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)

The term "Turcot's syndrome" has been used to describe approximatively 55 patients with an association of colonic polyposis and primary neuroepithelial tumors of the central nervous system. The p53 tumor suppressor gene is a possible candidate underlying the syndrome because (a) mutations in the p53 gene are ubiquitous in human cancer, including colon carcinoma and gliomas, and (b) somatic or germ line mutations of the p53 tumor suppressor gene cause the Li-Fraumeni syndrome, which is characterized by the association of breast and soft tissue tumors. We determined the DNA sequence of the conserved regions of the p53 gene (exons 5 to 9) in the tumor tissues and lymphocytes of two patients with glioma-polyposis and found that mutations did occur as independent tumor-specific alterations but did not involve the germ line of these patients, suggesting that p53 may play a role in progression but not initiation of the disease.
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PMID:Turcot's syndrome of glioma and polyposis occurs in the absence of germ line mutations of exons 5 to 9 of the p53 gene. 843 70

Genetically engineered tumor cells secreting immunostimulatory molecules could facilitate the obtention of a vaccination against tumor antigens. To test this approach, we transfected genes encoding for rat and mouse IL-2 into PROb cells. These cells originate from a dimethylhydrazine induced colon carcinoma of BD IX rats. We observed an inhibition of the in vivo tumor growth directly proportional to the IL-2 secretion. An immunohistochemical analysis revealed that the tumors were infiltrated by leucocytes expressing the IL-2 receptor, suggesting their activation within the tumor. A strong delay of tumor growth was observed in rats challenged with PROb cells after a previous rejection of IL-2 secreting cells. Yet two rats out of six were completely protected. This protection is specific since rejection of PROb-IL-2 does not confer protection towards the syngeneic glioma A15A5. In addition, we could show by depletion experiments that NK/LAK, CD8, and CD4 lymphocytes were involved in the rejection of cells secreting large amounts of IL-2. Macrophages appear to be involved in the rejection process too, but also in the induction of an immune memory. Vaccination experiments using irradiated PROb IL-2 cells were performed. Only a partial protection towards a challenge with parental PROb cells could be obtained, also depending on the amount of secreted IL-2: the best protection being obtained after vaccination with cells synthesizing a small amount of IL-2. However, this protection was not superior to that obtained by coinjection of irradiated PROb cells and BCG.
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PMID:[Vaccination with genetically modified IL-2 secreting cells in a rat model of colonic carcinoma]. 869 24

A small series of 2,2'-diselenobis(1H-indoles) was synthesized as redox-modified congeners of our earlier reported 2,2'-dithiobis(1H-indole) series. Utilizing chemistry similar to that developed earlier for the disulfur series, compounds were made from 2-halogeno-3-indolecarboxylic acid precursors bearing various polar functionality at the C-3 position and small alkyl substituents at the N-1 position of the indole nucleus. Additional compounds were derived from (R)- or (S)-tryptophan via a novel application of diselenium dichloride as an electrophilic source of diselenium, and a much improved process to a 2,2'-dithiobis(1H-indole) congener was developed utilizing disulfur dichloride as a source of disulfur. Against isolated epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), and v-src tyrosine kinases, compounds in this series displayed broad inhibitory activity with IC50 = 0.9 to > 100 microM vs EGFr, 3.4 to > 50 microM vs PDGFr, and 0.4-6.7 microM vs v-src. In general, compounds derived from tryptophan displayed the greatest potency against EGFr and those from 2-halogeno-3-indolecarboxylic acids greater potency against PDGFr and v-src. Enzyme kinetics studies showed that both classes of compounds display primarily noncompetitive inhibition with respect to either ATP or peptide substrate. The sulfhydryl reducing agent dithiothreitol (DTT) caused a general decrease in inhibition of the EGFr and v-src tyrosine kinases by both the diselenium and disulfur series with the reversal of enzyme inhibition occurring less readily within the diselenium series. In whole cell studies, compounds of this class were growth inhibitory against Swiss 3T3 mouse fibroblasts with IC50 values from 0.5 to 19.5 microM, and the observed SAR was different from that of the 2,2'-dithiobis(1H-indoles). A comparative study in the same cell line on the effects of the 2,2'-diselenobis(1H-indole) derived from (R)-tryptophan vs its disulfur congener on growth factor mediated tyrosine phosphorylation showed that this compound significantly inhibited EGFr and PDGFr (in response to its ligand) autophosphorylation with complete suppression at 25 and 5 microM, respectively. Tyrosine phosphorylation of an 85 kDa protein typically phosphorylated in response to bFGF was also exquisitely sensitive to this compound, and it displayed inhibitory effects on DNA, RNA, and protein synthesis at submicromolar concentrations. The disulfur congener exhibited a qualitatively similar pattern; however, its potency was 10-fold less. This same diselenium/disulfur pair was evaluated in vivo against the B16 melanoma, colon carcinoma 26, and M5076 sarcoma murine tumors, and the A431 epidermoid, and C6 glioma human tumor xenografts. At maximum tolerated doses (1.8 and 5.0 mg/kg/injection, respectively), neither the diselenium nor disulfur congener was effective against the C6 glioma when administered intraperitoneally on a d1-9 schedule. Studies were also carried out against the A431 epidermoid xenograft to evaluate the same pair of compounds via continuous subcutaneous infusion from Alzet miniosmotic pumps. The maximum dose that could be administered daily was limited by compound solubility. Neither compound produced an antitumor effect in a 7-day continuous infusion study. In the 27-day study, the disulfur compound was inactive whereas the diselenium compound produced a 10.8-day growth delay without appreciable treatment related weight loss. The in vitro and in vivo findings offer a mechanistic rationale as to why the 2,2'-diselenobis(1H-indoles) are more potent inhibitors than their disulfur congeners.
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PMID:Tyrosine kinase inhibitors. 6. Structure-activity relationships among N- and 3-substituted 2,2'-diselenobis(1H-indoles) for inhibition of protein tyrosine kinases and comparative in vitro and in vivo studies against selected sulfur congeners. 904 31

