression is also induced by growth factors, hormones, and cytokines. Transforming growth factor beta activates RGC-32 through Smad and RhoA signaling, thus initiating smooth muscle cell differentiation. Accumulating evidence has drawn attention to the deregulated expression of RGC-32 in human malignancies, hyper-immunoglobulin E syndrome, and fibrosis. RCG-32 expression is up-regulated in cutaneous T cell lymphoma and colon, ovarian, and breast cancer, but down-regulated in invasive prostate cancer, multiple myeloma, and drug-resistant glioblastoma. A better understanding of the mechanism by which RGC-32 contributes to the pathogenesis of these diseases will provide new insights into its therapeutic potential. In this review we provide an overview of this field and discuss the most recent research on RGC-32.
 ...
PMID:Role of response gene to complement 32 in diseases. 1837 39

Cell cycle arrest of malignant cells is an important option for cancer treatment. In this study, we modified the structure of antimitotic 2-phenylindole-3-carbaldehydes by condensation with hydrazides of various benzoic and pyridine carboxylic acids. The resulting hydrazones inhibited the growth of MDA-MB 231 and MCF-7 breast cancer cells with IC(50) values of 20-30 nM for the most potent derivatives. These 2-phenylindole derivatives also exerted an inhibitory effect on the growth of both proliferating and resting U-373 MG glioblastoma cells. Though the hydrazones exhibited similar structure-activity relationships as the aldehydes, they did not inhibit tubulin polymerization as the aldehydes but were capable of blocking the cell cycle in G(2)/M phase. The cell cycle arrest was accompanied by apoptosis as demonstrated by the activation of caspase-3. Since these 2-phenylindole-based hydrazones display no structural similarity with other antitumor drugs they are interesting candidates for further development.
 ...
PMID:Aroyl hydrazones of 2-phenylindole-3-carbaldehydes as novel antimitotic agents. 1851 74

One of the specific forms of progression of malignant tumors of the central nervous system is meningeal dissemination. Meningeal dissemination is a condition in which tumor cells migrate to the brain surface and sub arachnoid space via cerebrospinal fluid and then infiltrate there. This condition can arise from both primary and metastatic brain tumors, with reported incidences of 4.2% for primary tumors and 5.1% for metastatic tumors. Meningeal dissemination frequently arises from germinoma, medulloblastoma, ependymoma and glioblastoma in cases of primary brain tumors and frequently arises from breast cancer, lung cancer and gastric cancer in cases of metastatic brain tumors, known as meningeal carcinomatosis. The prognosis of meningeal dissemination is poor, and conventional treatments such as systemic chemotherapy and radiation therapy are ineffective. Intrathecal infusion of anti neoplastic agents is one of the options for treatment of meningeal dissemination. The advantage of intrathecal chemotherapy is that the anti neoplastic agent is rapidly diffused in the sub arachnoid space, and its duration of activity is long due to its slow clearance and metabolism. Routes of administration include infusion into the lateral ventricle by puncture of the Ommaya reservoir, infusion into the sub arachnoid space by lumbar puncture, or both of these procedures performed alternately or simultaneously, and methods of infusion include bolus injection and ventriculo lumbar perfusion. Commonly used drugs include methotrexate (MTX), cytarabine (Ara-C), and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)- 1-nitrosourea hydrochloride (ACNU), and some new drugs have also begun to be used clinically. Although there are differences depending on the histological type of the tumor, the anti neoplastic agent administered and the method of administration, the response rate is about 40-80% and mean survival time is about 4-25 months. Although side effects of the anti neoplastic agents are not as severe as with agents used for systemic chemotherapy, specific side effects include nonspecific drug-induced meningitis or ventriculitis, transient or permanent paralysis and leukoencephalopathy. These side effects can be alleviated by reducing the dose or discontinuing the anti neoplastic agents, and a small dose of an adrenocorticosteroid is sometimes administered simultaneously. Bacterial meningitis is another complication and requires discontinuation of anti neoplastic agents, removal of the Ommaya reservoir, or systemic or intrathecal administration of antibiotic agents. Although meningeal dissemination is a rare metastatic condition with a poor prognosis, there have been some reports of successful treatment using this method, which is expected to be widely used in the future.
 ...
PMID:[Intrathecal infusion of the antineoplastic agents for meningeal dissemination]. 1863 17


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>