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)

Suramin is a polyanionic compound currently used under evaluation for antineoplastic activity. One of the main problems encountered during clinical trials was an adverse neurotoxic effect, probably due to a direct cytotoxic effect on neural cells. Suramin is also known to trigger differentiation of human colon cancer cells, yet a chronic treatment induces a lysosomal storage disorder. The aim of this study was to evaluate suramin analogs for their effect: (i) on the lysosomal system of the human colon cancer cell clone HT29-D4; and (ii) on C6 glioma cell growth and morphology. One of the derivatives tested, NF036, induced terminal differentiation of HT29-D4 cells without any impairment of the lysosomal system. Furthermore, in contrast to suramin, NF036 did not alter C6 cell growth and morphology. We conclude that there is a relationship between the ability of a suramin derivative to induce a lysosomal storage disorder in human colon cancer cells and its neurotoxic effect. A double screening of suramin analogs on HT29-D4 and C6 cells allowed us to identify a new candidate antineoplastic drug: NF036.
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PMID:Double screening of suramin derivatives on human colon cancer cells and on neural cells provides new therapeutic agents with reduced toxicity. 175 11

The present study describes a new microscopic perifusion technique for detecting momentary alterations in cell volume and shape. The method has been applied for evaluating early signs of cytotoxicity following chemotherapeutic treatments. The effects of estramustine phosphate (EMP) have been evaluated. EMP is a complex between oestradiol-17 beta and the alkylating agent nor-nitrogen mustard and has recently demonstrated a marked cytotoxicity against malignant glioma cells. The results showed a concentration-dependent increase in cell size and a concomitant decrease in shape factor following EMP-treatment of glioma cells. These changes correlated with cytotoxicity evaluated as cell proliferation and cell membrane alterations shown by 86Rb fluxes and ultrastructural visible membrane damage. The colon cancer line HT-29 displayed no reactions at all following EMP treatment. It is suggested that acute alterations in cell morphology and shape display a strong correlation to the cytotoxicity of EMP encountered by traditional cell culture systems. The findings are discussed with respect to cell membrane disturbances caused by EMP and its potential role as an early test of cytotoxicity.
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PMID:Early morphological detection of estramustine cytotoxicity measured as alteration in cell size and shape by a new technique of microperifusion. 183 1

An in-gel renaturation method allows the visualization, quantitation, and initial characterization of reiterated DNA restriction fragments (RRFs) without prior possession of their probes. Using this method we analyzed EcoRI restricted DNAs from ten human tumors, paired normal tissues from these patients, ten unpaired tumors, and 26 noncancer patients. Frequent qualitative and quantitative differences in the relative radioactive intensities of all or specific RRFs in the DNA from different individuals have been observed. However, we also report frequent two- to ten-fold alterations in the relative radioactive intensities of several specific RRFs in tumor-control analyses of DNA from the same individual. A 0.65-kb alphoid-like DNA RRF was decreased in six tumors and increased in none. Moreover, a new 1.55-kb RRF was observed in two colon cancer DNAs. Several new RRFs, suggestive of gene amplification, were detected in a neuroblastoma, two of which were also seen in a glioma. These data support frequent qualitative and quantitative alterations of specific reiterated DNA sequences in human cancer when compared with paired controls. This approach will allow the future characterization of specific DNA sequences whose patterns of altered reiteration suggest a role in the emergence of specific malignancies.
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PMID:Frequent alterations of specific reiterated DNA sequence abundances in human cancer. 288 12

