Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multicellular spheroids (MCS) were yielded in vitro by early stages of human glioblastoma cell cultures. The spheroids were grown in suspension in the culture medium in agarose-coated (0.65%) dishes. The volume doubling time during the exponential growth phase was longer (13 days) than the population doubling time of monolayer cultures (2-3 days). Pathological examination of MCS showed a thin proliferative outer layer and areas of necrosis in the center. In two experiments BCNU caused a growth delay of MCS which was dose-related. The cells were sensitive to BCNU in monolayer cultures (CFE's assay), whereas the tumor was resistant in vivo. The usefulness and pitfalls of studies using MCS cultured from early passages of human malignant gliomas are discussed.
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PMID:[Kinetics of multicellular spheroids developed from a human glioblastoma, and effect of 1,3-bis (2-chloroethyl)-1-nitrosourea]. 630 87

Twenty-five adults who harbored malignant gliomas received 72 courses of intraarterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (100 mg/m2) and 67 courses of systemic vincristine (1.0 mg/m2) and procarbazine (100 mg/m2) as induction therapy (BVP) followed by 106 courses of systemic 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU) (130 mg/m2), vincristine, and procarbazine as maintenance therapy (MVP). With a 6-week interval between each treatment, the median and range for the number of courses of BVP were 3 and 1 to 4 and those for MVP were 3 and 0 to 14, respectively. Fifteen patients (60%) responded to both BVP and MVP, and 10 (40%) did not. The overall median survival time was 12.7 months (range, 1.8 to 48.5+ months). Two of 3 patients who had recurrent gliomas responded and survived for 37+ to 45+ months. Seven of 10 who had nonirradiated glioblastomas responded and survived for 9 to 22 months. Four who had nonirradiated anaplastic astrocytomas all responded and survived for 38+ to 48.5+ months. Two who also received radiotherapy (1 glioblastoma and 1 primitive neuroectodermal tumor) benefited and survived for 16.9 and 28.5+ months. All who did not respond favorably died within 8 months. During the infusion of BCNU, complications included transient orbital and head pain, periorbital and scleral erythema in all patients, and a focal seizure in 1 (4%). During the 6-month induction periods, leukopenia and thrombocytopenia occurred in 1 (4%), deep vein thrombosis occurred in 9 (36%), pulmonary emboli occurred in 8 (32%), upper respiratory infections occurred in 6 (24%), pneumonia occurred in 9 (36%), and herpes zoster occurred in 1 (4%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intraarterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and systemic chemotherapy for malignant gliomas: a follow-up study. 631 73

Recently, the RTOG and ECOG concluded a joint randomized study on malignant gliomas that was in progress for the past five years. A total of 626 patients entered this protocol. Sixty-seven percent of the 535 evaluable patients have died and thus this represents a preliminary report of a major joint clinical trial. The objective of this study was to evaluate the efficacy after neurosurgery of three new treatment options as compared with control treatment of radiotherapy alone. The four options were: (1) control radiation; 6000 rad/6-7 weeks to whole brain; (2) a higher radiation dose; Control dose plus a booster dose of 1000 rad/1-2 weeks to the tumor; (3) control radiation dose plus BCNU (80 mg/m2/day IV X 3 and repeat BCNU every 8 weeks); (4) Control radiation dose plus combination methyl-CCNU (125 mg/m2/day orally X 1 and repeat methyl-CCNU every 8 weeks), and DTIC (150 mg/m2/day IV X 5 and repeat DTIC every 4 weeks). All pertinent patient characteristics were studied and several important prognostic factors have been identified. Notably, age, histologic type (Astrocytoma with anaplastic foci, versus glioblastoma multiforme), initial performance status, time since first symptoms and presence or absence of seizure. At this time, it appeared that there was no treatment option which was significantly better than the control. The study identified that age was the most important prognostic factor. Patients who were younger than age 40 years had an 18-month survival of 64%, patients who were age 40-60 years had an 18-month survival of 20%, and patients who were older than age 60 had an 18-month survival of 8%. The study also demonstrated that a modified histologic classification of anaplastic astrocytoma versus glioblastoma provided better prognostic information than the astrocytoma grading system of Kernohan. Patients with anaplastic astrocytoma had a median survival of 27 months as compared to 8 months for patients with glioblastoma. In further evaluation of any beneficial effect of chemotherapy, it was identified that only among the 40-60-year-old groups, BCNU treated patients appeared to have significantly increased survival than patients in the control groups (P = 0.01, one-sided). Similarly, methyl-CCNU + DTIC was suggestively better than the control (P = 0.08, one-sided). The higher radiation dose, 7000 rad/8-9 weeks appeared to give no significantly better survival over the control dose option. Both BCNU and methyl-CCNU + DTIC produced some toxicity. The combination of methyl-CCNU + DTIC was more toxic than BCNU, producing severe or worse thrombocytopenia in 23% of the patients as compared to 6% on BCNU.
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PMID:Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study. 634 85

