Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of systemic injection of modified hemoglobin (Hb) prepared from bovine, human, or mouse Hb on tumor oxygenation was investigated. Hb was modified by (1) diisothiocyanatobenzenesulfonate (DIBS) to yield cross-linking within a tetramer; (2) glycolaldehyde (Glyal) to yield cross-linking between and within tetramers; (3) carboxymethylation (Cm) to change oxygen affinity; or (4) poly(ethylene glycol) (PEG) to yield attachment between tetramers. HGL9 (human glioma) in nude mice and FSaII (mice fibrosarcoma) in C3H mice were used as tumor models. Dose and time dependency were detected in the oxygenation effect by bovine-PEG-Hb. Internal cross-linkage prolonged the half-life in the circulation, and thus showed a significant effect. Compared to bovine-CmHb, bovine-DIBS-Hb and bovine-DIBS-CmHb were more effective. Decreasing the oxygen affinity by Cm significantly enhanced tumor oxygenation. Human-DIBS-CmHb was more effective than human-DIBS-Hb. These effects were caused by oxygen carrying capacity of modified Hbs as well as hemodynamic factors, and the injection seemed to reduce both perfusion-limited (acute) and diffusion-limited (chronic) hypoxia.
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PMID:Oxygenation in tumors by modified hemoglobins. 864 36

Human brain gliomas overexpress the receptor for epidermal growth factor (EGF), and radiolabeled EGF is a potential peptide radiopharmaceutical for imaging human brain tumors, should this peptide be made transportable through the blood-brain barrier (BBB) in vivo. Peptide drug delivery to the brain may be facilitated by conjugating peptide radiopharmaceuticals to BBB drug delivery vectors such as the OX26 monoclonal antibody (MAb), which undergoes receptor-mediated transcytosis through the BBB via the brain capillary endothelial transferrin receptor. EGF was biotinylated with NHS-XX-biotin, where NHS = N-hydroxysuccinimide and -XX- = bis (aminohexanoyl) spacer arm. The [125I]EGF-XX-biotin rapidly bound to C6 rat glioma cells transfected with the human EGF receptor. However, no binding to the C6 EGF receptor was detected when the [125I]EGF-XX-biotin was bound to a conjugate of streptavidin (SA) and the OX26 MAb. An alternative linker strategy using poly(ethylene glycol) (PEG) of 3400 Da molecular mass (PEG3400) was evaluated, wherein EGF was monobiotinylated with NHS-PEG3400-biotin. Attachment of the [125I]EGF-PEG3400-biotin to the OX26/SA conjugate did not impair binding of the construct to the EGF receptor in C6 glioma cells. The length of the -PEG- spacer arm and the -XX- spacer arm was >200 atoms and 14 atoms, respectively. These studies demonstrate that the use of the extended PEG linker releases steric hindrance of MAb transport vectors on binding of EGF to its cognate receptor on glioma cells. Attachment of EGF peptide radiopharmaceuticals to BBB drug delivery systems such as the OX26 MAb using extended PEG linkers allows for retention of the bifunctionality of the conjugate with binding to both EGF and transferrin receptors.
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PMID:Retention of biologic activity of human epidermal growth factor following conjugation to a blood-brain barrier drug delivery vector via an extended poly(ethylene glycol) linker. 989 61

Liposomes are of interest as drug delivery tools for therapy of cancer and infectious diseases. We investigated conjugation of epidermal growth factor, EGF, to liposomes using the micelle-transfer method. EGF was conjugated to the distal end of PEG-DSPE lipid molecules in a micellar solution and the EGF-PEG-DSPE lipids were then transferred to preformed liposomes, either empty or containing the DNA-binding compound, water soluble acridine, WSA. We found that the optimal transfer conditions were a 1-h incubation at 60 degrees C. The final conjugate, (125)I-EGF-liposome-WSA, contained approximately 5 mol % PEG, 10-15 EGF molecules at the liposome surface, and 10(4) to 10(5) encapsulated WSA molecules could be loaded. The conjugate was shown to have EGF-receptor-specific cellular binding in cultured human glioma cells.
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PMID:Development of EGF-conjugated liposomes for targeted delivery of boronated DNA-binding agents. 1212 Nov 28