Radiolabeled monoclonal antibodies have been used for radioimmunotherapy studies with human tumor spheroids and murine and human tumor xenografts in experimental animals. This paper reviews the work that has been performed in these models with different types of cancer, and highlights those papers that have presented dosimetry estimates and attempts to correlate the findings. Radioimmunotherapy studies in multicell spheroids, as a model for micrometastases, have been performed in human neuroblastoma, colon cancer, and melanoma cell lines using 131I-, 125I-, 186Re-, and 212Bi-labeled antibodies. The uniform geometry of the spheroid has allowed radiation dose estimates to be made. Up to three logs of cell kill have been achieved with 131I- and 186Re-specific antibody with minimal toxicity from labeled nonspecific antibody, but 212Bi-antibody had little effect because of its short half-life as shown by Langmuir. It appears that the two most important factors for therapeutic efficacy in this model are good penetration of the radiolabeled antibody and an adequate radionuclide half-life to allow penetration of the immunoconjugate prior to significant radionuclide decay. Radioimmunotherapy studies in animals bearing transplants of colon cancer, leukemia, lymphoma, hepatoma, renal cell carcinoma, neuroblastoma, glioma, mammary carcinoma, small cell lung carcinoma, cervical carcinoma, ovarian carcinoma, and bladder cancer have been performed with 131I, 90Y, 186Re, 153Sm, and 177Lu beta emitting, and 212Bi alpha emitting radionuclides conjugated to monoclonal antibodies. A few studies compared different radionuclides in the same model system. The approaches that have been used in these studies to estimate tumor dosimetry include the MIRD approach, thermoluminescent dosimetry, autoradiography, and comparison to external irradiation. The majority of investigators have estimated the dose to tumor and normal organs using MIRD-based calculations (time-activity curve and equilibrium dose constant method). The range of tumor doses has been between 17 and 11 171 mGy/MBq of administered radioactivity. The effectiveness of radiolabeled monoclonal antibody therapy depends on a number of factors relating to the antibody such as specificity, affinity, and immunoreactivity. The density, location, and heterogeneity of expression of tumor-associated antigen within tumors will affect the localization and therapeutic efficacy of radiolabeled antibodies, as will physiological factors such as the tumor vascularity, blood flow, and permeability. These factors are discussed and examples are presented.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Experimental radioimmunotherapy. 849 64

Experimental studies in rodents using chemical carcinogens and viral oncogenes show a high susceptibility to malignant transformation. Analytical epidemiological studies have revealed an increased risk of human brain tumor development in association with certain occupations but, with the exception of therapeutic X-irradiation, attempts to identify a specific exposure or causative environmental agent have so far been unsuccessful. Thus, endogenous mutations and genetic factors may play a more important role. This view is supported by recent studies on the nature of DNA alterations in human brain tumors. More than 70% of p53 mutations observed during glioma progression are G:C-->A:T transitions, predominantly at CpG sites, i.e. likely to be produced by deamination of 5-mcC or related spontaneous mechanisms. No specific mutations or mutational hot spots were found which could be suggestive of environmental carcinogens operative in the etiology of human brain tumors. A similar pattern of mutation is found in colon cancer, sarcomas, and lymphomas, i.e. neoplasms with largely unknown etiology. This is similarly true for p53 germline mutations which again show a strong preference for G:C-->A:T transitions at CpG sites.
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PMID:Genetic and environmental factors in the etiology of human brain tumors. 859 15

The imaging characteristics of monoclonal antibody SZ39 against glioma were evaluated in glioma-bearing nude mice. Monoclonal antibody SZ39 is a murine IgG2a that reacts with a glycoprotein epitope (molecular weight 180,000), a human glioma-associated membrane antigen. Monoclonal antibody SZ39 was labeled with 131I using a modified chloramine T method. Each glioma-bearing nude mouse was given 50 microCi/40 micrograms of the experimental agent, 131I-labeled monoclonal antibody, or 50 microCi/46 micrograms of a control agent, 131I-labeled monoclonal antibody C50, an antibody against colon cancer. Single-photon emission computed tomography (SPECT) was performed every 24 hours in the first week after administration. Glioma-bearing nude mice were killed in groups of 3 at 24 hours and daily up to 72 hours. The ratio of radioactivity uptake in glioma to normal organs was calculated. After administration of the labeled SZ39, glioma was visualized with SPECT on days 1 to 7, particularly at 72 hours. There was no accumulation of radioactivity in glioma with the labeled C50 antibody. All glioma-organ ratios increased with time. At 72 hours, the ratio of glioma to brain was 22.46 and of the other organs was 2.64 on average. SZ39 had a relatively low endocytosis rate and was favorable for 131I labeling. These characteristics were helpful to reduce free 131I in the blood and reduce the uptake by other organs. The results suggest that 131I-labeled SZ39 selectively accumulates in glioma, representing a potential strategy for SPECT imaging of these lesions.
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PMID:Preclinical evaluation of SPECT imaging with 131I-labeled monoclonal antibody SZ39 in nude mice bearing human glioma xenografts. 863 89

