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)

Amethopterin and 5-bromodeoxyuridine (BUdR) were used to induce morphological changes in cloned rat glioma (C6). The expression of S-100 protein, an acidic protein localized in glial cells, and steroid sulfatase, an ubiquitously distributed enzyme found in high concentration in glial cells, were followed during cell growth, from subculture to well into the stationary phase of control and drug-treated cultures. Amethopterin and BUdR differed in their effects on glioma morphology and in the expression of the biochemical parameters. Amethopterin coordinately stimualted both the production of S-100 protein and steroid sulfatase activity when cell division was inhibited during early logarithmic growth phase. BUdR stimulated steroid sulfatase activity but repressed production of S-100 protein. The results are discussed with respect to the mechanism of regulation of the differentiated state of tumor cells.
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PMID:Drug-induced differentiation of a rat glioma in vitro: II. the expression of S-100, a glial specific protein and steroid sulfatase. 64 75

An intracranial mouse glioma model was used to study the effectiveness of chemotherapy with methotrexate )MTX) or radiotherapy. Maximum tolerable doses of MTX were established by toxicity studies in nontumor-bearing mice for the intraperitoneal and intracerebral routes of drug administration with and without leucovorin as an antidote. These maximum tolerable doses were then given either by the intraperitoneal route or directly into the tumor to mice bearing intracerebral tumors. The glioma model proved to be extremely useful for assessing the modalities studied, including repeated intraneoplastic injection of MTX. Dosage schedules were successfully developed for administering large amount of MTX and for preventing systemic toxicity by the administration of the antidote. Radiotherapy in single doses and 800 rads delayed the median day of death and produced several long-term survivors. Higher doses were toxic. Intraperitoneal or intraneoplastic MTX was completely ineffective as a chemotherapeutic agent for this tumor, even though very large amounts could be delivered due to the protection from systemic toxicity afforded by leucovorin. It is concluded that MTX is a poor chemotherapeutic agent for this experimental brain tumor, but that the technique of intraneoplastic administration of chemotherapeutic agents is feasible with this model system and should be studied further.
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PMID:Therapy of an experimental glioma with systemic or intraneoplastic methotrexate or radiation. 83 34

FK 973, a new substituted dihydrobenzoxazine, was obtained by chemical modification of a novel antibiotic which was isolated from the fermentation products of streptomyces sandaensis No. 6897. FK 973 had cytotoxic effects against in vitro cultured human and murine glioma cells. The concentration of FK 973 required to inhibit cell growth by 50% was 0.06-5 micrograms/ml, after 2-day exposure of this drug against human glioblastoma (ONS-6, 12, 23, and ONS-12/ACNU), human medulloblastoma (ONS-76, 81), human neuroblastoma (ST), and murine glioblastoma (RSV-M glioma). FK 973 showed antitumor efficacy in the meningeal gliomatosis models by RSV-M glioma cells. The median survival time (MST) of models treated by FK 973 (i.t.) was 30 days. However, the MST of control group was 23 days. In the in vitro neurotoxicity test, FK 973 proved to be slightly more toxic than ACNU and MTX, but it had no crucial problems, compared with ADM.
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PMID:[Antitumor efficacy of FK 973 on malignant glioma cells]. 275 17

Four children treated for acute lymphoblastic leukemia developed intracranial gliomas between 40 and 120 months following multiagent chemotherapy, prophylactic whole brain irradiation, and intrathecal Methotrexate. The diagnosis of glioma was confirmed in each case with biopsy or autopsy. These children were part of a larger series of 73 patients with acute lymphoblastic leukemia treated at Indiana University receiving 24 Gy as per the protocol guidelines of the Children's Cancer Study Group. Currently 42 patients of the original 73 children survive in continuous remission.
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PMID:Gliomas in children following radiation therapy for lymphoblastic leukemia. 298 May 85

Three of 37 adolescents in long-term remission from childhood acute lymphoblastic leukemia (ALL) developed malignant multifocal gliomas several years after completing treatment that included central nervous system (CNS) prophylaxis with radiation (RT) and intrathecal methotrexate (IT-MTX). No recurrence of the leukemia was evident when the CNS tumors were discovered. Seventeen other similar cases have been recorded. The occurrence of second malignancies is reviewed in the context of this development and of the oncogenic effects of radiation. It is probable that prolonged exposure to IT-MTX may have had a synergistic effect with radiation in contributing to the unusual incidence of glial tumors in these patients.
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PMID:Late multifocal gliomas in adolescents previously treated for acute lymphoblastic leukemia. 347 82

Increasingly vigorous chemotherapy of cancer including primary and metastatic central nervous system disease has resulted in prolonged good-quality survival. However, there has been an associated increase in neurotoxicity from both radiation therapy and chemotherapy. All classes of chemotherapeutic agents contain drugs that are potentially neurotoxic, often only at high doses. Mechlorethamine, the first nitrogen mustard, is not neurotoxic at conventional dosage, but at high doses, it may produce both an acute and a delayed encephalopathy. Methotrexate administered intrathecally often induces reversible aseptic meningitis, but chronic administration, either intrathecally or high-dose intravenously, may produce fatal leukoencephalopathy. 5-Fluorouracil at high dosage may cause cerebellar ataxia, but may also do so at low dosage when combined with thymidine infusions. Cytosine arabinoside at high dosage may also produce cerebellar ataxia. Vincristine produces a peripheral neuropathy, and less commonly causes both autonomic and cranial neuropathy. The enzyme L-asparaginase can produce a dose-related reversible encephalopathy. BCNU, now the mainstay of glioma chemotherapy, may combine with radiation to produce long-term cerebral atrophy. Both intracarotid and high-dose intravenous BCNU administration may cause encephalopathy. Several other chemotherapeutic agents have also been reported to cause neurotoxicity under certain circumstances.
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PMID:Neurological complications of antineoplastic therapy. 638 4

