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)

CD95 ligand (CD95L)-induced apoptosis is a novel immunotherapeutic approach to malignant glioma. Here, we report that interferon-alpha (IFN-alpha) sensitizes LN-229 and T98G human malignant glioma cells to CD95L-induced apoptosis. In contrast to the effects of IFN-gamma and TNF-alpha which sensitize glioma cells to CD95 antibody-induced apoptosis in part by enhancing CD95 expression, IFN-alpha has no effect on CD95 expression at the cell surface of LN-229 and T98G cells. To confirm that changes in CD95 expression are not required for the effects of IFN-alpha, we show that IFN-alpha enhances CD95L-induced apoptosis even in CD95-transfected LN-308 glioma cells. These LN-308 cells have little endogenous CD95 expression but express high levels of CD95 from a stably integrated CD95 expression plasmid. The sensitizing effects of IFN-alpha appear to be independent of cell cycle effects of IFN-alpha and are unaffected by ectopic expression of the bcl-2 proto-oncogene. IFN-alpha enhances CD95L-induced activation of caspase-3, a critical mediator of CD95L-induced cell death. IFN-alpha also increases the cytotoxic effects of BCNU, teniposide and cytarabine in both cell lines, and of vincristine in LN-229 cells. Doxorubicin and 5-fluorouracil toxicity are unaffected by IFN-alpha. IFN-alpha may be a useful adjunct to novel strategies of immunochemotherapy for malignant gliomas that target CD95-mediated apoptosis.
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PMID:Interferon-alpha enhances CD95L-induced apoptosis of human malignant glioma cells. 967 Aug 53

Here, we report that nonsteroidal anti-inflammatory drugs (NSAID) enhance the cytotoxic effects of doxorubicin and vincristine in T98G human malignant glioma cells. The cytotoxicity of BCNU, cisplatin, VM26, camptothecin, and cytarabine is unaffected by NSAID. No free radical formation is induced by doxorubicin or vincristine in the absence or presence of NSAID. Doxorubicin and vincristine cytotoxicity in the absence or presence of NSAID are unaffected by free radical scavengers. Functional inhibitors of phospholipase A2 (PLA2), such as dexamethasone and quinacrine, do not mimick the effects of NSAID. T98G cells, but not LN-18, LN-229, LN-308, or A172 glioma cells, express cyclooxygenase (COX-1) and NSAID do not modulate drug cytotoxicity in the other cell lines, except T98G. Thus, augmentation of doxorubicin and vincristine cytotoxicity by NSAID correlates with COX-1 expression. However, ectopic expression of COX-1 in LN-229 cells does not induce the phenotype of T98G cells, indicating that COX-1 inhibition does not mediate the effects of NSAID on drug cytotoxicity. In contrast, a multidrug resistance (MDR) phenotype due to expression of the multidrug resistance-associated protein (MRP) is most prominent in T98G cells and is amenable to modulation by indomethacin, suggesting that inhibition of MRP is at least in partly responsible for the potentiation of doxorubicin and vincristine cytotoxicity by NSAID.
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PMID:Selective potentiation of drug cytotoxicity by NSAID in human glioma cells: the role of COX-1 and MRP. 1036 64

Glioblastoma is the most invasive form of primary brain tumors, and is often refractory to chemotherapy. Herein, we provide evidence that two highly invasive human glioma cell lines U-87 MG and U-373 MG, entered apoptosis after 48 hours following 24 h growth arrest induced by Doxorubicin (10 micrograms/2 x 10(5) cells/ml). Apoptosis depended solely on the level of intracellular drug accumulation, and it was not related to a functional p53 tumor suppressor factor. The multidrug resistance gene 1 (mdr-1) encoded P-glycoprotein (P-gp) was weakly expressed in these cells upon exposure to Doxorubicin, and exerted no influence on the extent of cellular drug efflux. Drug efflux occurred only in U-373 MG glioma cells subsequent to physical damage of the membrane upon exposure to Doxorubicin. Pretreatment of tumor cells with 10 micrograms/ml Doxorubicin precluded tumor formation on the chorioallantoic membrane (CAM) of embryonated hen eggs. Single-dose application of 0.4 microgram Doxorubicin on CAM/U-87 MG and CAM/U-373 MG tumor transplants inhibited tumor invasion in CAM tissue by 40 to 50%. These data suggest that highly invasive glioblastomas can be driven to apoptosis following growth arrest induced by Doxorubicin, providing that intracellular drug accumulation suffices cytotoxic levels.
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PMID:Doxorubicin-induced cell death in highly invasive human gliomas. 1036 37

