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)

Butyrate treatment results in the rapid formation of processes on F98 anaplastic glioma cells. The morphological differentiation occurs more rapidly and to a greater extent than that induced by nerve growth factor (NGF). The incorporation of [3H]thymidine is virtually stopped 1 day after treatment of F98 cells with sodium butyrate. Butyrate also caused a large increase in ornithine decarboxylase activity in F98 cells between 6 and 12 h after treatment. This was inhibited by both cycloheximide and actinomycin-D. NGF did not cause these effects. Butyrate also caused an increase in neuron-specific enolase (NSE) content in F98 cells. This effect appeared to be specific for butyrate. Since NSE induction is characteristic only of neurons and neuroendocrine cells, this finding indicates that butyrate is capable of inducing biochemical differentiation along neuronal lines in undifferentiated glioma cells.
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PMID:Butyrate-induced increase in neuron-specific enolase and ornithine decarboxylase in anaplastic glioma cells. 713 40

The antiproliferative properties of inhibitors of polyamine synthesis were evaluated in cultured neuroblastoma and glioma cells. The diamines (1,3-propanediamine, 1,5-pentanediamine, and 1,6-hexanediamine) dramatically decreased neuroblastoma replication and inhibited the rate-limiting enzyme, ornithine decarboxylase. Glioma cells were less sensitive to the diamines in spite of significant drug-induced decreases in enzyme activity. The fact that ornithine decarboxylase was inhibited in both cell lines with different effects on proliferation suggests that the activity of other enzymes in polyamine biosynthesis may be altered selectively by these inhibitors.
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PMID:Antiproliferative effects of inhibitors of polyamine synthesis in tumors of neural origin. 720 97

The in vivo effects of the single or combined administration of alpha-difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, and cis-diamminedichloroplatinum (cisplatin) on the growth of G-XII glioma cells inoculated subcutaneously in rats were tested. Treatment with DFMO or cisplatin significantly decreased the bromodeoxyuridine (BrdU) labeling index of tumor tissues. Combined treatment with DFMO and cisplatin achieved a further significant decrease in the BrdU labeling index. All treatments significantly reduced the tissue levels of N1-acetylspermidine and putrescine, and the ornithine decarboxylase (ODC) activity, but little affected the tissue levels of spermidine and spermine, and the activity of spermidine/spermine N1-acetyltransferase. The reduction of ODC activity by cisplatin treatment may be associated with the anti-tumor effect.
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PMID:alpha-Difluoromethylornithine increases the anti-tumor effect of cis-diamminedichloroplatinum in G-XII rat glioma. 759 63

The polyamine inhibitor DL-alpha-difluoromethylornithine (DFMO) is a specific irreversible inhibitor of ornithine decarboxylase which is a rate-limiting enzyme in the polyamine bio-synthesis pathway. The present study describes the effects of DFMO on glioma cell proliferation, migration and invasion using multicellular spheroids from three glioma cell lines (GaMg, U-251 Mg and U-87 Mg). 10 mM DFMO reduced cell migration in the three cell lines by about 30-50%. 1 mM putrescine, added together with DFMO inhibited the DFMO effect. A stronger effect was observed in the growth assay where 10 mM DFMO reduced the spheroid growth, for all cell lines, by 90%. This effect was also reversed by adding 1 mM of putrescine. In vitro tumor cell invasion experiments indicated after 3 days of confrontation, an extensive invasion also after 10 mM DFMO treatment. The brain aggregate volumes were reduced to about the same extent as in the absence of drug, suggesting essentially no effects of DFMO on the invasive process. It is concluded that the tumor spheroids retained their ability to invade normal brain tissue even after DFMO exposure. However, DFMO inhibited spheroid growth and cell migration which supports the notion that cell growth, migration and invasion are biological properties that are not necessarily related to each other.
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PMID:Effects of DFMO on glioma cell proliferation, migration and invasion in vitro. 952 11

Interferons alpha and beta have been reported to cause tumor regression in a small proportion of patients with recurrent glioma. Eflornithine, an irreversible inhibitor of ornithine decarboxylase, reduces cellular polyamine levels and has also been reported to cause tumor regression in patients with recurrent anaplastic astrocytoma and glioblastoma multiforme. In vitro evidence suggests that interferon and eflornithine are synergistic. In this phase II trial, we investigated the combination of recombinant alpha interferon (36 x 10(6) units/m2 subcutaneously days 3 to 7) and eflornithine (2.25 g/m2 QID PO days 1 to 7) repeated every 28 days. All 29 patients entered in the study were evaluable for toxicity and efficacy. Toxicity consisted primarily of fever, chills, myalgia, weakness and fatigue as well as cortical dysfunction including somnolence, confusion, and exacerbation of underlying neurologic deficits. One patient died from cerebral herniation attributable to interferon. None of the patients experienced objective tumor regression. Seven patients (24%) were stable for more than six months, but the disease stability could also be explained by indolent underlying disease or inability to distinguish recurrent tumor from delayed radiation effects. Intermittent high-dose recombinant interferon alpha plus eflornithine demonstrated no definite antitumor effects in this trial.
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PMID:Phase II trial of recombinant interferon-alpha-2a and eflornithine in patients with recurrent glioma. 952 27

