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)

Glioma cells express high protein kinase C (PKC) activity, which may represent an important therapeutic target. Tamoxifen (TAM) has moderate PKC-inhibiting activity, blocking DNA synthesis and cellular proliferation in human glioma cells at concentrations that can be achieved therapeutically. Carboplatin (CBDCA), a second-generation platinum derivative, induces intra- and interstrand DNA-protein crosslinks producing inhibition of tumor-cell growth. In the present study, the effect of TAM, CBDCA, and the combination of both was evaluated against the human established U-138 glioma cell line during the exponential growth phase (48-72 h) by means of both the Biorad protein assay (BPA) method and Trypan blue exclusion study (TBES). Both TAM and CBDCA reduced the cellular growth rate, with a median 50%-inhibiting concentration (IC50) of 12.5 microM for TAM and 350 microM for CBDCA. The U-138 glioma cell line showed a moderate response to 100 microM of CBDCA, with < or = 10% reduction of the growth rate. The association of both chemotherapeutic agents induced a 98% reduction of the IC50 dose of TAM (0.1 microM), and a 71% reduction of the IC50 dose of CBDCA (100 microM). During the combinational TAM CBDCA exposure we observed a cytotoxic effect of TAM at concentrations lower than 0.1 microM, not recognized using it as a single drug. The differences observed among the IC50 doses (TAM, CBDCA, TAM-CBDCA) and among treated and untreated matched control cells were statistically significant (P < 0.01). Our results confirm previous observations about the efficacy in vitro of TAM against human glioma cell lines and show a marked enhancement of this activity by CBDCA.
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PMID:Tamoxifen modulation of carboplatin cytotoxicity in a human U-138 glioma cell line. 974 94

RMP-7, a nine amino acid peptide bradykinin agonist, increases the delivery of hydrophilic compounds across the blood-tumour barrier. In this dose ranging study, 14 patients with progressing malignant glioma (9 glioblastoma multiforme, 4 anaplastic astrocytoma, 1 anaplastic oligodendroglioma; age range 31-68 years, baseline Karnofsky range 60-90%, 5 having had prior chemotherapy) were treated with intravenous RMP-7 and carboplatin to assess the safety, tolerability, and side-effect profile of increasing doses of this combination. Carboplatin dosing was by target area under the curve (AUC) according to the Calvert protocol. Patients were allocated to one of five treatment regimes: cohort A (n = 2) received 50 ng/kg RMP-7 and target AUC 5 mg/ml/min carboplatin; cohort B (n = 3) 100 ng/kg RMP-7 + AUC 5; cohort C (n = 2) 100 ng/kg RMP-7 + AUC 7; cohort D (n = 2) 200 ng/kg RMP-7 + AUC 7; cohort E (n = 5) 300 ng/kg RMP-7 + AUC 7. Treatment was given once every 4 weeks with magnetic resonance imaging scans every 2 months. Patients received 37 cycles in total (median 2, range 1-7). The drug combination, as a cancer treatment, was tolerated in all groups. Effects possibly related to RMP-7 included flushing, nausea, headache and mild increase in heart rate, all transient. 3 patients in cohort E experienced grade 3/4 neutropenia and thrombocytopenia. These toxicities are consistent with known effects of carboplatin at this dose range. In cohort E (n = 5) 1 patient improved and another remained stable for > or = 6 months. In summary, the dose was escalated to the maximum dose of RMP-7 given to volunteers without additional related side-effects. The side-effects of the combination were consistent with giving the two drugs alone and would merit further study for efficacy.
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PMID:A phase I study of intravenous RMP-7 with carboplatin in patients with progression of malignant glioma. 989 73

The effect of intracarotid infusion of etoposide on the permeability of the blood-brain barrier (BBB) and brain-tumor barrier (BTB) was investigated using a model of rats injected with C6 glioma cells. Fifty four glioma-bearing rats were divided into 3 groups and treated with 0, 3, or 15 mg/kg of etoposide infused into the internal carotid artery. BBB or BTB permeability was evaluated qualitatively by the leakage of Evans blue (6 animals in each group) or quantitatively by the diffusion of carboplatin [cis-diammine (1,1-cyclobutane-dicarboxylato) platinum(II); CBDCA] (12 animals in each group) into the normal brain or the tumor tissue. BBB and BTB disruption augmented significantly in proportion to the dose of etoposide. The degree of disruption of BTB was greater than that of BBB, but the rate of disruption of BBB in proportion to increasing the dose of etoposide was higher than that in the BTB. Histopathologically, no obvious changes were observed in the animals of either the control group or the 3 mg/kg group but degenerative changes in the neurons of the hippocampus of the infused hemisphere were seen in the 15 mg/kg group. This change is thought to be caused by apoptosis because of the positive reaction with TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method. Our results suggest that intracarotid infusion of etoposide can increase drug delivery of concurrent antitumor agents into tumor tissue, but cerebral parenchymal cell damage is expected with a higher dosage of etoposide. Therefore, the dosage of etoposide for intracarotid infusion should be lower than 15 mg/kg in order to reduce neurotoxicity of both etoposide and concurrent anticancer drugs.
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PMID:Effect of intracarotid infusion of etoposide: modification of the permeability of the blood-brain barrier and the blood-tumor barrier in rat brain tumor model. 1009 32

