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)

Fifteen patients were treated in a Phase I study of intracarotid carboplatin (200-400 mg/m2) in 5% dextrose and water infused over 15 to 30 minutes through a transfemoral catheter with a 0.2-micron inline filter. This study was done because intravenous carboplatin has less neurotoxicity than cisplatin and is active against brain tumors. Eleven men and four women ranging in age from 37 to 72 years (median, 59 years) were treated. The Eastern Cooperative Oncology Group performance status was 1 in 3, 2 in 4, and 3-4 in 8 patients. Eight patients had one to three previous chemotherapy regimens; previous radiotherapy had failed in 13 patients. The response of patients in the Phase I study follows: glioblastoma, 6 failed; not evaluated because of early death from pulmonary embolus, 1; recurrent Grade II and III glioma, 1 stable (minor response with neurologic improvement) and 2 failed; malignant oligodendroglioma, 1 failed; brain metastases from nonsmall cell lung cancer, 1 partial remission, 1 stable (minor response), and 1 failed; brain metastases from unknown primary, 1 stable (minor response with neurological improvement). Median survival was 9 weeks. Nausea was mild to moderate. One patient had granulocytopenia, and 2 had thrombocytopenia (mild). At 200 mg/m2 (2 patients), 1 had a focal seizure. At 300 mg/m2 (9 patients), 2 with abnormally small arteries had severe pain early in the treatment and posttreatment ipsilateral conjunctival edema, decreased vision, and cerebral edema (with partially reversible increased hemiparesis); 1 other had mild decrease in ipsilateral vision and 1 had transient aphasia on removal of the catheter (possibly the result of a vascular spasm).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phase I study of intracarotid administration of carboplatin. 131 64

Two monoclonal antibodies (mAb), termed ED6 and LD6, were obtained by immunizing mice with cytotoxic T cell lines expressing the T cell receptor (TcR) gamma/delta. These mAb were selected according to their ability to trigger the cytolytic program of the immunizing cell lines in a redirected killing assay. Both mAb recognized molecule(s) expressed on the surface of most long-term cultured TcR gamma/delta +, TcR alpha/beta + and CD3-CD16+ lymphocytes, while it was absent on resting peripheral blood lymphocytes. In addition both mAb reacted with neoplastic B cell lines, Epstein-Barr virus-transformed B cell lines, small cell lung cancer and glioma cell lines, while no surface reactivity was detected on ovarian, breast, colon and non-small cell lung cancer lines. The functional activity of these mAb was studied by two cytolytic assays. Both mAb were able to trigger the cytolytic program of CD3+TcR gamma/delta + polyclonal cell lines and of a CD3-CD16+ NK cell clone against the murine mastocytoma target cell line P815 (Fc receptor+) in a 4-h 51Cr-release assay. In addition, ED6 and LD6 hybridomas were lysed by TcR gamma/delta + effector cells while other hybridomas (obtained from the same fusion) were not lysed. ED6 and LD6 mAb (in the presence of submitogenic doses of the phorbol 12-myristate 13-acetate) also induced the secretion of interleukin 2 by ED6/LD6+ T cell clones expressing TcR gamma/delta or alpha/beta. mAb-induced surface antigen modulation experiments showed that the antigenic determinant recognized by ED6 and LD6 co-modulated, thus indicating that the two mAb probably recognize the same or closely associated molecules. The molecular characteristics of the antigen recognized by the mAb were investigated by Western blot analysis. The LD6 mAb recognized a major band of approximately 65 kDa, both under nonreducing and reducing conditions. These data indicate that ED6 and LD6 mAb recognize a novel non-lineage-specific activation antigen which is involved in the induction of the functional program of long-term cultured T or natural killer cells.
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PMID:A novel surface molecule expressed by long-term cultured T and natural killer cells is involved in cell activation. 183 83

