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

Several investigators have reported that a high concentration of drugs in a tumour can be achieved using intra-arterial (IA) chemotherapy. This treatment was highly effective, especially in brain tumours, but the actual therapeutic advantage is still unknown. There are also indications that human malignant gliomas can effectively be treated using interstitial hyperthermia. Therefore, a combined treatment of IA chemotherapy and interstitial hyperthermia should be very promising and this has been studied in a tumour model. Wistar rats with isotransplanted C(6) gliomas in the brain were treated with adriamycin (ADR, 1.0 mg/kg body weight) either infused via the carotid artery (i.a.) or via the tail vein (i.v.), with or without interstitial hyperthermia. Hyperthermia of the tumours was applied using a homemade radiofrequency antenna (RF-heating) and a heating device that maintained the tumour temperature above 40 degrees C. Concentration of adriamycin in tumours after treatment was measured using HPLC. The effectiveness of treatment was determined by the survival time of the animals and histopathological examinations. The highest uptake of adriamycin in the rat C(6) glioma was obtained when the animals were treated with hyperthermia and i.a. ADR infusion (p <0.01). These animals also showed significantly longer overall survival time (SF50 =46 days) in comparison to the other treatments (p < 0.05). The histological studies demonstrated a necroti c tumour; however, the surrounding normal brain tissue remained intact. Thus, a combination of IA chemotherapy with adriamycin and localized interstitial hyperthermia enhances considerably the efficacy of adriamycin and has a greater antitumour effect for malignant brain tumours. This method is suitable for clinical use, and may be a new strategy for treating gliomas not successfully treated today.
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PMID:Combination therapy of rat brain tumours using localized interstitial hyperthermia and intra-arterial chemotherapy. 1262 42

Differential expression of folate receptor has been exploited to target liposomes to tumors. Astrogliomas express low folate receptor levels and are typically surrounded by normal cells expressing little or no folate receptors. While targeting cells with high over-expression of folate receptor (KB and HeLa) has been demonstrated, it is unclear whether targeting tumors expressing low levels of folate receptor is possible. In this study, it was demonstrated that optimizing the number of targeting ligands (folic acid) enables differential liposomal doxorubicin uptake in C6 glioma while sparing healthy cortical cells. By micellization of folate conjugates and their controlled insertion into pre-formed liposomes, tight control over the number of targeting ligands per liposome was demonstrated. Doxorubicin uptake in KB and C6 cells was dependent on the number of targeting ligands, while cortical cells showed increasing non-specific uptake with ligand number. Co-culture of C6 glioma with cortical cells confirmed preferential uptake in C6 glioma relative to cortical cells. A cell kill experiment showed that folate-targeted liposomal doxorubicin is cytotoxic and slows proliferation of KB and C6 cells with minimal effect on cortical cells. Therefore modulation of targeting ligand number enables significant differential uptake of doxorubicin in cells with low levels of folate receptor.
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PMID:Controlled targeting of liposomal doxorubicin via the folate receptor in vitro. 1449 85

A method was developed of targeting chemotherapy using thermosensitive liposomes to treat malignant gliomas. Using the brain heating system, when the tumour core is heated to >43 degrees C, the tumour infiltrating zone is exposed to mild hyperthermia (40-43 degrees C). Thermosensitive liposomes were designed to release their contents at 40 degrees C to target both the tumour core and tumour infiltrating zone. The present study investigated the anti-tumour effect on rat glioma models in tumour drug uptake and tumour growth delay studies. Elevated accumulation of ADR in the rat C6 glioma after treatment was obtained in the area heated to >40 degrees C. However, there was no significant difference between the areas heated to 40-42 degrees C and >43 degrees C. Furthermore, it was found that ADR concentrations in the mildly hyperthermic areas were significantly higher following treatment with liposomal ADR than with free ADR. The animals treated with the new combination therapy had significantly longer overall survival time in comparison to those receiving other treatments. Thus, thermosensitive liposomes release their contents in response to mild hyperthermia and this combination therapy has a greater therapeutic efficacy for malignant brain tumours. This method is a promising approach for the treatment of malignant glioma patients.
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PMID:Therapeutic efficacy of targeting chemotherapy using local hyperthermia and thermosensitive liposome: evaluation of drug distribution in a rat glioma model. 1537 Aug 16

Doxorubicin (DOX), also known as adriamycin, is an anthracycline drug commonly used in cancer chemotherapy. Unfortunately, its therapeutic potential has been restricted by its dose limited cardiotoxicity and the resistance developed by the tumor cells to the molecule after some time of treatment. One way to overcome these problems is to encapsulate the drug in poly (D, L-lactide-co-glycolide) (PLGA) microparticles. This paper investigates the release characteristics of DOX from polymeric carriers fabricated using the spray-drying technique. The encapsulation efficiency, size and morphology of the various polymeric devices were also determined. In order to improve the release characteristics, Pluronic P105 (PLU) and poly (L-Lactide) (PLLA) are individually used in combination with PLGA. Finally, a cytotoxicity test was performed using Glioma C6 cancer cells to investigate the cytotoxicity of DOX delivered from PLGA microparticles. It has been found that the cytotoxicity of DOX to Glioma C6 cancer cells is enhanced when DOX is delivered from PLGA polymeric carrier.
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PMID:In vitro study of anticancer drug doxorubicin in PLGA-based microparticles. 1570 77

