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)

Experimental evidence indicating potentiation of the cytotoxic effect of drugs at high temperatures suggests that the utilization of drug-heat combinations for gliomas of the brain might be therapeutically useful. Hyperthermia may increase the cytotoxicity of a particular drug in areas of low drug concentration/time and in cell populations resistant to the drug. We report in vitro experiments with a BCNU resistant, U-373MG, and a BCNU sensitive, U-87MG, human derived glioma cell lines under hyperthermic conditions. Temperatures equal or above 42 degrees C potentiate BCNU cell kill in both lines. The thermo-sensitizer lidocaine increases thermal cell kill but only minimally with concentrations corresponding to therapeutic plasma lidocaine levels. Within our experimental conditions, the best strategy to overcome BCNU resistance involved a combination of heat, BCNU and cis-DDP. BCNU resistant cells have no cross resistance to cis-DDP and the combination of BCNU and cis-DDP is synergistic. At modest hyperthermic conditions (42 degrees C) 99.4% BCNU resistant cells are killed by a combination of BCNU and cis-DDP at drug concentrations identical to plasma concentrations after standard IV doses. Clinical protocols using heat and drug may need to incorporate two or more drugs for optimal effects.
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PMID:Hyperthermic potentiation of BCNU toxicity in BCNU-resistant human glioma cells. 191 44

Intratumoral heterogeneity was observed in two tumor lines (SbC11 and SbC12) derived from a single biopsy of a melanoma patient. Differences in drug sensitivity were observed in three cell lines of small cell lung carcinoma derived from the same patient, before (AE1), and after (AE2 and AE3) therapy with Adriamycin (ADM) and Cisplatinum (DDP). Moreover, heterogeneity in biological features and in drug sensitivity was observed in three continuous human glioma derived cell lines (LI, DF, and DP). The results show the importance of continuous cell lines for studying tumor heterogeneity and evaluating the effectiveness of antineoplastic agents.
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PMID:[The use of continuous cell cultures for the study of tumor heterogeneity and drug sensitivity]. 196 94

A cell line, 497-P(1), derived from the VM spontaneous murine astrocytoma has been used to develop an in vitro therapeutic model of human glioma. In this study we describe the preparation of MTS from this cell line. The in vitro chemosensitivity of 497-P(1) MTS has been examined and compared to the sensitivity of the monolayer culture. BCNU and CCNU both produced growth delay in MTS at doses below the ID50 of the monolayer culture. MTS, however, were considerably more resistant to vincristine and procarbazine when compared to the monolayer culture.
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PMID:The VM model of glioma: preparation of multicellular tumour spheroids (MTS) and their response to chemotherapy. 226 97

The nitrosourea-induced rat glioma clone RG2 was tested for its capacity to form multicellular tumor spheroids (MTS's). Resulting spheroids were investigated by light and electron microscopy with regard to their proliferation patterns and morphological features. Using microsurgical techniques and avoiding mechanical injury of the brain tissue, the authors successfully transplanted avascular MTS's under the dura of the cerebellum, above the vermis, in 43 adult syngeneic Fischer CD rats. The rate of tumor establishment was 93%, and the tumors that were solid and spheroid in shape grew exponentially. Neovascularization could be observed at 3 days after implantation, and invasion of the cerebellum occurred by 3 to 5 days. Neurological deterioration, including ataxia, impairment of walking, and apathy, could be observed after 10 days. The mean survival time was approximately 16 days. The subdural cerebellar tumors were studied by histological techniques, and two morphometric methods were applied to check the growth of implanted spheroids. All tumors were deeply stained with the Evans blue dye-albumin complex, demonstrating disturbance of the blood-brain barrier. The easy accessibility of the cerebellar vermis in rats, the microsurgical implantation of glioma spheroids under the dura avoiding nerve tissue disruption, and the high percentage of reproducible establishment of tumors favor this experimental brain-tumor model. This should be an excellent model for study of experimental therapies.
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PMID:RG2 glioma growth in rat cerebellum after subdural implantation. 242 62