Deletions of chromosomal band 9p21 have been detected in various tumor types including melanoma, glioma, lung cancer, mesothelioma, and bladder cancer. Recently, the CDKN2 gene (p16INK4A, MTS I, CDK41) has been proposed as a candidate tumor suppressor gene because it is frequently deleted in cell lines derived from multiple tumor types. We performed fluorescence in situ hybridization (FISH) with interphase cells using yeast artificial chromosome clones and a cosmid contig of the CDKN2 region. In 10 cell lines (4 glioma, 2 melanoma, 2 non-small cell lung cancer, 2 bladder cancer) with 9p alterations detected by molecular or cytogenetic analysis, interphase FISH with the CDKN2 cosmid contig detected all 9p deletions previously identified by molecular analysis. Using this probe, FISH analysis of primary glioblastoma tumors revealed homozygous deletions of the CDKN2 region in 6 of 9 tumors (67%) whereas a yeast artificial chromosome probe containing the interferon type I (IFN) gene cluster was deleted in only 4 cases (44%). Thus, it is likely that the CDKN2 region is the target of 9p deletions in gliomas. Interphase FISH will play an important role in defining the clinical significance of 9p deletions in primary tumors because it is especially applicable to clinical samples which may be contaminated by normal cells.
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PMID:Detection of CDKN2 deletions in tumor cell lines and primary glioma by interphase fluorescence in situ hybridization. 786 8

Fotemustine is a new chloroethylnitrosourea characterized by the grafting of a phosphonoalanine group onto a nitrosourea radical. Clinical studies using fotemustine have been conducted in malignant glioma, brain metastasis of non-small cell lung cancer, and disseminated malignant melanoma. In recurrent malignant glioma, fotemustine has been used as a single agent: assessed by computed tomography scan, after 8 weeks, the objective response rate was 26.3% among 38 evaluable patients. Median duration of response was 33 weeks. The main toxicity was hematological (thrombocytopenia and leucopenia). A trial with high-dose fotemustine and autologous bone marrow rescue in newly diagnosed glioma was conducted in 26 patients, and 6 showed a partial response. The median overall survival was approximately 11 months. Myelosuppression was noted in all patients except 1, and other toxicity reported was central nervous system toxicity and epigastric pain. Combined with radiotherapy in 55 patients, a 29% response rate was observed, and this combination was well tolerated and easily manageable on an outpatient basis. Finally, fotemustine has been used intraarterially, with 10 objective responses observed among 26 evaluable patients. In brain metastases of non-small cell lung cancer, fotemustine proved to be active with a response rate of 16.7%. Combined with cisplatinum, fotemustine is still under study, but preliminary results are promising. In cerebral metastases of disseminated malignant melanoma, fotemustine has been evaluated in a total of 140 patients in the various studies: median response rate is 24.3%, ranging from 8.3% to 60.0%. Fotemustine appears to be a good candidate in the treatment of primary brain tumors and metastases.
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PMID:Fotemustine in the treatment of brain primary tumors and metastases. 803 64

A novel derivative of camptothecin, 9-aminocamptothecin (9-AC), is currently under Phase II evaluation in various cancers. Exceptionally mild toxicities were observed in patients with brain tumors who were treated with anticonvulsants. To investigate a pharmacokinetic interaction between 9-AC and anticonvulsants, and to evaluate the pharmacodynamics of 9-AC, we investigated the clinical pharmacology of 9-AC, administered by a 72-h infusion, in three Phase II studies. Plasma concentrations of total 9-AC (lactone plus carboxylate) at a steady state were measured in 56, 10, and 14 patients with non-small cell lung cancer, malignant glioma, and head and neck cancer, respectively. For lung cancer or glioma patients, 9-AC was infused at 45 (51 patients) or 59 (15 patients) microg/m2/h, and 9-AC was infused at 35.4 microg/m2/h in head and neck cancer patients. All glioma patients had been treated with phenytoin or carbamazepine. 9-AC clearance did not differ among the dosage rates, but differed according to the diseases (P = 0.002). Glioma patients had a higher clearance (1.0-18.0; median, 2.0 liters/h/m2) than lung cancer patients (0.3-5.1; median, 0.9 liters/h/m2). A logistic regression model described the relationship between the 9-AC concentration and the probability of grade 4 neutropenia, which was the main toxicity. Observed incidences of grade 4 neutropenia for patients with model-predicted probability of 0-20%, 20-40%, and 40-100% were 10%, 32%, and 67%, respectively, and corresponded to 9-AC concentration of <54, 54-86, and >86 ng/ml, respectively. Anticonvulsants seem to induce the clearance of 9-AC, and the concentration of 9-AC predicts the probability of grade 4 neutropenia.
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PMID:Pharmacokinetics and pharmacodynamics of 9-aminocamptothecin infused over 72 hours in phase II studies. 1038 15

