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

Chemotherapeutic drug delivery can be enhanced by administering drugs into the internal carotid or vertebral artery circulation after osmotic opening of the blood-brain barrier (BBB). As evidence of the clinical implications of this technique, radiographic documentation of central nervous system (CNS) tumor regression was observed in three patients concurrent with the development of new tumor nodule(s) in portions of the brain distant from the region of osmotic blood-brain barrier opening. These three patients, one with metastatic carcinoma of the breast, one with glioblastoma, and one with primary CNS lymphoma, highlight the importance of drug delivery to CNS malignancies.
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PMID:Osmotic blood-brain barrier modification and combination chemotherapy: concurrent tumor regression in areas of barrier opening and progression in brain regions distant to barrier opening. 609 Sep 73

The sensitivity of polymerase chain reaction (PCR)-based methods for the detection of DNA offers opportunities for tumor diagnosis from the small amounts of tumor-derived DNA released into body fluids. Tumor-derived DNA can be distinguished from DNA derived from non-neoplastic cells by the presence of tumor specific genomic alterations, such as mutations in the p53 gene. This case report describes the use of allele-specific PCR (A-PCR) to detect a C-->T transition in p53 codon 273 in DNA extracted from the cerebrospinal fluid (CSF) of a patient whose glioblastoma contained the same mutation. The results of this study were confirmed by a second independent A-PCR reaction that detected the corresponding G-->A transition on the opposite strand. The specificity of the A-PCR protocol was demonstrated by negative controls, including pooled human placental DNA and the patient's non-tumor DNA, and by the use of A-PCR primers to detect all four possible bases at the site of the mutation. The methodology used in this study is suitable for use as a diagnostic clinical test. Because about half of all human tumors contain p53 mutations, PCR examination of CSF for the presence of mutant p53 sequences may be useful in the diagnosis of recurrent or metastatic tumors. Patients with known carcinoma of the breast or lung might be particularly benefited by this test.
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PMID:PCR-detection of tumor-derived p53 DNA in cerebrospinal fluid. 772 35

EGFRvIII is a mutant epidermal growth factor receptor found in glioblastoma, and in carcinoma of the breast, ovary, and lung. The mutant receptor has a deletion in its extracellular domain that results in the formation of a new, tumor-specific extracellular sequence. Mice were immunized with a synthetic peptide corresponding to this sequence and purified EGFRvIII. A single chain antibody variable domain (scFv) phage display library of 8 x 10(6) members was made from the spleen of one immunized mouse. A scFv specific for EGFRvIII was isolated from this library by panning with successively decreasing amounts of synthetic peptide. This was used to make an immunotoxin by fusing the scFv DNA sequence to sequences coding for domains II and III of Pseudomonas exotoxin A. Purified immunotoxin had a Kd of 22 nM for peptide and a Kd of 11 nM for cell-surface EGFRvIII. The immunotoxin was very cytotoxic to cells expressing EGFRvIII, with an IC50 of 1 ng/ml (16 pM) on mouse fibroblasts transfected with EGFRvIII and an IC50 of 7-10 ng/ml (110-160 pM) on transfected glioblastoma cells. There was no cytotoxic activity at 1000 ng/ml on the untransfected parent glioblastoma cell line. The immunotoxin was completely stable upon incubation at 37 degrees C for 24 h in human serum. The combination of good affinity, cytotoxicity and stability make this immunotoxin a candidate for further preclinical evaluation.
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PMID:Recombinant immunotoxins specific for a mutant epidermal growth factor receptor: targeting with a single chain antibody variable domain isolated by phage display. 896 38