The present paper investigates the pharmacokinetics of etoposide (VP-16) and carboplatin (CBDCA) in plasma and the cerebrospinal fluid (CSF), in the space left by tumor removal, of patients with glioma. Eight Japanese patients with glioma received a course of hyperosmotic disruption of the blood-brain barrier (HODBBB) and intraarterial combination chemotherapy with 60 mg/m2 of VP-16 and 300 mg/m2 of CBDCA. All patients were initially administered mannitol, followed by infusion of the anticancer drugs into the right internal carotid artery. Blood samples and samples of CSF in the space left by tumor removal were obtained. VP-16 and CBDCA concentration were measured by HPLC, and the pharmacokinetic parameters of these drugs estimated in CSF and plasma. The plasma concentrations of VP-16 and CBDCA peaked at the end of infusion, then decreased in a bi-exponential decay pattern during the remainder of the treatment period. Both VP-16 and CBDCA were detectable in CSF beginning 0.5 h after the initiation of each infusion, and were then slowly eliminated from the space left by tumor removal. The mean maximum CSF concentration of VP-16 and CBDCA was 0.17 and 15.25% of that in plasma, respectively. The mean area under the time-CSF concentration curve from 0 to 24 h after VP-16 and CBDCA infusion was 1.91 and 113.6% of plasma, respectively. In two of the eight patients, the clinical response to treatment was a partial response and other patients showed no change. HODBBB and intraarterial combination chemotherapy with VP-16 and CBDCA may be useful in patients with brain tumors for maintenance chemotherapy.
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PMID:Pharmacokinetics of etoposide and carboplatin in cerebrospinal fluid and plasma during hyperosmotic disruption of the blood brain barrier and intraarterial combination chemotherapy. 1032 68

Management of low grade optic glioma in children and adolescents remains controversial. Treatment with chemotherapy may delay or eliminate the need for radiation therapy. Children with newly diagnosed optic chiasm glioma were eligible for enrollment in this phase II trial and received intravenous carboplatin (CBDCA) (560 mg/m2) every four weeks. Patients were monitored closely for toxicity and tumor status. Twelve children were enrolled. Six patients had stable disease, four a partial response and two progressed on therapy. Overall progression free survival was 83 +/- 11%. The median duration of follow-up was 38.6 months (range 18-63 months). No deaths were noted in our series. Thrombocytopenia was the major toxicity, and two patients required platelet transfusions. One child developed an urticarial reaction requiring discontinuation of therapy. Another child developed unilateral high frequency hearing loss. No renal toxicity was encountered. We have demonstrated that carboplatin can eliminate or delay radiation therapy in children and adolescents with low grade optic glioma. CBDCA deserves further investigation in larger clinical trials as a treatment for children with optic chiasm glioma.
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PMID:Carboplatin for the treatment of children with newly diagnosed optic chiasm gliomas: a phase II study. 1035 45

The objective of this paper was to determine the time course and extent of platinum uptake into human malignant glioma tissue. An intraoperative, intravenous infusion of carboplatin was given to nine patients (seven glioblastoma and two anaplastic glioma) undergoing tumour excision. Carboplatin dosage was calculated individually to achieve a target systemic free carboplatin exposure. Tumour and peritumoural tissue was harvested at timed intervals following carboplatin administration. Plasma and tumour platinum concentrations were measured by graphite furnace flameless atomic absorption spectrophotometry. Histological examination was also performed on a piece of each tissue sample. The mean carboplatin dose administered was 783, SEM 56 mg (range 485-903). Plasma pharmacokinetics showed a typical elimination curve. The mean peak plasma platinum concentration was 44, SEM 5 micrograms/ml (range 27-74). The mean total elemental plasma platinum area under the curve (AUC) was 9.0, SEM 1.4 mg/ml/min. Platinum was detected in 61 tumour samples, the mean peak concentration being 13 SEM 2 micrograms/g (range 5-21). Platinum was also detected in peritumoural brain and necrotic tumour. No correlation was apparent between the degree of necrosis in each tumour specimen and tumour platinum concentration. Platinum concentrations achieved in tumour were similar to levels that would be cytotoxic for glioma cells in vitro. The results of this study have implications for future studies using capillary permeability modifying agents as adjuncts to brain tumour chemotherapy.
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PMID:Platinum distribution in malignant glioma following intraoperative intravenous infusion of carboplatin. 1061 80