Astrocytes harbour functional receptors to many neurotransmitters, including substance P (SP), an undecapeptide belonging to the tachykinin family of peptide transmitters. SP activates malignant glial cells to induce cytokine release and proliferation, both responses being relevant for tumour progression. In tumours developed in nude mice transplanted subcutaneously (s.c.) to U373 MG human glioma cells, the presence of SP was observed at immunohistochemistry. Although the administration of exogenous SP did not significantly affect the size or development of U373 MG xenograft, a role of SP in supporting glioma progression in vivo was highlighted by the tumour growth inhibition induced by highly specific and selective human tachykinin NK1 receptor antagonists (MEN 11467 and MEN 11149). The anti-tumour activity of MEN 11467 was observed both with s.c. or intravenous treatments and was partially reverted by the concomitant administration of exogenous SP. Doxorubicin did not show any activity in controlling U373 MG growth in this in vivo model. A novel therapeutic approach to treat malignant gliomas with tachykinin NK1 receptor antagonists is suggested by these findings.
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PMID:Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft. 1064 8

Efficacy of chemotherapy is limited in numerous tumors by specific cellular mechanisms that inactivate cytotoxic antitumoral drugs, such as ATP-dependent drug efflux and/or drug detoxification by glutathione. In reducing ATP pools and/or glutathione synthesis, it might be possible to enhance the efficacy of drugs affected by such resistance mechanisms. Reduction of the ATP pool and glutathione content is achievable in cancer cells by depleting the exogenous methionine (Met) supply and ethionine. Thus, the rationale for the present study was to use Met depletion to decrease the ATP and glutathione pools so as to sensitize tumors refractory to cytotoxic anticancer drugs. Met depletion was achieved by feeding mice a methionine-free diet supplemented with homocysteine. The effects of Met depletion combined with ethionine and/or chemotherapeutic agents were studied using human solid cancers xenografted into nude mice. TC71-MA (a colon cancer) SCLC6 (a small cell lung cancer), and SNB19 (a glioma) were found to be refractory to cisplatin, doxorubicin, and carmustine, respectively. These three drugs are used to treat such tumors and are dependent for their activity on the lack of cellular ATP- or glutathione-dependent mechanisms of resistance. TC71-MA, SCLC6, and SNB19 were Met dependent because their proliferation in vitro and growth in vivo were reduced by Met depletion. Cisplatin was inactive in the treatment of TC71-MA colon cancer, whereas a methionine-free diet, alone or in combination with ethionine, prolonged the survival of mice by 2-fold and 2.8-fold, respectively. When all three approaches were combined, survival was prolonged by 3.3-fold. Doxorubicin did not affect the growth of SCLC6, a MDR1-MRP-expressing tumor. A Met-deprived diet and ethionine slightly decreased SCLC6 growth and, in combination with doxorubicin, an inhibition of 51% was obtained, with survival prolonged by 1.7-fold. Combined treatment produced greater tumor growth inhibition (74%) in SCLC6-Dox, a SCLC6 tumor pretreated with doxorubicin. Growth of SNB19 glioma was not inhibited by carmustine, but when it was combined with Met depletion, survival duration was prolonged by 2-fold, with a growth inhibition of 80%. These results indicate the potential of Met depletion to enhance the antitumoral effects of chemotherapeutic agents on drug-refractory tumors.
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PMID:Methionine depletion enhances the antitumoral efficacy of cytotoxic agents in drug-resistant human tumor xenografts. 1069 May 50

Recent advances in liposome technology have shown promise relative to the introduction of chemotherapeutic agents with reduced toxicity, extended longevity, and potential for cell-specific targeting. In this study we report the engineering of a liposomal delivery system for the chemotherapeutic drug doxorubicin. The system was targeted specifically to C6 glioma in vitro by coupling transferrin to the distal ends of liposomal polyethylene glycol (PEG) chains. The transferrin receptor is overexpressed on glioma, with the extent of overexpression correlated to the severity of the tumor. Significantly increased gliomal doxorubicin uptake was achieved by drug encapsulation within transferrin-coupled liposomes compared to other liposome populations. Doxorubicin encapsulated within transferrin-coupled liposomes exhibited 70% of free doxorubicin uptake as compared to 54, 14, and 34% for non-PEG, PEG, and albumin-coupled PEG liposomes, respectively. Competitive binding assays support the receptor-mediated mechanism of targeting. The addition of one microM free transferrin reduced the uptake of doxorubicin encapsulated within transferrin-coupled liposomes by 30%.
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PMID:Targeted drug delivery to C6 glioma by transferrin-coupled liposomes. 1081 39