There has been increasing interest in attempts to harness the body's normal inflammatory response mediated through the eicosanoid pathway to treat tumors. Accumulating data indicate that the growth of several different cancers is modulated by a group of pro-inflammatory bioactive lipids, the best known of which are the eicosanoids. Eicosanoid pathway constituents modulate cell function in several important ways, and an agent that activates PLA(2) and up-regulates LTB(4) levels could be expected to be an effective cytotoxic tumor agent, especially if it stimulated NK cells. PLAP is a 28-kDa polypeptide that is a member of the WD-repeat protein, G-protein-transducin superfamily. The pro-inflammatory properties of PLAP have been elucidated using a number of different approaches. PLAP has been found in inflamed tissues and synovial fluid from patients with rheumatoid arthritis. Based on knowledge of PLAP as a pro-inflammatory agent, its capacity to modulate the immune response and the role of the inflammatory and immune responses in immune surveillance, the role of PLAP in cancer therapy was explored. Significant tumor regression was observed 72 hours following a single treatment with PLAP in an animal air pouch model of glioma. PEG-PLAP treatment increased the life expectancy of animals with Lewis lung cancer, and in preliminary studies in MTVL breast tumors in mice, PLAP treatment resulted in a similar increase in life expectancy. These findings suggest that PLAP holds promise as a potential therapy for cancer, and warrants further study.
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PMID:Phospholipase A2 activating protein induces tumor regression. 1561 58

Deregulated phosphatidylinositol 3-kinase (PI3K) signaling pathway is widely implicated in tumor growth and resistance to chemotherapy. While a strong rationale exists for pharmacological targeting of PI3K, only a few proof-of-principle in vivo efficacy studies are currently available. PWT-458, pegylated-17-hydroxywortmannin, is a novel and highly potent inhibitor of PI3K in animal models. Upon in vivo cleavage of its poly(ethyleneglycol) (PEG), PWT-458 releases its active moiety 17-hydroxywortmannin (17-HWT), the most potent inhibitor in its class. Here we show that a single intravenous injection of PWT-458 rapidly inhibited PI3K signaling, as measured by a complete loss of AKT (Ser-473) phosphorylation in xenograft tumors grown in nude mice. Following a daily X5 dosing regimen, PWT-458 demonstrated single-agent antitumor activity in nude mouse xenograft models of U87MG glioma, nonsmall cell lung cancer (NSCLC) A549, and renal cell carcinoma (RCC) A498. Efficacious doses ranged from 0.5 mg/kg to 10 mg/kg, achieving a superior therapeutic index over 17-HWT. PWT-458 augmented anticancer efficacy of a suboptimal dose of paclitaxel against A549 and U87MG tumors. Combination treatment of PWT-458 and an mTOR inhibitor, Pegylated-Rapamycin (Peg-Rapa), resulted in an enhanced antitumor efficacy in U87MG. Finally, PWT-458 in combination with interferon-alpha (Intron-A) caused a dramatic regression of RCC A498, which was not achieved by either agent alone. These studies identify PWT-458 as an effective anticancer agent and provide strong proof-of-principle for targeting the PI3K pathway as novel anticancer therapy.
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PMID:PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors. 1590 1

A multifunctional nanoprobe capable of targeting glioma cells, detectable by both magnetic resonance imaging and fluorescence microscopy, was developed. The nanoprobe was synthesized by coating iron oxide nanoparticles with covalently bound bifunctional poly(ethylene glycol) (PEG) polymer, which were subsequently functionalized with chlorotoxin and the near-infrared fluorescing molecule Cy5.5. Both MR imaging and fluorescence microscopy showed significant preferential uptake of the nanoparticle conjugates by glioma cells. Such a nanoprobe could potentially be used to image resections of glioma brain tumors in real time and to correlate preoperative diagnostic images with intraoperative pathology at cellular-level resolution.
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PMID:Optical and MRI multifunctional nanoprobe for targeting gliomas. 1594 33

Ultrafine fibers containing water-soluble drugs were successfully electrospun from water-in-oil (W/O) emulsions, in which the aqueous phase contained the water-soluble drugs and the oily phase was a chloroform solution of amphiphilic poly (ethylene glycol)-poly (L-lactic acid) (PEG-PLLA) diblock copolymer. The diameter of the electrospun fibers was in the range of 300 nm-1 microm. A water-soluble anticancer agent, doxorubicin hydrochloride (Dox), was used as the model drug. Its content in the fibers was 1-5 wt.% and it was entirely encapsulated inside the electrospun fibers. Its release from the fibers was controlled by the combined diffusion mechanism and enzymatic degradation mechanism. At the early stage, the diffusion mechanism was predominant and a certain time later, the enzymatic degradation mechanism became predominant. The antitumor activity of the Dox incorporated in the PEG-PLLA fibers against mice glioma cells (C6 cell lines) was evaluated by MTT method. The results showed that the Dox could be released from the fibers without losing cytotoxicity.
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PMID:Ultrafine medicated fibers electrospun from W/O emulsions. 1616 43