Cyclopentenyl cytosine (CPEC) exerts an antiproliferative effect against a wide variety of human and murine tumor lines, including a panel of human gliosarcoma and astrocytoma lines. This effect is produced primarily by the 5'-triphosphate metabolite CPEC-TP, an inhibitor of cytidine-5'-triphosphate (CTP) synthase (EC 6.3.4.2). Because previous studies with human glioma cell lines utilized cells in long-term tissue culture, we have undertaken to determine whether the activity of CPEC in such model systems is also demonstrable in freshly excised human glioblastoma cells. Glioma cells obtained at surgery and in log phase growth were exposed to the drug at levels ranging from 0.01 to 1 microM for 24 h, and CPEC-TP and CTP levels were determined by HPLC. Dose-dependent accumulation of CPEC-TP was accompanied by a concomitant decrease in CTP pools, with 50% depletion of the latter being achieved at a CPEC level of ca. 0.1 microM. Human glioma cell proliferation was inhibited 50% by 24-h exposure to 0.07 microM CPEC. Postexposure decay of CPEC-TP was slow, with a half-time of 30 h. DNA cytometry showed a dose-dependent shift in cell cycle distribution, with an accumulation of cells in S-phase. The pharmacological effects of CPEC on freshly excised glioblastoma cells are quantitatively similar to those seen in a range of established tissue culture lines, including human glioma, colon carcinoma, and MOLT-4 lymphoblasts, supporting the recommendation that the drug may be advantageous for the treatment of human glioblastoma.
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PMID:Antiproliferative effects of cyclopentenyl cytosine (NSC 375575) in human glioblastoma cells. 922 Apr 96