A human medulloblastoma (BN-2) and a glioblastoma (BN-3) which were previously established in nude mice were used to determine the effect of combined modality therapy with gamma-radiation, and three chemotherapeutic agents, procarbazine, 1,4-cyclohexadiene-1,4-dicarbamic acid, 2,5-bis(1-aziridinyl)-3,6-dioxo diethylester (AZQ), and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The tumor cells were grown in tissue culture and implanted intracranially in the right cerebral hemisphere of NIH Swiss nude mice to a depth of 3 mm. The mice were randomized, and treatment was started 3 days after tumor implantation. Procarbazine and AZQ were injected i.p. every 5 days for three treatments. BCNU was injected one time for a single treatment. Radiation was localized to the head. A 60Co unit was used for irradiation at the rate of 125 rads/min 3 days after tumor implantation. Ten experiments were performed using six to nine mice per group and different drug-radiation dose combinations. The drug dose ranged from 400 to 500 mg/kg/injection for procarbazine, 7.5 mg/kg/injection for AZQ, and 10 to 20 mg/kg/injection for BCNU. The radiation dose ranged from 320 to 1050 rads/mouse (whole head). The day of death was recorded for each animal, and the mean of each treatment group was used to calculate the percentage increase in life span (ILS) compared to the untreated control group. Chemotherapy alone produced a minimal effect, while radiation alone produced minimal effects at 320 to 640 rads with progressively positive effects at 800 and 1050 rads. When the combination treatment of the human medulloblastoma xenograft with procarbazine was used, the ILS was significantly increased in all four experiments, ranging from 25 to 41%, and was superior to single-modality treatment in all but the 1050-rad treatment, where it showed an equal effect. The combination treatment using AZQ and BCNU showed no ILS for the medulloblastoma tumor. Combination treatment of the human glioblastoma xenograft using BCNU produced significant ILSs of 105 and 119% and was superior to single-modality treatment with a drug dose of 10 mg/kg and radiation doses of 540 and 800 rads, respectively. The nude mouse-human tumor xenograft model was found to be useful for combined modality studies and should give valuable information for the experimental design of pilot Phase III clinical studies against a variety of brain tumors.
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PMID:Combined modality treatment using radiation and/or chemotherapy in an athymic nude mouse-human medulloblastoma and glioblastoma xenograft model. 705 79