Chemotherapy was applied for experimental subarachnoid dissemination model of brain tumor which was established in male Wister-SPF (SLC) rats inoculated intracisternally with 2 X 10(5) C6 rat glioma cells. Nontreated animals died about 24 days after inoculation. Autopsy findings of the animals showed localized or multifocal invasion of the tumor on leptomeninges in cisterna magna, and partially infiltration into the parenchyma of the cerebellum and medulla oblongata. Three days after inoculation, the tumor deposition and proliferation already occurred. Several tumor cell layers were found in the subarachnoid space over the cerebellomedullary surface. Tumor bearing animals were at first treated by single agent. These are ACNU administered intraperitoneally, methotrexate administered intracisternally, and OK-432 administered intraperitoneally. In the next stage, combination of these drugs was applied. ACNU, 3 mg/kg i. p., on Day 3, was effective in elongation of median survival time by 23.6%, statistically significant (P less than 0.02). Methotrexate, 0.25 mg/kg i.th., on Day 3, was also effective in elongation of median survival time by 8.4%, statistically significant (P less than 0.05). OK-432, 0.1 KE/kg i. p., daily, 14 times, from Day 3 to Day 16, was ineffective in elongation of median survival time. Combination of ACNU, methotrexate and OK-432, in the same schedule as described above, produced the longest median survival time of 42.4%, statistically significant (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Chemotherapy for experimental subarachnoid dissemination model of brain tumor]. 658 81

A novel magnetic microsphere-methotrexate (MM-MTX) drug delivery system was synthesized and evaluated in rats bearing rat glioma-2 (RG-2) tumors. Methotrexate was linked to the surface of the magnetic particle via an aminohexanol linker that would release free drug following hydrolysis. Male Fischer 344 rats bearing RG-2 tumors were administered 3 mg/kg of methotrexate (MTX) either as MM-MTX or as a solution (MTX-S) over 5 min. A 6000 gauss magnetic field was applied for 15 min from the end of MM-MTX administrations. Serial sacrifices were conducted at 15 min, 30 min and 45 min after drug administrations, organs collected, and analyzed for total MTX by a radioassay. At all times, MTX right brain (ipsilateral), brain tumor, and left brain concentrations were approximately 3.5 to 5-fold greater in the MM-MTX group compared to the MTX-S group. MTX concentrations in all other organs were less following administration of MM-MTX than MTX-S except in lung at 30 and 45 min. The targeting efficacy, an index for site-specificity, for both MM-MTX and MTX-S were similar and indicated some enhancement in MTX localization in brain tumor. Confocal and conventional light microscopic analyses demonstrated a diffuse distribution of MM-MTX in tumor consistent with extravascular uptake, whereas a predominant capillary distribution of MM-MTX was observed in normal brain. Following 45 min, the animals treated with MM-MTX died possibly due to redistribution of particles to the lung. This toxicity was dose-dependent. High brain MTX concentrations coupled with extravascular uptake of MM-MTX provide a basis for further investigations with this novel drug delivery system.
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PMID:Tissue distribution of methotrexate following administration as a solution and as a magnetic microsphere conjugate in rats bearing brain tumors. 756 1

We have constructed a drug delivery vehicle that targets the epidermal growth factor receptor (EGFR) and its mutant isoform EGFRvIII. The monoclonal antibody, cetuximab, previously known as C225, which binds to both EGFR and EGFRvIII, was covalently linked via its Fc region to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. As measured by mass spectrometry and UV/vis spectroscopy, the resulting bioconjugate, designated C225-G5-MTX, contained 12.6 molecules of methotrexate per unit of dendrimer. Specific binding and cytotoxicity of the bioconjugate was evaluated against the EGFR-expressing rat glioma cell line F98(EGFR). Using a competitive binding assay, it was shown that the bioconjugate retained its affinity for F98(EGFR) cells, with a 0.8 log unit reduction in its EC(50). Only cetuximab completely inhibited binding of the bioconjugate, which was unaffected by methotrexate or dendrimer. Cetuximab alone was not cytotoxic to F98(EGFR) cells at the concentration tested, whereas the IC(50) of the bioconjugate was 220 nmol/L, which was a 2.7 log unit decrease in toxicity over that of free methotrexate. The biodistribution of C225-G5-MTX in rats bearing i.c. implants of either F98(EGFR) or F98(WT) gliomas was determined 24 hours following convection enhanced delivery of (125)I-labeled bioconjugate. At this time, 62.9 +/- 14.7% ID/g tumor was localized in rats bearing F98(EGFR) gliomas versus 11.3 +/- 3.6% ID/g tumor in animals bearing F98(WT) gliomas, thereby showing specific molecular targeting of the tumor. The corresponding radioactivity of normal brain from the F98(EGFR) tumor-bearing right and non-tumor-bearing left cerebral hemisphere were 5.8 +/- 3.4% and 0.8 +/- 0.6% ID/g, respectively. Based on these results, therapy studies were initiated in F98(EGFR) glioma-bearing rats. Animals that received C225-G5-MTX, cetuximab, or free methotrexate had median survival times of 15, 17, and 19.5 days, respectively, which were not statistically different from each other or untreated control animals. Our results, which are both positive and negative, show that specific molecular targeting is but one of several requirements that must be fulfilled if an antibody-drug bioconjugate will be therapeutically useful.
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PMID:Targeted delivery of methotrexate to epidermal growth factor receptor-positive brain tumors by means of cetuximab (IMC-C225) dendrimer bioconjugates. 1643 62

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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