The objective of this study was to develop chemical strategies to improve the uptake and accumulation of melphalan (L-Mel and D-Mel), a cytotoxic agent, into cancer cells. Dipeptides synthesized from L- (or D-) Mel and L-glutamic acid (L-Glu) or L-valine (L-Val) and their methyl or ethyl esters (all compounds were trifluoroacetic acid salts) were evaluated for cytotoxicity and cellular uptake using Caco-2 cells, a human colon carcinoma cell line, and RT-2 cells, a rat brain glioma cell line. Treatment of Caco-2 cells with L-Mel or D-Mel (0.5 mg/ml equivalent of melphalan) for 48 h resulted in approximately 50% cell survival. Treatment of the Caco-2 cells with dipeptide derivatives of L-Mel (or D-Mel) (11c-d, 12c-d and 13) caused similar cytotoxicity effects (approximately 50-70% of cell survival). When the cytotoxicities of the esters of L-Mel, D-Mel and their dipeptide derivatives (11a-b, 12a-b and 14) in Caco-2 cells were determined, less than 10% cell survival was observed. Similar results were observed in RT-2 cells. When the cellular uptake properties of these compounds were determined in Caco-2 cell monolayers, L-Glu-L-Mel (12c), L-Glu-D-Mel (12d), and L-Mel-L-Glu (11c) generated slightly lower intracellular levels of L-Mel or D-Mel than when the cell monolayer was treated with the amino acids (L-Mel or D-Mel). In Caco-2 cells treated with 11c, 12c or 12d, low levels of the dipeptides were also detected. Caco-2 cell monolayers treated with D-Mel-L-Glu (11d) or D-Mel-L-Val (13) showed very low levels of the amino acids (L-Mel or D-Mel), but generally higher levels of the dipeptides. In contrast to the amino acids (L-Mel, D-Mel) or the dipeptide derivatives (11c-d, 12c-d and 13), the ester derivatives of the amino acids [L-Mel(OEt), D-Mel(OEt)] or the dipeptides (11a-b, 12a-b and 14) produced 5-20 times higher intracellular concentrations of potentially cytotoxic metabolites (e.g., L-Mel, D-Mel, Mel-containing dipeptides or Mel-containing dipeptide monoesters). L-Mel(OEt), D-Mel(OEt), L-Glu(OEt)-L-Mel(OEt) (12a), L-Glu(OEt)-D-Mel(OEt) (12b), and L-Mel-L-Glu(OEt)2 (11a) accumulated mainly as either L-Mel or D-Mel, and the percentages of L-Mel or D-Mel were 99%, 99%, 90%, 75% and 98% of the total intracellular concentration of potentially cytotoxic agents, respectively. D-Mel-L-Glu(OEt)2 (11b) accumulated as its monoester (> 95%) and D-Mel-L-Val(OMe) (14) accumulated as its dipeptide metabolite (> 98%). Inclusion of Gly-Pro, carnosine, L-Phe or L-Glu did not inhibit uptake of the dipeptide derivatives of L-Mel (or D-Mel) or their esters. These results suggest that the cellular uptake of the dipeptide derivatives of melphalan and their esters is probably via passive diffusion rather than being facilitated by an amino acid transporter or a di/tripeptide transporter. The higher intracellular levels of cytotoxic agents generated from the ester derivatives of the amino acids and the dipeptides are probably due to their higher lipophilicity and the overall neutral charge of the esters and subsequent intracellular formation of the more polar amino acids (L- or D-Mel) and/or Mel-containing dipeptides. Finally, these studies suggest that dipeptides of D-Mel [11b, 11d, 13] have inherent cytotoxicity properties.
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PMID:Derivatives of melphalan designed to enhance drug accumulation in cancer cells. 923 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

Dexamethasone (DEX)-mediated inhibition of drug-induced, but not CD95 ligand-induced, apoptosis in malignant glioma cells correlates with wild-type p53 status. Here, we examined mechanisms underlying DEX-mediated protection from apoptosis. DEX did not induce p53 expression in two p53 wild-type cell lines (U87MG, LN-229) and did not alter drug-induced p53 accumulation. Forced expression of temperature-sensitive p53val135 in mutant conformation failed to prevent accumulation of endogenous wild-type p53 but acted in a transdominant negative manner to inhibit p53-mediated, camptothecin-induced p21WAF1/CIP1 expression. p53val135-transfected cells retained responsiveness to DEX at restrictive temperature, suggesting that p53 activity is not required for cytoprotection. Forced expression of wild-type p53val135 abrogated the protective effect of DEX, suggesting redundant cytoprotective effects of DEX and p53. Indeed, DEX induced moderate accumulation of p21WAF1/CIP1 in U87MG, LN-229 and p53 mutant LN-18 cells, but not in p53 mutant LN-308 or T98G cells. LN-18 is also the p53 mutant cell line with the best cytoprotective response to DEX. p21WAF1/CIP1 accumulation occurred in the absence of changes in p21WAF1/CIP1 mRNA expression. Wild-type p53 was not required for this DEX effect since DEX induced p21WAF1/CIP1 accumulation in p53val135-transfected LN-229 cells, too. DEX failed to induce p21WAF1/CIP1 expression or cytoprotection in untransformed rat astrocytes. The same lack of modulation of p21WAF1/CIP1 expression and drug toxicity was observed in p21(+/+), p21(+/-) and p21(-/-) human colon carcinoma cells. Paradoxically, while only p21(+/+) and p21(+/-) mouse embryonic fibroblasts showed enhance p21WAF1/CIP1 levels after exposure to DEX, only p21(-/-) fibroblasts were protected from drug toxicity by DEX. The present study links DEX-mediated protection from cancer chemotherapy to a p53-independent pathway of regulating p21WAF1/CIP1 expression in glioma cells but this effect appears to cell type-specific.
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PMID:Dexamethasone-mediated protection from drug cytotoxicity: association with p21WAF1/CIP1 protein accumulation? 979 34