The purpose of the present study was to develop implantable BCNU-loaded poly(ethylene glycol)-poly(L-lactic acid) (PEG-PLLA) diblock copolymer fibers for the controlled release of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU was well incorporated and dispersed uniformly in biodegradable PEG-PLLA fibers by using electrospinning method. Environmental Scanning Electron Microscope (ESEM) images indicated that the BCNU-loaded PEG-PLLA fibers looked uniform and their surfaces were reasonably smooth. Their average diameters were below 1500 nm. The release rate of BCNU from the fiber mats increased with the increase of BCNU loading amount. In vitro cytotoxicity assay showed that the PEG-PLLA fibers themselves did not affect the growth of rat Glioma C6 cells. Antitumor activity of the BCNU-loaded fibers against the cells was kept over the whole experiment process, while that of pristine BCNU disappeared within 48 h. These results strongly suggest that the BCNU/PEG-PLLA fibers have an effect of controlled release of BCNU and are suitable for postoperative chemotherapy of cancers.
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PMID:BCNU-loaded PEG-PLLA ultrafine fibers and their in vitro antitumor activity against Glioma C6 cells. 1689 Oct 29

A novel amphiphilic polymer-paclitaxel conjugate P(LGG-paclitaxel)-PEG-P(LGG-paclitaxel) has been prepared. It was derived from its parent polymer P(LGG)-PEG-P(LGG), poly{(lactic acid)-co-[(glycolic acid)-alt-(l-glutamic acid)]}-block-poly(ethylene glycol)-block-poly{(lactic acid)-co-[(glycolic acid)-alt-(l-glutamic acid)]}, which was prepared by ring-opening copolymerization of l-lactide (LLA) with (3s)-benzoxylcarbonylethyl-morpholine-2,5-dione (BEMD) in the presence of dihydroxyl PEG with molecular weight of 4600 as a macroinitiator using stannous octoate (Sn(Oct)(2)) as catalyst, and by subsequent catalytic hydrogenation. It could self-assemble into micelles in an aqueous system with P(LGG-paclitaxel) block in the core and PEG in the shell. ESEM and DLS analysis of the micelles revealed a homogeneous spherical morphology and a unimodal size distribution. In vitro release of paclitaxel from the conjugate micelles showed that its release rate depended on pH value and was higher at lower pH than in neutral condition. In vitro antitumor activity of the paclitaxel conjugate against rat brain glioma C6 cells was evaluated by MTT method. The results showed that the paclitaxel can be released from the conjugate without losing cytotoxicity.
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PMID:A novel polymer-paclitaxel conjugate based on amphiphilic triblock copolymer. 1718 76

We report the development of a biostable methotrexate-immobilized iron oxide nanoparticle drug carrier that may potentially be used for real-time monitoring of drug delivery through magnetic resonance imaging. Methotrexate (MTX) was immobilized on the nanoparticle surface via a poly(ethylene glycol) self-assembled monolayer (PEG SAM). The cytotoxicity of the nanoparticle-drug conjugate (NP-PEG-MTX) to target cells was studied with 9L glioma cells. Cellular uptake experiments showed that the uptake of NP-PEG-MTX conjugates by glioma cells was considerably higher than that of control nanoparticles. Magnetic resonance imaging in 9L cells cultured with NP-PEG-MTX of various concentrations showed significant contrast enhancement. NP-PEG-MTX demonstrated higher cytotoxicity in 9L cells to free MTX in vitro. Leucovorin, an MTX antidote, was used to rescue the cells that had been exposed to NP-PEG-MTX or free MTX, and the experiment verified the biocompatibility of NP-PEG-MTX conjugates and the MTX on NP-PEG-MTX conjugates to be the true source of the cytotoxicity to the target cells. TEM results showed that NP-PEG-MTX conjugates were internalized into the 9L cellular cytoplasm and retained its crystal structure therein for up to 144 h, as identified by electron diffraction. This prolonged particle retention may allow physicians to image tumor cells exposed to the NP-PEG-MTX conjugate over an extended therapeutic time course.
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PMID:Methotrexate-immobilized poly(ethylene glycol) magnetic nanoparticles for MR imaging and drug delivery. 1719 23


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