A series of diamines with the general structure NH2(CH2)xNH2, x=2-12, was tested for their potential effects on cell proliferation of cultured rat C6 glioma cells in comparison to natural polyamines. Long chain diamines reduced cell number after 48 h in culture with a sequence of 1,12-diaminododecane (1,12-DD) >1,10-diaminodecane >1,9-diaminononane. Polyamines (putrescine, spermidine and spermine) as well as diamines up to a CH2-chain length of x=8 were found to be ineffective. The spermine analogue 1,12-DD was the most effective molecule in reducing cell number in an irreversible, dose-dependent manner (EC50=3 microM under serum-free conditions). In further experiments we investigated the mechanisms of action of 1,12-DD. The compound had only a minor effect on cell cycle and did not affect free internal calcium concentration. Under physiological conditions 1,12-DD interacts with triplex DNA but not with duplex DNA. Ornithine decarboxylase activity as well as the concentration of internal polyamines were found to be reduced by 1,12-DD. Polyamine application, however, was not able to reverse the effect of 1,12-DD, indicating a polyamine-independent or non-competitive mechanism of action. 1,12-DD reduced cell number by induction of apoptosis as well as necrosis. In molecular modeling studies it was found that a minimal hydrophobic intersegment of at least 4 A was required to make a diamine an effective drug in respect to cellular growth. A hydrophobic gap of this size fits the minimum requirement expected from molecular modeling to provide space for hydrophobic interactions with parts of proteins like a CH3-group. Our results show that 1,12-DD acts as a potent drug, reducing the number of C6 glioma cells, and suggest that its spatial and hydrophobic properties are responsible for its mechanism of action.
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PMID:Long chain diamines inhibit growth of C6 glioma cells according to their hydrophobicity. An in vitro and molecular modeling study. 1073 Oct 35

We compared the properties of mammalian arginine decarboxylase (ADC) and ornithine decarboxylase (ODC) in rat liver and brain. Mammalian ADC is thermally unstable and associated with mitochondrial membranes. ADC decarboxylates both arginine (Km = 0.75 mM) and ornithine (Km = 0.25 mM), a reaction not inhibited by the specific ODC inhibitor, difluoromethylomithine. ADC activity is inhibited by Ca2+, Co2+, and polyamines, is present in many organs being highest in aorta and lowest in testis, and is not recognized by a specific monoclonal antibody to ODC. In contrast, ODC is thermally stable, cytosolic, and mitochondrial and is expressed at low levels in most organs except testis. Although ADC and ODC are expressed in cultured rat C6 glioma cells, the patterns of expression during growth and confluence are very different. We conclude that mammalian ADC differs from ADC isoforms expressed in plants, bacteria, or Caenorhabditis elegans and is distinct from ODC. ADC serves to synthesize agmatine in proximity to mitochondria, an organelle also harboring agmatine's degradative enzyme, agmatinase, and a class of imidazoline receptor (I2) to which agmatine binds with high affinity.
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PMID:Characterization of arginine decarboxylase in rat brain and liver: distinction from ornithine decarboxylase. 1080 Sep 66

Although the efficacy of the nitrosourea-based combination chemotherapy procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, and vincristine (PCV) has been previously demonstrated in the setting of anaplastic/intermediate-grade gliomas, the benefit for glioblastoma patients remains unproven. In the current study, we sought to determine whether the addition of alpha-difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, which has shown encouraging results in the setting of recurrent glioma patients, to a nitrosourea-based therapy (PCV) would constitute a more effective adjuvant therapy in the treatment of glioblastoma multiforme patients in the postradiation therapy setting. Following conventional radiation therapy, 272 glioblastoma (GBM) patients were randomized to receive either alpha-difluoromethylornithine-PCV (DFMO-PCV; 134 patients) or PCV alone (138 patients), with survival and time to tumor progression being the primary endpoints. The starting dosage of DFMO was 3.0 g/m2 p.o. q8h for 14 days before and after treatment with N-(2-chloroethyl)-N-cyclohexyl-N-nitrosurea; PCV was administered as previously described1. Clinical and radiological (Gadolinium-enhanced MRI) follow-ups were nominally at the end of each 6 or 8 week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks). Laboratory evaluations for hematologic and other adverse effects were at 2 week intervals. There was no difference in median survival or median time-to-tumor progression between the two treatment groups, as measured from day of commencement of postradiotherapy chemotherapy [MS (months): DFMO-PCV, 10.5; Overall survival, as measured from time of tumor diagnosis at first surgery, was 13.3 and 14.2 months at the median and 6.2 and 8.7% at 5 years, respectively, for the DFMO-PCV and PCV arms. The treatment effect was unchanged after adjustment for age, performance status (KPS), extent of surgery, and other factors using the multivariate Cox proportional hazard model. Adverse effects associated with DFMO consisted of gastrointestinal (diarrhea nausea/vomiting), cytopenias, and minimal ototoxicity (limited to tinnitus) at the dose range tested. The addition of DFMO to the nitrosourea-based PCV regimen in this phase III study demonstrated no additional benefit in glioblastoma patients, underscoring the resistance of glioblastoma multiforme tumors to alkylating agents. For patients with anaplastic (intermediate grade) gliomas, in which the previously demonstrated benefit of post-radiation chemotherapy is more substantial, the evaluation of DFMO-PCV vs. PCV is still ongoing and hopefully will yield more encouraging results.
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PMID:Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme. 1105 Dec 33