Alteration of the tumor suppressor gene p53 is the most frequent genetic feature of human cancer and leads to over-expression and loss of function of the p53 protein in affected cells. Patients with many types of cancer, including breast, lung, and colon carcinoma, were shown to develop auto-immune response against the overexpressed protein and to produce autoantibodies directed to immunodominant epitopes common for both wild type and mutants. The presence of p53 autoantibodies (p53-aAb) seems to be, at least in patients with breast and bronchial tumors, related to an unfavorable prognosis. The present study aimed to investigate the presence of p53-aAb in patients with malignant glioma. Sera from 70 consecutive patients with gliomas graded WHO G III and IV were collected and assayed together with sera from 30 controls. A new photometric sandwich-ELISA was used for semiquantitative analysis of p53-aAb titers. p53 gene and its protein product were examined in formalin-fixed and fresh-frozen tumor tissues using immunohistochemistry, PCR-single-strand conformational polymorphism, and sequencing. Sixty percent of the glioma cases showed immunohistochemically positive cells, thus indicating intracellular accumulation of p53. Sequencing of the hot-spot exons 5-8 revealed mutations in 39% of the tumor cases. In contrast to results in other types of malignant tumors, where up to 40% of patients have high serum titers of p53-aAb, no such antibodies were found in patients with malignant cerebral glioma despite the presence of mutated or alterated p53 protein in the primary tumors. None of the non-cancer control patients had detectable titers of p53-aAb, although sera from five of six lung cancer patients had medium to high titers. The presented data suggest that glial tumors are unusual in the absence of serum antibodies to p53. It is hypothesized that impaired function of most immunocompetent cells invading brain tumors could be the cause for the absence of an autoimmune response.
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PMID:Absence of p53 autoantibodies in sera from glioma patients. 981 45

The activity of temozolomide, which has shown clinical activity against malignant glioma, has been assessed in vitro against short-term cultures derived from these tumors using an intermediate duration microtitration assay with MTT reduction as the end-point This assay has previously been shown to correlate closely with a monolayer clonogenic assay. Sensitivity was assessed in 15 short-term cultures (passage levels 3-9) derived from WHO grade III and IV astrocytomas. These cultures had a median ID50 value of 258 microM for temozolomide and 16.13 microM for CCNU. Maximum serum concentrations of temozolomide are of the order of 75 microM but only three of 15 (20%) cultures had ID50s below this value. Fourteen of 15 (93%) cultures displayed cross-resistance between temozolomide and CCNU, although one line which was extremely resistant to CCNU retained sensitivity to temozolomide. Comparative studies of published clonogenic survival curves indicate that the short-term glioma cell lines used in this study have similar sensitivities to established glioma cell lines, whilst colon carcinoma cell lines and bladder carcinoma are often more resistant to these drugs. Cell lines from testicular teratoma cell lines may show exquisite sensitivity to temozolomide and this level of sensitivity is seen only occasionally in short-term cultures derived from malignant glioma.
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PMID:Sensitivity of short-term cultures derived from human malignant glioma to the anti-cancer drug temozolomide. 1021 48

Turcot's syndrome is characterized clinically by the occurrence of primary brain tumor and colorectal tumor and has in previous reports been shown to be associated with germline mutations in the genes APC, hMLH1, and hPMS2. Here we describe three patients with Turcot's syndrome, each having colorectal adenocarcinoma and malignant glioma. All the colorectal and brain tumors from these patients showed replication errors in most of the microsatellite loci investigated. Search for underlying germline mutations in the nucleotide mismatch repair genes revealed three different hMSH2 mutations. All colorectal tumors showed a frameshift in the A(10) tract in the coding sequence of the transforming growth factor beta type II receptor (TGFBRII) gene, but no such change was detected in any of the brain tumors. Frameshift mutation in the BAX gene was found in one colon carcinoma and mutations in insulin-like growth factor type II receptor (IGFIIR) gene in one glioma. Our data have broadened the possible mutation spectrum of patients with Turcot's syndrome. The difference in the mutation spectrum of TGFBRII, BAX, and IGFIIR between brain and colorectal tumors in these individuals suggests that the mutator phenotype may target different pathogenic pathways in the oncogenic process of the two organs.
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PMID:Germline hMSH2 and differential somatic mutations in patients with Turcot's syndrome. 1033 89


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