Conventional radiolabeled antibody targeting utilized in radioimmunotherapy has resulted in limited success clinically due in part to inadequate tumor localization resulting from low expression of human tumor-associated antigens on target cells. We hypothesized that one could improve upon these limitations by genetically inducing tumor cells to express high levels of a new membrane-associated receptor with high affinity for a radioligand. As a preliminary strategy, we induced a human glioma cell line (D54 MG) to express human carcinoembryonic antigen (CEA) in vitro. To accomplish this, we constructed a recombinant adenoviral vector encoding the CEA cDNA inserted downstream of a cytomegalovirus (CMV) promoter (AdCMVCEA). D54 MG cells were transfected with AdCMVCEA or an adenoviral vector encoding lacZ reporter gene as a control (AdCMVlacZ). LS174T human colon cancer cells, known to express CEA constitutively, served as positive controls. Immunofluorescence and immunohistochemistry assays employing unlabeled anti-CEA COL-1 monoclonal antibody demonstrated expression of CEA antigen on the cell surface of transduced D54 MG cells in culture. In addition, assays utilizing 125I-labeled COL-1 indicated high binding to transduced D54 MG cells expressing CEA (4.7 +/- 0.5 x 10(5) COL-1 molecules bound per cell) as compared with minimal binding to nontransduced D54 MG cells. LS174T cells demonstrated only 2.7 +/- 0.5 x 10(6) COL-1 molecules bound per cell. Thus, AdCMVCEA was able to induce levels of cell surface CEA in target cells at a higher level than CEA-overexpressing tumor cells (P < 0.01). The efficacy of transduction of recombinant AdCMVCEA by direct intratumoral injection into D54 MG xenografts was investigated by immunohistochemical analysis, immunofluorescence and by measuring 131I-labeled COL-1 uptake through external scintigraphic imaging and biodistribution studies. Expression of CEA in the tumor xenografts by, and radiolabeled antibody tumor targeting to, AdCMVCEA transduced D54 MG xenografts was comparable to that seen with LS174T xenografts. Results of these studies indicate the potential of adenovirus-mediated delivery of targets to improve radiopharmaceutical tumor localization.
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PMID:Enhancement of radiolabeled antibody binding and tumor localization through adenoviral transduction of the human carcinoembryonic antigen gene. 881 43

Folinic acid (leucovorin) is frequently used to augment and modulate the clinical activity of 5-fluorouracil (5-FU) in patients with advanced gastrointestinal (Gl) cancer. However, there are conflicting opinions concerning the optimal doses for these patients, and whether folinic acid modulates the clinical activity of 5-FU in patients with non-Gl cancer. To elucidate these questions, model experiments have been performed on human tumor cell lines in vitro to determine the modulatory activity of various concentrations of folinic acid on 5-FU mediated cytotoxicity using a clonogenic assay. Three cell lines of colon cancer and 3 of glioblastoma origin were exposed to 5-FU alone or with folinic acid for 24 hours. It was observed that relatively low concentrations of folinic acid enhanced the cytotoxicity of 5-FU against the colon cancer lines whereas higher concentrations were less effective. Folinic acid did not enhance the 5-FU mediated killing of the glioma cell lines at any concentration (0.01-100 micrograms/ml). On the contrary, folinic acid seemed to counteract the cytotoxic effect of 5-FU in a reasonably dose-dependent fashion. These results may suggest that the value of folinic acid in the treatment of non-Gl cancer with 5-FU should be evaluated within the framework of controlled clinical trials, and that high doses of folinic acid may not necessarily be more effective than low.
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PMID:Dual effects of folinic acid in 5-fluorouracil induced killing of human tumor cell lines in vitro. 891 76