We investigated the involvement of protein kinase C (PKC) in the in vitro invasiveness of the A-172, U-87 and U-373 human glioma cell lines, as well as the role of ornithine decarboxylase (ODC) and/or extracellular-signal-regulated kinase (ERK) in the actions of PKC. Thus, cells were treated under serum-free conditions with the PKC activator phorbol 12-myristate 13-acetate (PMA), or with the PKC inhibitors bisindolylmaleimide I (GF 109203X) or calphostin C in the absence or presence of the ODC inhibitor D,L-alpha-difluoromethylornithine (DFMO), and/or the mitogen-activated protein kinase/extracellular-signal-regulated kinase inhibitor 2'-amino-3'-methoxyflavone (PD 098059). Subsequently, cells were assessed for membrane-type 1 matrix metalloproteinase (MT1-MMP) mRNA contents, 72-kD latent, and 59/62-kD activated matrix metalloproteinase 2 (MMP-2) in conditioned media, as well as invasiveness. For these purposes, we used Northern blot analysis, gelatine zymography, and an in vitro filter invasion assay, respectively. Data were related to those found with untreated cells. PKC activity was 2- to 3-fold stimulated by PMA (100 nM for 30 min), and about 2-fold inhibited by calphostin C (40 nM for 2 h) or GF 109203X (5 microM for 20 min). This was accompanied by a similar increase or decrease, respectively, in MT1-MMP mRNA expression, 59/62-kD MMP-2 activity, and in vitro invasion. Inhibition of ODC activity (about 2-fold by 24 h DFMO 5 mM), ERK activation (almost completely by 20 min PD 098059 50 microM), or both these enzymes simultaneously led to a reduction by about half in levels of MT1-MMP mRNA, 59/62-kD MMP-2 activity, and invasion in untreated as well as PMA-stimulated cells. The use of these compounds did not significantly alter the inhibitory effects of GF 109203X or calphostin C. Modulation of PKC and/or ERK activity resulted in corresponding changes in ERK and/or ODC activities, but interference with ODC affected neither ERK nor PKC. Our data suggest a regulatory role for PKC, in co-operation with ERK and ODC, in glioma cell invasion, by modulation of MT1-MMP mRNA expression and MMP-2 activation.
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PMID:Protein kinase C-mediated in vitro invasion of human glioma cells through extracellular-signal-regulated kinase and ornithine decarboxylase. 1117 68

Biosynthesis of the polyamines putrescine, spermidine, and spermine, and activation of the first key enzyme ornithine decarboxylase (ODC) are closely associated with cellular proliferation. In the present study, the distribution of ODC activity and polyamine levels was investigated for the first time regionally in experimental brain tumors of the cat. Brain tumors were produced by stereotactic xenotransplantation of rat glioma cells. Twenty days after implantation, the brains were frozen in situ, cut into slices, and cryostat sections and tissue samples were taken to determine ODC activity and polyamine levels biochemically. The quantified data were color-coded to present the regional distribution of ODC activity and polyamine levels in the respective section. ODC activity significantly increased in some areas within the tumor, whereas peritumoral tissue showed no difference to the non-tumoral, contralateral hemisphere. This increase turned out in parallel to a high number of mitoses in the same tumor parts (r=0.861). Putrescine levels increased both, in the whole tumor and in the peritumoral edema. Regional differences in putrescine content did not correlate with solid and proliferative parts of the tumor. Spermidine and spermine levels were only slightly increased in some parts of the tumor. Thus, these experiments show the close correlation of a high mitotic rate and activation of ODC within experimental gliomas and underline the relevance of ODC as a biochemical marker of proliferation in brain tumors.
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PMID:Regional distribution of ornithine decarboxylase activity and polyamine levels in experimental cat brain tumors. 1140 92


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