Twenty-eight patients with high-grade cerebral gliomas (16 biopsy-proven and 12 diagnosed clinically and by computed tomography scan) were treated with altered fraction radiation and concomitant cisplatin (C-DDP). Twenty cases (Groups IA and IB) whose Karnofsky performance status (KPS) was 60% or less received hypofractionation and C-DDP. All these patients had received high-dose Decadron (Merck Sharp & Dohme, West Point, PA), and their conditions were not improving or progressively deteriorating. The first 11 patients (Group IA) received from 600 cGy twice weekly to 3600 cGy over 3 weeks combined with C-DDP IV at 40 mg/M2 every 2 weeks for two courses. The nine subsequent patients (Group IB) received from 600 cGy weekly to 3600 cGy over 5 to 6 weeks with C-DDP IV at 40 mg/M2 every 1 to 2 weeks for four courses. The target volume in all cases was confined to the tumor as defined on computed tomography (CT) scan with a 2 cm to 3 cm margin. The C-DDP at 40 mg/M2 was administered immediately (within 5 minutes after radiation). Eight cases (Group II) with a KPS of more than 60% were treated with hyperfractionation, i.e., from 200 cGy twice daily to 4800 cGy in just under 3 weeks. The C-DDP was administered every 2 weeks for a total of two courses, as for Group IA. In Group I, 15 of 20 (75%) patients experienced rapid improvement in their performance status, which usually becoming evident within 1 to 2 weeks from the initiation of treatment, and progressed over time. Four patients with a KPS of 10% improved their KPS to over 60%. This regimen was both well tolerated and logistically very convenient both for the patients and attending staff. Follow-up CT scans in three of 16 evaluable patients in the hypofractionated group showed complete tumor resolution. Median survival for Group IA was 7 months, for Group IB was 12 months, and overall was eight months. The Group II median survival was 9 months. This experience suggests that hypofractionated radiation in combination with C-DDP may offer rapid palliation with improvement in functional status in severely compromised patients with malignant glioma.
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PMID:Hypofractionated radiation therapy and concurrent cisplatin in malignant cerebral gliomas. Rapid palliation in low performance status patients. 247 66

Cisplatin (DDP) is a chemotherapeutic agent that has shown efficacy against primary CNS malignancies. Intra-arterial (IA) administration of DDP to patients with brain tumors should produce higher peak levels of drug than intravenous (IV) administration of an identical dose and reduce systemic toxicity. Twelve patients with malignant glioma were entered into the study. All had failed irradiation, 11 had failed IA BCNU. Each patient received IA DDP, 58-100 mg/m2, into the internal carotid artery at four to six week intervals. One of 12 patients had a partial response of 6 months. The remaining 11 patients had progressive disease or severe complications. Toxicity included seizures in four patients, weakness and/or aphasia in four patients, coma in two patients, and visual deterioration in two patients. IA DDP has very limited efficacy in patients with malignant gliomas after failure of nitrosoureas and is associated with an unacceptable level of toxicity. IA DDP may be more effective when used as initial chemotherapy of malignant gliomas.
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PMID:Intra-arterial cisplatin for the treatment of malignant gliomas. 254 32

DNA damaging agents such as nitrosoureas are widely used for the treatment of malignant gliomas. Therefore, quantitative measurement of DNA damages induced by antineoplastic drugs is useful to judge the efficacy of the drug and understand the pharmacological action of the drug. We have utilized in situ nick translation method to demonstrate "nicks" in DNA of glioma cells treated by various antineoplastic agents. Exponentially growing rat 9 L glioma cells (4 x 10(4] were seeded in the chamber slide. After fourty eight hours, the medium was changed to that containing various concentration of the drug (ACNU, cis-DDP, BLM, ADM and VP-16) and the cell was treated for 1 hour. Then, the cell was fixed for 10 minutes in methanol-acetic acid (v/v 3:1). Following fixation, the cell was incubated in the nick translation mixture containing E. coli DNA polymerase I, 3H-TTP, and 4 dNTP's (ATP, GTP, CTP, CTP and TTP) for 10 minutes at room temperature. The slide was dipped in the autoradiographic emulsion, exposed for 4 days at 4 degrees C, and then developed, the number of the silver grains over nuclei was counted under the microscope. For comparison of the effect of the drug to glioma cells, IC50 (inhibitory concentration of the drug for 50% cell kill) of each drug was determined by treating the cell for 48 hours at the various concentration of the drug. Small number of the silver grains was noted in cells with no treatment. Over IC50 as the concentration of the drug increased, the number of the nick increased in cells treated with bleomycin or adriamycin which are known to produce single strand breaks in DNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[In situ nick translation for detection of DNA damages in glioma cells]. 262 7