Surgical resection followed by local field radiotherapy is currently our most effective approach to treatment for most patients with malignant glioma. Carboplatin chemotherapy has direct cytotoxic effects on glioma cells and acts as a radiation sensitizer to enhance cell killing. Its demonstrated efficacy as a sensitizer in other solid tumors led to this clinical trial of carboplatin as a radiation sensitizer in the treatment of newly diagnosed glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). Fourteen patients (nine GBM and five AA) were treated with daily low-dose carboplatin 25 mg/m2 intravenously within 2 h of their fractionated radiotherapy to a total dose of 600 mg/m2. No significant toxicities attributable to this combined therapy were observed. All patients have progressed, with median time to progression of 16 weeks. Eleven patients have died, with median survival of 38 weeks for the entire cohort. Although this regimen appeared safe, there was no benefit in survival time compared to historical patients treated with radiotherapy. The limitations and future potential for the strategy of radiation sensitization are discussed.
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PMID:Daily low-dose carboplatin as a radiation sensitizer for newly diagnosed malignant glioma. 1167 27

Polymer microspheres can be easily injected into the brain to provide a local and sustained delivery of chemotherapeutics to a tumor or surrounding tissue subject to high rates of tumor recurrence following surgery. Building on previous studies that established the clear advantage of local, peritumoral injections of sustained release microspheres, the following experiments utilized two different approaches for maximizing the survival benefit in glioma-bearing rats. In the first experiment, a previously grown cortical tumor was debulked and animals received either one or two treatments with carboplatin-loaded microspheres (either 200 or 800 microg total carboplatin per treatment). In each case, the microspheres were injected along the perimeter of the resection cavity with each treatment separated by 20 days. Survival studies clearly demonstrated that two, temporally spaced injections were superior to a single series of injections. At the lowest dose tested (200 microg), median survival was increased an additional 40% over that in animals receiving one treatment. At the higher dose (800 microg), one third of the animals receiving two separate treatments were long-term survivors (> 150 days) and showed complete eradication of the tumor on histological examination. In the second experiment, we directly compared the efficacy produced by sustained release carboplatin or 1,3-bis[2-chloroethyl]-1-nitrourea (BCNU) alone versus injecting carboplatin and BCNU-loaded microspheres blended together as a single suspension. Carboplatin and BCNU both enhanced survival, with BCNU being significantly less effective than carboplatin. However, the greatest improvements in survival were seen when a blended suspension of carboplatin and BCNU microspheres was injected around the surgical cavity. In contrast, spatially alternating injections of BCNU and carboplatin microspheres was significantly less effective and the increase in survival was no greater than that achieved with BCNU alone. These data offer further support for the potential utility of local, sustained release chemotherapeutic microspheres for treating glioma. Moreover, they suggest that injectable chemotherapeutic microspheres may offer important advantages by (a) permitting multiple, temporally spaced injections to be made, as needed, and (b) providing the opportunity to deliver combinations of several different efficacious drugs directly to the tumor site to enhance survival beyond what can be achieved with delivery of any single chemotherapeutic agent.
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PMID:Injection of chemotherapeutic microspheres and glioma. IV: Eradicating tumors in rats. 1209 19

RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.
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PMID:A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. 1267 81

Two types of chemotherapy used in the treatment of patients with malignant glioma are carboplatin and Gliadel wafer [(3.85% 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU)]. To date there have been no published data examining their concurrent use in this disease. The purpose of this study was to evaluate combination chemotherapy with Gliadel wafer and carboplatin in patients with high-grade, malignant glioma. In this prospective phase I study, 16 patients underwent surgery, Gliadel wafer implantation (up to 8 wafers), intravenous carboplatin given postoperatively (day 3 or 4) at a dose escalation range of area under the curve (AUC)=2-6, and external beam radiation. Median age was 55 years (range 27-66 years). Fourteen (88%) patients had glioblastoma multiforme and 2 (12%) had anaplastic astrocytoma. Performance status was as follows: Eastern Cooperative Oncology Group (ECOG)=0 (2 patients), ECOG=1 (13 patients), and ECOG=2 (2 patients). Three patients were treated at each dosing level (AUC=2-6), and 4 patients were treated at an AUC=5. Carboplatin was administered to all patients by postoperative day 4. Radiation was begun on day 14-36. No grade 3 or 4 toxicities were noted in this study. Median progression-free and overall survival was 266 and 679 days, respectively. We conclude that administering systemic carboplatin is safe and well tolerated in the postoperative period immediately following resection and implantation of Gliadel wafer for the treatment of malignant glioma. Further evaluation in a phase II setting, at maximal carboplatin dose to establish potential efficacy, with this combination is warranted.
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PMID:A phase I trial of surgery, Gliadel wafer implantation, and immediate postoperative carboplatin in combination with radiation therapy for primary anaplastic astrocytoma or glioblastoma multiforme. 1593 47


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