Prinomastat (formerly AG3340, Agouron Pharmaceuticals, Inc.) is a potent, selective oral inhibitor of matrix metalloproteinase-2, -9, -13 and -14. This peculiar selectivity should represent an advantage for prinomastat in terms of efficacy/tolerability. The drug has been shown to inhibit tumour growth and angiogenesis in a variety of preclinical models, including cancer of colon, breast, lung and intriguingly in melanoma and glioma models. Moreover, the combination of prinomastat and several chemotherapeutic agents was shown to induce additive effects. The drug is currently in Phase III clinical trials for patients with non-small cell lung cancer in combination with paclitaxel and carboplatin, as well as in advanced hormone refractory prostate cancer in combination with mitoxantrone. The most common side effects are musculoskeletal pain and stiffness. These side effects generally cease with treatment interruption. Finally, considering the pathophysiology of MMPs, Agouron is exploring the utility of prinomastat in ophthalmology and dermatology.
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PMID:Prinomastat, a hydroxamate-based matrix metalloproteinase inhibitor. A novel pharmacological approach for tissue remodelling-related diseases. 1106 Aug

Pharmacyclics is developing Gd-Tex (gadolinium texaphyrin) as a radiosensitizer for the potential treatment of various cancers including brain metastases and primary brain tumors, pancreatic tumors, lung tumors and pediatric cancers [196711], [348919]. The compound entered phase III pivotal trials for brain metastases in September 1998 [323929]. Phase I clinical trials for the treatment of primary brain tumors and pancreatic cancer have been initiated while several trials in other cancer types are in the planning stages [367716]. In September 1998, Pharmacyclics announced the initiation of a pivotal phase III trial for the treatment of patients with brain metastases. This multicenter trial originally included 30 sites in the US, Canada and Europe, and was expected to enroll 425 patients. The FDA agreed that this trial qualified for Fast Track review if efficacy end-points are met [301265]. By October 2000, nearly all 450 patients in 50 sites had been completed [375959], [387023]. In September 2000, Pharmacyclics and the National Cancer Institute (NCI) initiated two phase I trials of Gd-Tex. The first was to determine the safety of two different dosing regimens of the drug during preoperative radiotherapy after induction chemotherapy in patients with stage IIA non-small cell lung cancer (NSCLC). The second would examine the use of Gd-Tex in combination with stereotactic Gamma Knife radiosurgery in patients with primary brain tumors known as glioblastoma multiforme [381561]. A phase Ib/II trial, for brain metastases, was conducted in America and France, and involved over 100 patients. At the ASCO 1998 meeting, interim tumor response data were presented for 37 patients. The overall tumor response rate (complete plus partial response rate) was 73%. Furthermore, MRI scanning confirmed that Gd-Tex accumulated selectively in tumors [287459]. Full results were announced in October 1998 at the American Society of Therapeutic Radiology and Oncology. Following ten daily injections followed by whole brain radiation, 77.7% of patients demonstrated a tumor response defined as greater than 50% reduction in tumor volume. Gd-Tex was well tolerated, and liver enzyme elevation was the dose-limiting effect, which was reversible. Death due to tumor progression was seen in 15% of the Gd-Tex group as opposed to 35% in the control group [302872]. In November 1999, Pharmacyclics commenced a phase I trial of Gd-Tex injection, sponsored by the NCI, for treating children with intrinsic pontine glioma. The goals of the phase I dose-ranging study were to determine the Gd-Tex dose and administration schedule that can be safely administered with radiation and to evaluate the localization of Gd-Tex in affected tumors using MRI [348035]. In March 1997 the Decision Network of the NCI voted to sponsor additional clinical indications including adult and pediatric brain tumors, as well as cancers involving the lung, head & neck, pancreas and prostrate. Two phase I trials of Gd-Tex for the treatment of primary brain tumors commenced in August 1998 under a CRADA with the NCI [237538], [295592], [348919]. Pharmacyclics is collaborating with the NCI under a CRADA in phase I trials in primary brain tumors and pancreatic tumors [323929], [323952], [346596]. Analysts expected a filing to occur by the end of 1999 or early 2000, with sales in 2001 [303186].
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PMID:Gd-Tex Pharmacyclics Inc. 1124 9