The multiple drug resistance protein (MDR1) is frequently overexpressed in human glioma. The aim of this study is to clone the MDR1 promoter from C6/ADR, construct the double suicide genes expressive vector controlled by MDR1 promoter, and explore its targeted expression in C6/ADR cells. MDR1 promoter from C6/ADR genomic DNA, which was linked with T vector, was amplified by using Polymerase chain reaction (PCR). After cut by NdeI and HindIII, MDR1 promoter was cloned into pcDNA3-TK (thymidine kinase) plasmid. The cytosine deaminase (CD) gene from pcDNA3-CD-TK plasmid was directly cloned into the above vector to construct pcDNA3-MDR1-promoter-CD-TK vector. Then this vector was transfected into C6 and C6/ADR cells respectively by liposome. After selection by G418, the tumor cell lines were stably established. Then these cell lines were examined through PCR and RT-PCR to respectively detect the integration and expression of TK and CD genes. The results showed the length and sequence of MDR1 promoter amplified by PCR were confirmed by DNA sequencing. The pcDNA3-MDR1-promoter-CD-TK expression vectors were constructed successfully. PCR indicated the double suicide genes were integrated into C6 and C6/ADR cells. RT-PCR revealed that CD and TK genes expressed in C6/ADR/CD-TK cells, whereas not in C6/CD-TK cells. In conclusions, construction of expressive vector containing double suicide genes controlled by MDR1 promoter with targeted expression in C6/ADR will provide a sound basis for targeted gene therapy for multidrug resistance (MDR) glioma.
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PMID:Construction of double suicide genes system controlled by MDR1 promoter with targeted expression in drug-resistant glioma cells. 1759 53

To develop a polymer-anticancer drug conjugate, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was employed as a carrier of doxorubicin (DOX) to enhance its therapeutic effects and reduce its side effects. Doxorubicin was chemically conjugated to TPGS. The molecular structure, drug loading efficiency, drug release kinetics and stability of the conjugate were characterized. The cellular uptake, intracellular distribution, and cytotoxicity were accessed by using MCF-7 breast cancer cells and C6 glioma cells as in vitro cell model. The conjugate showed higher cellular uptake efficiency and broader distribution within the cells. Judged by IC(50), the conjugate was found 31.8, 69.6, 84.1% more effective with MCF-7 cells and 43.9, 87.7, 42.2% more effective with C6 cells than the parent drug after 24, 48, 72 h culture, respectively. The in vivo pharmacokinetics and biodistribution were investigated after an i.v. administration at 5 mg DOX/kg body weight in rats. Promisingly, 4.5-fold increase in the half-life and 24-fold increase in the area-under-the-curve (AUC) of DOX were achieved for the TPGS-DOX conjugate compared with the free DOX. The drug level in heart, gastric and intestine was significantly reduced, which is an indication of reduced side effects. Our TPGS-DOX conjugate showed great potential to be a prodrug of higher therapeutic effects and fewer side effects than DOX itself.
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PMID:Doxorubicin conjugated to D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS): conjugation chemistry, characterization, in vitro and in vivo evaluation. 1860 45

Malignant glioma patients have a life expectancy reduced to about 15 months despite aggressive surgery, radiotherapy (RT), and chemotherapy. Doxorubicin has shown a marked cytotoxic effect against malignant glioma cells in vitro. The brain exposure to this drug is, however, hindered by the blood-brain barrier. Encapsulation of doxorubicin in liposomal carriers has been shown to reduce toxicities and to improve brain tumors exposure to doxorubicin. In this study, we evaluated the radiosensitizing properties of a nonpegylated liposomal doxorubicin (Myocet, MYO) on two subcutaneous (U87 and TCG4) and one intracranial (U87) malignant glioma models xenografted on nude mice. Doxorubicin biodistribution was assessed by a high-performance liquid chromatography method. Antitumor efficacy was investigated by tumor volume measurements and mice survival determination. We showed that (i) encapsulation of doxorubicin ensured a preferential deposition of doxorubicin in tumoral tissue in comparison with free doxorubicin; (ii) doxorubicin accumulated in both subcutaneous and intracranial tumors during repeated injections of MYO and this accumulation was linked to the potentiation of RT efficacy on two subcutaneous models; (iii) MYO was unable to improve the antitumoral efficacy of RT on an intracranial glioma model. Finally, this study emphasizes the importance of performing preclinical studies on models closer as possible of human tumors and localization to be more predictive of therapeutic effects observed in humans.
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PMID:Interest of liposomal doxorubicin as a radiosensitizer in malignant glioma xenografts. 1882 64