O6-Benzylguanine effectively inactivates the DNA-repair protein O6-alkylguanine-DNA alkyltransferase in tumor cells and has been shown to increase the cytotoxicity of chloroethylnitrosoureas. This study was undertaken to ascertain the optimal vehicle for further toxicological evaluation and eventual clinical trials of O6-benzylguanine. The solubility, metabolism, bioavailability and effectiveness of O6-benzylguanine as an adjuvant therapy with BCNU were compared using two vehicles, cremophor-EL and PEG 400. Nude mice bearing s.c. D456 MG glioblastoma xenografts were injected i.p. with 10-30 mg/kg O6-benzylguanine dissolved in either 40% PEG 400/saline or 10% cremophor-EL/saline. The number of tumor regressions noted after treatment with 10 mg/kg O6-benzylguanine followed by 12.7 mg/kg BCNU were 8/9 for the drug dissolved in PEG and 1/10 for the drug given in cremophor-EL. Using the same treatment regimen but increasing the dose of O6-benzylguanine to 30 mg/kg led to a growth delay of 45.2 and 11.5 days for the drug dissolved in PEG 400 and cremophor-EL, respectively, although the number of regressions observed were the same for both treatments. 8-[3H]-O6-Benzylguanine was more rapidly distributed to the tumor when it was delivered in PEG vehicle than when it was given in cremophor-EL. In contrast, there was a 3-fold greater amount of O6-benzylguanine in the small intestine of mice at 1 h after i.p. injection of the drug in cremophor-EL as compared with PEG 400. The rate and extent of metabolism in the liver was the same, whether the parent drug was given in PEG 400 or in cremophor-EL. These studies demonstrate that O6-benzylguanine is a more effective enhancer of the antitumor activity of BCNU when it is given in PEG 400 than when it is delivered in cremophor-EL, which may be due to a more rapid distribution of the drug to the tumor.
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PMID:Biodistribution of O6-benzylguanine and its effectiveness against human brain tumor xenografts when given in polyethylene glycol or cremophor-EL. 798 87

Temozolomide, a methylating agent with clinical activity against brain tumors, demonstrated excellent antitumor activity following p.o. administration to athymic mice bearing human brain tumor xenografts. In the early stage s.c. implanted SNB-75 astrocytoma model, a 400-mg/kg dose administered on Day 5 produced 10 of 10 Day 54 tumor-free mice. In later staged s.c. U251 and SF-295 glioblastoma models, a single 600-mg/kg dose produced 9 of 10 Day 86 and 2 of 10 Day 40 tumor-free mice, respectively. In the latter group, a tumor growth delay of > 315% was attained. Similar levels of activity were attained with equal total doses on schedules of daily for 5 doses and every fourth day for 3 doses. A single 40-mg/kg i.v. dose of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) also demonstrated excellent activity, producing 9 of 10 tumor-free mice in the SNB-75 model and growth delays of 283 and 301% in the U251 and SF-295 models, respectively. Temozolomide was also highly effective against intracerebral implants of the U251 and SF-295 glioblastomas. Administration of either 600 mg/kg on Day 1 or 200 mg/kg on Days 1, 5, and 9 produced 7 of 9 Day 90 tumor-free mice in the U251 model. In the SF-295 model, a single 400-mg/kg dose or three 200-mg/kg doses produced 3 and 4 of 10 Day 90 tumor-free mice, respectively, and prolonged survival by 127%. A single 40-mg/kg i.v. dose of BCNU was more effective than temozolomide in the intracerebral SF-295 model, and less effective in the intracerebral U251 model. The synergistic potential of temozolomide and BCNU in combination was evaluated in an advanced stage s.c. implanted SF-295 model. When temozolomide was administered 2 h after BCNU on a single treatment day, a dramatic synergistic therapeutic effect was observed in two experiments. For example, single agent doses of temozolomide (600 mg/kg) and BCNU (60 mg/kg) and a combination (400 mg/kg + 27 mg/kg) demonstrating equivalent toxicity produced growth delays of 190, 258, and > 492% (includes 5 of 10 Day 51 tumor-free mice), respectively. Analysis of the data by a quadratic dose response model indicated synergism with significance at P = 0.0001 in both experiments. Synergism also was demonstrated by the isobole method. The reverse sequence was more toxic, but at lower combination doses a synergistic effect was still observed (P = 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Preclinical antitumor activity of temozolomide in mice: efficacy against human brain tumor xenografts and synergism with 1,3-bis(2-chloroethyl)-1-nitrosourea. 803 99