Rat C6 glioma cells were cultured for 3-4 days in MEM supplemented with bovine serum. After 10 min incubation of cells with 0.075, 1.0 or 7.5 micrograms ml-1 cis-DDP the basal cAMP levels (7.87 +/- 0.4 pmoles mg-1 protein) were not affected. In the presence of a phosphodiesterase inhibitor, IBMX, an increase of cAMP occurred; the later was more pronounced in cis-DDP treated cells than in the controls. This suggests that both adenylate cyclase and cAMP-phosphodiesterase were proportionally influenced at this period and that the stimulatory effect of cis-DDP on AC could be demonstrated only when increased activity of PDE had been blocked by IBMX. At later time intervals (10 h-40 h), a 5- to 17-fold elevation of cAMP levels was observed even in the absence of IBMX. Pretreatment of the cells with cis-DDP significantly potentiated cAMP accumulation in response to NE alone and to cis-DDP plus NE could be prevented to a large extent by propranolol; in cis-DDP treated cells the propranolol protection was more effective, both in the absence and the presence of IBMX. The pretreatment of cells with an alpha-blocker, Regitin, did not significantly influence cAMP accumulation. The results indicate that the cis-DDP stimulated cAMP response to NE is mediated via an interaction with beta-adrenergic receptors. The late increase in cAMP content may be a mediator of the morphological changes in these cells following exposure to cis-DDP.
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PMID:Cyclic AMP levels of C6 glioma cells treated with cis-dichlorodiammine platinum (cis-DDP). 303 19

The malignant glioma cell line U-87MG was used for 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), aziridinylbenzoquinone (AZQ), cis-diaminodichloroplatinum (II) (cis-DDP), and spirohydantoin mustard (SHM) treatments at 37 degrees and 42 degrees C. With the exception of SHM, all drugs killed a greater proportion of cells at the higher temperature, as assessed by the colony-formation assay. Drug-dose enhancement ratios were 1.6, 2.8, 2, and 1:1 for BCNU, AZQ, cis-DDP, and SHM, respectively. Because methods to heat discrete volumes of brain are now available, we conclude that hyperthermic increase of BCNU, AZQ, and cis-DDP cytotoxicity might have therapeutic application for malignant gliomas.
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PMID:Drug cytotoxicity at elevated temperature. In vitro study on the U-87MG glioma cell line. 368 26

The kinetics of formation and repair of total genomic DNA interstrand crosslinks (ISCs) induced by BCNU and cis-DDP were studied in cells of 6 human malignant gliomas and related with their degree of drug resistance. DNA ISCs were formed rapidly (peak 6-12 h) following a 2 h exposure to 50 microM BCNU or 25 uM cis-DDP, and on an equimolar basis higher levels of crosslinking were observed with cis-DDP than with BCNU. Repair of cis-DDP induced crosslinks was characteristically bi-phasic and the rate was significantly higher than that for BCNU induced crosslinks. Overall, a low crosslink index and a high crosslink repair rate correlated with cis-DDP and BCNU resistance. The data demonstrate, conclusively, the ability of human glioma cells to repair cis-DDP and, for the first time, BCNU induced DNA ISCs and that DNA crosslink repair is a significant contributing factor to the resistance of these tumors to the two agents.
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PMID:Formation and repair of 1,3-bis-(2-chloroethyl)-1-nitrosourea and cisplatin induced total genomic DNA interstrand crosslinks in human glioma cells. 776 97


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