A new type of block copolymer micelles for pH-triggered delivery of poorly water-soluble anticancer drugs has been synthesized and characterized. The micelles were formed by the self-assembly of an amphiphilic diblock copolymer consisting of a hydrophilic poly(ethylene glycol) (PEG) block and a hydrophobic polymethacrylate block (PEYM) bearing acid-labile ortho ester side-chains. The diblock copolymer was synthesized by atom transfer radical polymerization (ATRP) from a PEG macro-initiator to obtain well-defined polymer chain-length. The PEG-b-PEYM micelles assumed a stable core-shell structure in aqueous buffer at physiological pH with a low critical micelle concentration as determined by proton NMR and pyrene fluorescence spectroscopy. The hydrolysis of the ortho ester side-chain at physiological pH was minimal yet much accelerated at mildly acidic pHs. Doxorubicin (Dox) was successfully loaded into the micelles at pH 7.4 and was released at a much higher rate in response to slight acidification to pH 5. Interestingly, the release of Dox at pH 5 followed apparently a biphasic profile, consisting of an initial fast phase of several hours followed by a sustained release period of several days. Dox loaded in the micelles was rapidly taken up by human glioma (T98G) cells in vitro, accumulating in the endolysosome and subsequently in the nucleus in a few hours, in contrast to the very low uptake of free drug at the same dose. The dose-dependent cytotoxicity of the Dox-loaded micelles was determined by the MTT assay and compared with that of the free Dox. While the empty micelles themselves were not toxic, the IC(50) values of the Dox-loaded micelles were approximately ten-times (by 24h) and three-times (by 48h) lower than the free drug. The much enhanced potency in killing the multi-drug-resistant human glioma cells by Dox loaded in the micelles could be attributed to high intracellular drug concentration and the subsequent pH-triggered drug release. These results establish the PEG-b-PEYM block copolymer with acid-labile ortho ester side-chains as a novel and effective pH-responsive nano-carrier for enhancing the delivery of drugs to cancer cells.
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PMID:Block copolymer micelles with acid-labile ortho ester side-chains: Synthesis, characterization, and enhanced drug delivery to human glioma cells. 2119 51

Multidrug resistance (MDR) is characterized by the overexpression of ATP-binding cassette (ABC) transporters that actively pump a broad class of hydrophobic chemotherapeutic drugs out of cancer cells. MDR is a major mechanism of treatment resistance in a variety of human tumors, and clinically applicable strategies to circumvent MDR remain to be characterized. Here we describe the fabrication and characterization of a drug-loaded iron oxide nanoparticle designed to circumvent MDR. Doxorubicin (DOX), an anthracycline antibiotic commonly used in cancer chemotherapy and substrate for ABC-mediated drug efflux, was covalently bound to polyethylenimine via a pH sensitive hydrazone linkage and conjugated to an iron oxide nanoparticle coated with amine terminated polyethylene glycol. Drug loading, physiochemical properties and pH lability of the DOX-hydrazone linkage were evaluated in vitro. Nanoparticle uptake, retention, and dose-dependent effects on viability were compared in wild-type and DOX-resistant ABC transporter over-expressing rat glioma C6 cells. We found that DOX release from nanoparticles was greatest at acidic pH, indicative of cleavage of the hydrazone linkage. DOX-conjugated nanoparticles were readily taken up by wild-type and drug-resistant cells. In contrast to free drug, DOX-conjugated nanoparticles persisted in drug-resistant cells, indicating that they were not subject to drug efflux. Greater retention of DOX-conjugated nanoparticles was accompanied by reduction of viability relative to cells treated with free drug. Our results suggest that DOX-conjugated nanoparticles could improve the efficacy of chemotherapy by circumventing MDR.
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PMID:Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro. 2127 20

The human glioma cell line, 2607, was observed with proton magnetic resonance spectroscopy (MRS) in the presence of a number of cell-cycle blockers (cysteamine, desferrioxamine, ADR 529). MR spectra of the arrested cells revealed a correlation between the intensity of the lipid methylene resonance at 1.3 ppm and the percentage of cells in G(2)/M. However, subsequent time course studies using ADR 529 on cells partially synchronised by contact inhibition showed that the emergence of the lipid signal in drug-treated cells is not strictly cell cycle dependent but increases with continuing exposure to ADR 529. This indicates that the accumulation of MR-visible lipid arises from drug cell interactions that specifically affect lipid metabolism in a non cell cycle dependent manner.
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PMID:The accumulation of H-1 MR-visible lipid in human glioma cells is independent of the cell cycle. 2152 45


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