Oxaliplatin is a new platinum analog of the DACH family. Recent preclinical data have confirmed its non overlapping spectrum of activity with cisplatin, including acquired and intrinsic platinum resistant cell lines (as KB-CP, A 2780, HT29, CaCo2 colon cancer). When combined with other cytotoxic agents (5FU, SN38, CDDP, carboplatin), oxaliplatin has additive and/or synergistic antitumoral effects on various in vitro and in vivo models (colon, breast, ovarian and epidermoid tumors). Phase II trials have confirmed a sensorial peripherical neuropathy as its limiting toxicity while neither ototoxicity nor renal toxicities and only limited myelotoxicity were noted. Available phase II studies have established its antitumoral activity as single agent in 5FU refractory colon carcinoma while preliminary results suggest efficacy in cisplatin resistant ovarian cancer, in non small cell lung cancer, non Hodgkin lymphoma. Antitumoral activity has been observed during phases 1 in melanoma, glioma, breast and oesophageal cancers. A high response rate (28-65%) with the triple association (FU/folinic acid/oxaliplatin) has been reported in advanced colon cancer treated in first and second line settings. The results of two randomized phase III studies (FU/folinic acid +/- oxaliplatin) are expected. The oxaliplatin/cisplatin combination as salvage regimen had produced significant antitumoral activity (response rate: 45%) in resistant/refractory ovarian cancer. Finally, recent experimental and clinical data have outlined the potential interest in the development of this new original platinum compound. New single agent phases II are expected in other tumor types as well as new oxaliplatin combinations are ongoing (phase I trials of oxaliplatin/CPT-11 and of oxaliplatin/carboplatin, phase II study of oxaliplatin-vinorelbine in lung cancer.
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PMID:[Oxaliplatin: the first DACH platinum in clinical practice]. 929 71

Although the prognosis of childhood cancers has dramatically improved over the last three decades, new active drugs are needed. Camptothecins represent a very attractive new class of anticancer drugs to develop in paediatric oncology. The preclinical and clinical development of two of these DNA-topoisomerase I inhibitors, i.e. topotecan and irinotecan, is ongoing in paediatric malignancies. Here we review the currently available results of this evaluation. Topotecan proved to be active against several paediatric tumour xenografts. In paediatric phase I studies exploring several administration schedules, myelosuppression was dose-limiting. The preliminary results of topotecan evaluation in phase II study showed antitumour activity in neuroblastoma (response rate: 15% at relapse and 37% in newly diagnosed patients with disseminated disease) and in metastatic rhabdomyosarcoma (40% in untreated patients). Topotecan-containing drug combinations are currently investigated. Irinotecan displayed a broad spectrum of activity in paediatric solid tumour xenografts, including rhabdo-myosarcoma, neuroblastoma, peripheral primitive neuroectodermal tumour, medulloblastoma, ependymoma, malignant glioma and juvenile colon cancer. For several of these histology types, tumour-free survivors have been observed among animals bearing an advanced-stage tumour at time of treatment. The clinical evaluation of irinotecan in children is ongoing. Irinotecan undergoes a complex in vivo biotransformation involving several enzyme systems, such as carboxylesterase, UDPGT and cytochrome P450, in children as well as in adults. Preclinical studies of both drugs have shown that their activity was schedule-dependent. The optimal schedule of administration is an issue that needs to be addressed in children. In conclusion, the preliminary results of the paediatric evaluation of camptothecin derivatives show very encouraging results in childhood malignancies. The potential place of camptothecins in the treatment of paediatric malignant tumours is discussed.
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PMID:Preclinical development of camptothecin derivatives and clinical trials in pediatric oncology. 961 66


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