We have shown recently that the multifunctional growth factor, scatter factor/hepatocyte growth factor (SF/HGF), and its receptor c-met enhance the malignancy of human glioblastoma through an autocrine stimulatory loop (R. Abounader et al., J. Natl. Cancer Inst., 91: 1548-1556, 1999). This report examines the effects of SF/HGF:c-met signaling on human glioma cell responses to DNA-damaging agents. Pretreating U373 human glioblastoma cells with recombinant SF/HGF partially abrogated their cytotoxic responses to gamma irradiation, cisplatin, camptothecin, Adriamycin, and Taxol in vitro. This cytoprotective effect of SF/HGF occurred at least in part through an inhibition of apoptosis, as evidenced by diminished terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling index and reduced DNA laddering. Anti-c-met U1/ribozyme gene transfer inhibited the ability of SF/HGF to protect against single-strand DNA breakage, DNA fragmentation, and glioblastoma cell death caused by DNA-damaging agents, demonstrating a requirement for c-met receptor function. Phosphorylation of the cell survival-promoting kinase Akt (protein kinase B) resulted from SF/HGF treatment of U373 cells, and both Akt phosphorylation and cell survival induced by SF/HGF were inhibited by phosphatidylinositol 3-kinase inhibitors but not by inhibitors of mitogen-activated protein kinase kinase or protein kinase C. Cytoprotection by SF/HGF in vitro was also inhibited by transient expression of dominant-negative Akt. Transgenic SF/HGF expression by intracranial 9L gliosarcomas reduced tumor cell sensitivity to gamma irradiation, confirming the cytoprotective effect of SF/HGF in vivo. These findings demonstrate that c-met receptor activation by SF/HGF protects certain glioblastoma cells from DNA-damaging agents by activating phosphoinositol 3-kinase-dependent and Akt-dependent antiapoptotic pathways.
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PMID:Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways. 1094 42

The objective of the study was to evaluate the safety and therapeutic efficacy of intralesional administration of doxorubicin in brain gliomas. Ten patients with recurrent grade III or IV glioma were enrolled in the study, after the second operation. All patients had not responded to radiation therapy. Chemotherapy was administered directly in the tumor through an Ommaya pump placed in the site of disease at the time of craniotomy. Doxorubicin 0.5 mg was administered in the Ommaya reservoir every 24 hours on days 1 to 10. Patients were evaluated at 6- to 8-week intervals until tumor progression and death. All patients were evaluated for response. Six of 10 patients had clinical improvement lasting from 12 to 73 weeks. Objective radiologic response was observed in 5 of 10 (50%) patients. One patient achieved complete response with time to disease progression of 119 weeks, and 4 patients had a partial response (duration 14-39 weeks) with 25% or more reduction of tumor volume on computed tomography scan compared with pretreatment measurements. Time to disease progression in patients who responded after the intratumoral chemotherapy was 39.83 +/- 40.5 weeks. One additional patient had stable disease for a duration of 12 weeks. The median survival of the patients with response was 55.17 +/- 54.22 weeks (range: 21-164 weeks), whereas survival of those who did not respond was 17.0 +/- 12.36 weeks (range: 8-35) (Mann Whitney U test: z = -2.13, p = 0.033). The median survival of all 10 patients was 39.9 +/- 45.52 weeks (range: 8-73 weeks). Bifrontal headache was reported in 4 of 10 patients immediately after the administration of doxorubicin. There were no other clinically significant adverse reactions either in the brain or systematically. Intralesional administration of doxorubicin appears to be a safe and effective treatment and should be further explored in the management of brain gliomas resistant to conventional forms of treatment.
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PMID:Intratumoral doxorubicin in patients with malignant brain gliomas. 1182 99

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

This study sought to assess the biocompatibility of P(DA-SA)-Adriamycin, a new controlled-release chemotherapy system, in rabbit brain, and to examine its controlled release effect both in vitro and in vivo and its curative effects in vitro. The reaction of animal brain to the implanted P(DA-SA) or P(DA-SA)-Adriamycin was observed. The controlled-release profiles in phosphate buffer solutions and in rabbit brain were measured by UV spectrometry. Then, through flow cytometer, the rate of apoptosis in cultured glioma cells was tested. The reaction of rabbit brain to P(DA-SA) polymer was moderate and not significantly different from that to Gelfoam. The controlled-release rate of P(DA-SA)-Adriamycin in vitro and in vivo was stable and the duration of controlled-release of P(DA-SA)-Adriamycin spanned three weeks. The rate for apoptosis of glioma cells of P(DA-SA)-Adriamycin group was 69.9%, which was significantly higher than that of the control group. In conclusion, P (DA-SA)-Adriamycin controlled release chemotherapy system that bears curative effect has favorable controlled-release effect and good biocompatibility in rabbit brain. This system has potential value in treatment of malignant brain tumor.
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PMID:[Basic study of biodegradable controlled release chemotherapy]. 1471 77


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