Nitrosoureas are the drugs most effective in the treatment of patients with intracerebral malignant glioma. Their limiting toxicity is delayed myelosuppression. A prospective, randomised crossover study of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was performed in patients receiving BCNU for relapsed glioblastoma, to investigate whether the resulting haematological toxicity profile could be modified by rhGM-CSF. Adequate data for analysis were obtained in 13 patients. Following BCNU, the nadir neutrophil count was higher in 12 out of 13 patients during the rhGM-CSF-protected cycles compared with the unprotected cycles. The median nadir was also significantly higher (1.79, CI 0.76-3.52, P < 0.005). Five episodes of neutropenia (< 2 x 10(9) l-1) occurred during the unprotected cycles compared with none in the rhGM-CSF-protected cycles (P = 0.076). There was no evidence of any effect on platelets. This result shows that the haematological toxicity profile following therapeutic doses of BCNU can be modified. It suggests that rhGM-CSF and other growth factors should be investigated for clinical efficacy in chemotherapy using nitrosoureas.
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PMID:rhGM-CSF ameliorates neutropenia in patients with malignant glioma treated with BCNU. 812 85

In vitro, when using low concentrations of ferritin (ng/ml) or CaCl2 (micrograms/ml), multiplication of a human, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU)-resistant glioblastoma cell line (U251) is enhanced 1.5 to 2 times more actively than multiplication of a normal astrocyte line (CRL 1656). Ferritin and Ca2+ ions exhibit a marked effect on DNA isolated from these cells: glioblastoma DNA relaxation is strongly increased (as evidenced by increased 260 nm ultraviolet absorbance), being from 5 to 6 times that of astrocyte DNA, which remains only slightly affected. Under identical experimental conditions, Zn2+ and gallium ions selectively inhibit glioblastoma cell multiplication but at the same concentrations do not inhibit astrocyte multiplication. Ultraviolet absorbance measurements demonstrate that both of these agents condense relaxed glioblastoma DNA in vitro. Zn2+ or gallium ions added to culture medium containing stimulatory concentrations of ferritin or Ca2+ ions selectively and strongly inhibit enhancement of glioblastoma cell multiplication by these mitogens while not affecting normal multiplication of astrocytes.
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PMID:Differential effects of ferritin, calcium, zinc, and gallic acid on in vitro proliferation of human glioblastoma cells and normal astrocytes. 814 3

Major drawbacks to present-day cancer chemotherapy are its intrinsic lack of selectivity for tumour cells, resulting in severe damage to normal rapidly dividing cells, and the widespread emergence of drug resistance. Here experimental evidence is presented demonstrating that PB-100, a beta-carboline alkaloid, selectively inhibits in vitro multiplication of human BCNU-resistant glioblastoma cells (U251), but has no effect on normal astrocyte (CRL 1656) multiplication. PB-100 activity is dose-dependent. In the presence of ferritin or CaCl2, which are highly mitogenic for glioblastoma cells, higher doses of the alkaloid are required to inhibit multiplication completely. PB-100 is one of several compounds which were selected for their specific action on cancer DNA and cells, together with lack of activity on normal DNA and cells. Both the selectivity of PB-100 and its ability to overcome drug resistance stem from its effect on cancer DNA secondary structure. This activity is described and discussed, and therapeutic applications are mentioned.
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PMID:PB-100: a potent and selective inhibitor of human BCNU resistant glioblastoma cell multiplication. 829 50

Twenty-two patients, aged 16 to 67, who had malignant gliomas after surgical resection were treated with carmustine and cisplatin intravenous infusion before, during, and after radiotherapy. All patients had subtotal or total resection, or biopsy as the initial procedure. Twenty-one patients who had at least 2 cycles of chemotherapy and finished the whole course of radiotherapy were considered to be evaluable for responses. Among them, 5 had glioblastoma multiforme, 16 had anaplastic astrocytoma. The median time to tumor progression was 35 weeks (range 12-130 weeks) and median survival time was 66 weeks (range 10-156 weeks). Early progression occurred more frequently in patients with biopsy only and subtotal resection, and in patients with glioblastoma than in those with anaplastic astrocytoma. This combined modality treatment program was associated with reversible hematologic toxicity which was severe in 2 patients, and with ototoxicity in 1 patient, nephrotoxicity in 2 patients. Combination of carmustine and cisplatin with cranial irradiation for malignant gliomas is moderately toxic and appears to offer no obvious survival advantage compared with radiation therapy plus BCNU alone.
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PMID:Combination chemotherapy with carmustine and cisplatin before, during, and after radiotherapy for adult malignant gliomas. 859 71


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