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)

From studies on sympathetically innervated peripheral tissues it is well known that both neuronal and non-neuronal transport systems contribute to the inactivation of released monoamine transmitters. The close proximity between synapses and glia cell processes in the CNS leads to the so far unresolved question whether non-neuronal transporters are involved in the inactivation of centrally released monamine transmitters such as noradrenaline, dopamine and 5-hydroxytryptamine. 1-Methyl-4-phenylpyridinium (MPP+) is a prototypical substrate of the extraneuronal monoamine transporter (uptake2). [3H]MPP+ was found to accumulate in various human glioma cell lines. [3H]MPP+ transport was characterized in more detail in HTZ146 human glioma cells. The Ki values of various compounds for the inhibition of initial rates of [3H]MPP+ transport into HTZ146 cells were closely correlated with known Ki values for the inhibition of the extraneuronal monoamine transporter (P < 0.01, r = 0.991, n = 7). The rank order of inhibitory potencies was decynium 22 > corticosterone > cyanine 863 > O-methylisoprenaline > quinine > clonidine > quinidine. [3H]MPP+ accumulation was investigated not only in various CNS tumour cell lines but also in primary cultures of human astrocytes and rat cerebral cortex slices. In all tested experimental systems, accumulation was sensitive to cyanine-related inhibitors of the extraneuronal monamine transporter. These findings suggest that the extraneuronal monamine transporter exists in glia cells. Furthermore, it was shown that MPP+ is able to make use of the extraneuronal monoamine transporter not only to enter but also to leave glia cells. This finding suggests that the extraneuronal monoamine transporter may play a key role in the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity.
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PMID:The extraneuronal transporter for monoamine transmitters exists in cells derived from human central nervous system glia. 875 96

A novel analogue of nitrosoureas, 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU), has demonstrated increased anticancer effects in vitro and in vivo. Our previous work suggested that SarCNU enters cells via the extraneuronal monoamine transporter (EMT), that contributes to its enhanced cytotoxicity. In the present study, comparative activities of SarCNU and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were evaluated in an EMT positive human glioma xenograft model. Athymic nude mice implanted subcutaneously or intracranially with human glioma SHG-44, a cell line that has been confirmed EMT positive by using reverse-transcription polymerase chain reaction (RT-PCR) assay, were treated with SarCNU at an optimal dose of 167 mg/kg, or BCNU at 20 mg/kg or 30 mg/kg, q4d x 3 intraperitoneally (i.p.). In 17 animals with subcutaneous tumor grafts treated with SarCNU, 9 animals became tumor free and 8 demonstrated tumor regression. While in the BCNU treated group, there were only 2 out of 10 mice in the 20 mg/kg group and 2 out of 7 in the 30 mg/kg group, which demonstrated some tumor regression. There were 4 drug related deaths in the BCNU (30 mg/kg) group, while there were no drug related deaths in the SarCNU group. In the intracranially implanted mice, the median survival time in the SarCNU group was more than 130 days, while in the BCNU treated group it was only 22 days which was similar to the control group (18 days). This is the first demonstration that SarCNU, in comparison to BCNU, has enhanced anticancer activity in an EMT positive human glioma xenograft model.
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PMID:Enhanced antitumor activity of sarCNU in comparison to BCNU in an extraneuronal monoamine transporter positive human glioma xenograft model. 1058 63

Treatment of malignant brain tumors with chloroethylnitrosoureas (CENUs) in addition to surgical resection and radiotherapy remains the foundation of glioma therapy. However, the clinical response to CENUs is at best modest. A novel analogue of nitrosoureas, 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU), as compared to the standard CENU, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), has been demonstrated to have increased anticancer effects both in vitro and in vivo. Unfortunately, many human tumors have been known to be resistant to CENUs since they express DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In order to assess whether SarCNU has an effect on MGMT positive tumors, we evaluated its antitumor efficacy using an MGMT positive human glioma (SF-767) nude mouse xenograft model. Since SF-767 has high MGMT levels, BCNU treatment (20 mg/kg, Q4D x 3 i.p.) alone did not result in a satisfactory anticancer effect (p > 0.05). As expected, O6-benzylguanine (O6-BG) (100 mg/kg), which was given prior to BCNU treatment, by depleting MGMT activity, significantly enhanced BCNU antitumor efficacy (p < 0.001). Moreover, SarCNU treatment (167 mg/kg, Q4D x 3 i.p.) alone had a better antitumor effect than O6-BG plus BCNU treatment (F = 51.7, p = 0.0004). However, in this xenograft model, O6-BG did not significantly enhance the anticancer efficacy of SarCNU (F = 0.8, p = 0.411). The SF-767 human glioma xenograft is positive for extraneuronal monoamine transporter EMT (EMT) as determined by reverse-transcription polymerase chain reaction (RT-PCR). Our present results suggest that SarCNU is also effective for MGMT positive tumor if they exhibit EMT.
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PMID:Antitumor efficacy of SarCNU in a human glioma xenograft model expressing both MGMT and extraneuronal monoamine transporter. 1134 76