DR-nm23 cDNA was cloned recently by differential screening of a cDNA library derived from chronic myelogenous leukemia-blast crisis primary cells. It is highly homologous to the putative metastasis suppressor nm23-H1 gene and the closely related nm23-H2 gene. When overexpressed in the myeloid precursor 32Dcl3 cell line, it inhibited granulocyte colony-stimulating factor-stimulated granulocytic differentiation and induced apoptosis. We have now found that the expression of DR-nm23 is not restricted to hematopoietic cells but is also detected in an array of solid tumor cell lines, including carcinoma of the breast, colon, and prostate, as well as the glioblastoma cell line T98G. We have also isolated both the gene and its 5'-flanking region and found that DR-nm23 localizes on chromosome 16q13. The gene consists of six exons and five introns. When fused in-frame to the nucleotide sequence for the green fluorescent protein and transfected in SAOS-2 cells, it generates a protein of the predicted size that localizes to the cytoplasm. The 5'-flanking region of DR-nm23 does not contain a canonical TATA box or a CAAT box, but it is G+C rich and contains two binding sites for the developmentally regulated transcription factor activator protein 2 (AP-2). Transient expression assays of DR-nm23 promoter-chloramphenicol acetyltransferase constructs demonstrated that the segment from nucleotides -1028 to +123 has the highest activity in hematopoietic K562 cells and in TK-ts13 hamster fibroblasts. Moreover, AP-2 induced a 3-fold transactivation of the DR-nm23 5'-flanking segment from nucleotides -1676 to +123 and interacted specifically with oligomers containing putative AP-2 binding sites (-936 to -909, and -548 to -519) as indicated by electrophoretic mobility shift assay. Furthermore, nuclear run-on assays from high and low DR-nm23-expressing cells (K562 and CCRF-CEM, respectively) revealed similar transcription rates. Therefore, the regulation of the DR-nm23 gene expression might involve other mechanisms occurring at posttranscriptional and/or translational levels.
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PMID:Gene structure, promoter activity, and chromosomal location of the DR-nm23 gene, a related member of the nm23 gene family. 906 90

EGFRvIII, a mutant form of epidermal growth factor receptor is highly expressed in glioblastoma, carcinoma of the breast, ovary, and lung but not in normal cells. This tumor specific antigen has emerged as a promising candidate for antibody based therapy of several cancers. The aim of the present study was isolation and characterization of a human single chain antibody against EGFRvIII as a promising target for cancer therapy. For this, a synthetic peptide corresponding to EGFRvIII protein was used for screening the naive human scFv phage library. Selection was performed using a novel screening strategy for enrichment of rare specific clones. After five rounds of screening, six positive scFv clones against EGFRvIII were selected using monoclonal phage ELISA, among them, a clone with an amber mutation in VH CDR2 coding sequence showed higher reactivity. The mutation was corrected through site directed mutagenesis and then scFv fragment was expressed after subcloning into the bacterial expression vector. Expression in BL21 pLysS resulted in a highly soluble scFv appeared in soluble fraction of E. coli lysate. Bioinformatic in silico analysis between scFv and EGFRvIII sequences confirmed specific binding of desired scFv to EGFRvIII in CDR regions. The specific reactivity of the purified scFv with native EGFRvIII was confirmed by cell based ELISA and western blot. In conclusion, human anti- EGFRvIII scFv isolated from a scFv phage library displayed high reactivity with EGFRvIII. The scFv isolated in this study can be the groundwork for developing more effective diagnostic and therapeutic agents against EGFRvIII expressing cancers.
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PMID:Isolation and characterization of a novel human scFv inhibiting EGFR vIII expressing cancers. 2798 65

Purpose: EGFRvIII as the most common mutant variant of the epidermal growth factor receptor is resulting from deletion of exons 2-7 in the coding sequence and junction of exons 1 and 8 through a novel glycine residue. EGFRvIII is highly expressed in glioblastoma, carcinoma of the breast, ovary, and lung but not in normal cells. The aim of the present study was identification of a novel single chain antibody against EGFRvIII as a promising target for cancer therapy. Methods: In this study, a synthetic peptide corresponding to EGFRvIII protein was used for screening a naive human scFv phage library. A novel five-round selection strategy was used for enrichment of rare specific clones. Results: After five rounds of screening, six positive scFv clones against EGFRvIII were selected using monoclonal phage ELISA, among them, only three clones had expected size in PCR reaction. The specific interaction of two of the scFv clones with EGFRvIII was confirmed by indirect ELISA. One phage clone with higher affinity in scFv ELISA was purified for further analysis. The purity of the produced scFv antibody was confirmed using SDS-PAGE and Western blotting analyses. Conclusion: In the present study, a human anti- EGFRvIII scFv with high affinity was first identified from a scFv phage library. This study can be the groundwork for developing more effective diagnostic and therapeutic agents against EGFRvIII expressing cancers.
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PMID:Development of a Novel Human Single Chain Antibody Against EGFRVIII Antigen by Phage Display Technology. 2810 63