In a study to evaluate celastroloids as potential anticancer agents, demethylzeylasterone (5), a 6-oxophenolic triterpenoid from Kokoona zeylanica, was found to be an inhibitor of the enzyme topoisomerase IIalpha (IC(50) = 17.6 microM). Studies of the relationship of this inhibitor to both DNA and the enzyme resulted in 5 being classified as a "catalytic inhibitor" of topoisomerase II. Demethylzeylasterone selectively inhibits the growth of the breast cancer cell line MCF-7 (IC(50) = 12.5 microM) without inhibiting the growth of non-small cell lung cancer (NCI-H460) and CNS glioma (SF-268) cell lines. This is the first report of topoisomerase II inhibitory activity in a celastroloid.
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PMID:Catalytic inhibition of topoisomerase IIalpha by demethylzeylasterone, a 6-oxophenolic triterpenoid from Kokoona zeylanica. 1167 53

Researchers at the University of California at San Diego (UCSD) are developing alanosine as a potential treatment for cancer [227466], [408222]. The compound was originally under development in collaboration with Triangle, which initiated its development in 1996 [227466], but later discontinued development of the compound [406677]. As of May 2001, UCSD's ongoing clinical trials of alanosine included phase II trials for non-small cell lung cancer (NSCLC) and phase I trials for acute lymphoid leukemia (ALL), while a phase II trial for glioma at UCSD had been suspended [408222]. Alanosine is an amino acid analog originally derived from Streptomyces alanosinicus. It interferes with the de novo synthesis of adenosine in both malignant and normal cells. In cancer cells that lack methyladenosine phosphorylase (MTAP, required in the salvage pathway), alanosine should deprive such cells (but not normal cells) of de novo synthesized adenosine [277968]. In early 1997, patients were being recruited for a phase II pilot efficacy trial of alanosine as a treatment for glioma and NSCLC, since a significant number of these tumor types lack MTAP and, it was hoped, would therefore be sensitive to alanosine [239280], [248260]. Phase I and II trials were completed in the 1980s by the NCI before they were discontinued because alanosine caused toxicity typically associated with chemotherapy, and did not produce significant response rates in common tumors such as breast or colon cancers. Researchers at UCSD found that some types of cancer lack MTAP, which was responsible for alanosine's previous clinical failure [227466]; phase II trials were being carried out at the university in 1997 [269338]. Triangle obtained an option for a worldwide license from the Regents of the University of California that expired in September 1998 (but had an option to extend the period for a further one year) [277968].
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PMID:Alanosine (UCSD). 1176 67

A novel cyclopentenedione, asterredione (1), two new terrecyclic acid A derivatives, (+)-5(6)-dihydro-6-methoxyterrecyclic acid A (2) and (+)-5(6)-dihydro-6-hydroxyterrecyclic acid A (3), and five known compounds, (+)-terrecyclic acid A (4), (-)-quadrone (5), betulinan A (6), asterriquinone D (7), and asterriquinone C-1 (8), were isolated from Aspergillus terreus occurring in the rhizosphere of Opuntia versicolor, using bioassay-guided fractionation. Acid-catalyzed reaction of 2 under mild conditions afforded 4, whereas under harsh conditions 2 yielded 5 and (-)-isoquadrone (9). Catalytic hydrogenation and methylation of 4 afforded 5(6)-dihydro-terrecyclic acid A (10) and (+)-terrecyclic acid A methyl ester (11), respectively. The structures of 1-11 were elucidated by spectroscopic methods. All compounds were evaluated for cytotoxicity in a panel of three sentinel cancer cell lines, NCI-H460 (non-small cell lung cancer), MCF-7 (breast cancer), and SF-268 (CNS glioma), and were found to be moderately active. Cell cycle analysis of 2, 4, and 5 using the NCI-H460 cell line indicated that 4 is capable of disrupting the cell cycle through an apparent arrest to progression at the G(1) and G(2)/M phases in this p53 competent cell line. A pathway for the biosynthetic origin of asterredione (1) from asterriquinone D (7) is proposed.
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PMID:Cytotoxic constituents of Aspergillus terreus from the rhizosphere of Opuntia versicolor of the Sonoran Desert. 1469 98


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