epidermal-growth-factor and Lymphoma

Inhibition of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) pathways may result in synergistic antitumour activity. We designed a phase I study to evaluate the combination of vandetanib, an investigational agent with activity against EGF receptor and VEGF receptor 2, and bevacizumab, a monoclonal antibody against VEGF.. Patients with advanced solid tumours and lymphomas were enrolled. Objectives were to determine the safety and maximum tolerated dose of the combination, characterise pharmacokinetics, measure angiogenic marker changes in blood, and assess tumour blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Vandetanib was given orally once daily and bevacizumab intravenously once in every 3 weeks in 21-day cycles utilising a standard dose-escalation design.. Fifteen patients were enrolled, and a total of 94 cycles of therapy were administered. No protocol-defined dose-limiting toxicities were observed; due to toxicities associated with chronic dosing, hypertension, proteinuria, diarrhoea and anorexia, dose escalation was stopped at the second dose level. We observed one partial response and one minor response; 9 patients experienced stable disease. There were significant changes in plasma VEGF and placental-derived growth factor levels, and decreases in K(trans) and k(ep) were observed by DCE-MRI.. In this trial, we safely combined two targeted agents that cause dual blockade of the VEGF pathway, demonstrated preliminary evidence of clinical activity, and conducted correlative studies demonstrating anti-angiogenic effect. The recommended phase II dose was established as vandetanib 200 mg daily and bevacizumab 7.5 mg/kg every 3 weeks.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Biomarkers, Tumor; Contrast Media; Epidermal Growth Factor; Female; Humans; Lymphoma; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasms; Piperidines; Quinazolines; Signal Transduction; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

DLK1 and GTL2 are reciprocally imprinted genes on human chromosome 14q32. DLK1 encodes a transmembrane protein that is a paternally expressed gene. The maternally expressed GTL2 allele encodes a non-translated RNA. Many of features of DLK1/GTL2 are remarkably similar to those of the prototypical IGF2/H19 reciprocally imprinted gene pair. Imprinting status of IGF2 has been studied in many types of tumors, and loss of imprinting (LOI) leads to biallelic expression of IGF2 in most of these tumors. The imprinting status of DLK1 has seldom been investigated in clinical tumor samples. We examined whether DLK1 was imprinted in brain tumors and lymphomas by analyzing a single nucleotide polymorphism (SNP), rs1802710. Analysis of 47 brain tumors and 55 lymphomas found that 23 and 29 of them were heterozygous for rs1802710, respectively. Monoallelic expression of DLK1 was detected in the heterozygous samples. These data show that imprinting of DLK1 is maintained in brain tumors and lymphomas, even though the DLK1 gene is very analogous to the IGF2 gene in its DNA structure and regulation. Also, the high frequency of heterozygosity (about 50%) showed that the polymorphic site that we chose is a good genomic marker for imprinting studies of the DLK1 gene in additional tumor types.

Topics: Alleles; Brain Neoplasms; DNA, Neoplasm; Epidermal Growth Factor; Gene Expression Regulation, Neoplastic; Genomic Imprinting; Glycoproteins; Heterozygote; Humans; Loss of Heterozygosity; Lymphoma; Polymorphism, Single Nucleotide; Polymorphism, Single-Stranded Conformational

A novel leukemia cell growth-promoting activity has been identified in the culture supernatant from a human B cell leukemia cell line, BALL-1. The supernatant from unstimulated cultures of the BALL-1 cells significantly promoted the growth of 16 out of 24 leukemia/lymphoma cell lines of different lineages (T, B and non-lymphoid) in a minimal concentration of fetal bovine serum (FBS), and of 5 out of 12 cases of fresh leukemia cells in FBS-free medium. The growth-promoting activity in the BALL-1 supernatant has been further characterized using FPLC chromatography, molecular weight (MW) sieve filtration and dialysis. The MW of the factor was less than 10 kDa. The growth-promoting activity was heat and acid stable and resistant to trypsin treatment. The factor isolated from the BALL-1 supernatant was distinct from known polypeptide growth factors with MW below 10 kDa, such as epidermal growth factor, transforming growth factor alpha, insulin-like growth factor I (IGF-I), IGF-II and insulin, as determined by specific antibodies and by cell growth-promoting tests. The factor in the BALL-1 supernatant did not promote the proliferation of normal human fresh peripheral blood lymphocytes or mouse fibroblast cell line, BALB/c3T3. In addition to the BALL-1 supernatant, a similar growth-promoting activity was found in the culture supernatants from 13 of 17 leukemia/lymphoma cell lines tested. The activity in these culture supernatants promoted the growth of leukemia/lymphoma cell lines in autocrine and/or paracrine fashions. These observations suggest that the low MW cell growth-promoting activity found in the BALL-1 culture supernatant is mediated by a novel factor which may well be responsible for the clonal expansion of particular leukemic clones.

Topics: Cell Division; Cell Line; Culture Media; Epidermal Growth Factor; Growth Substances; Humans; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leukemia; Leukemia, B-Cell; Lymphoma; Recombinant Proteins; Tumor Cells, Cultured

Physiological activation of protein kinase C (PKC) is believed to occur by redistributing soluble enzyme to the phospholipid environment of membranes. Currently available in vitro methods of measuring PKC activation all involve prior extraction of membrane-associated enzyme and its reconstitution in an artificial phospholipid environment or modification (such as partial trypsinization) of the enzyme itself. Here we report a novel method which, for the first time, allows measurement of active PKC still in its native, membrane-associated state using a specific, physiological substrate. Thus, with this new method PKC activity can be measured while still in an environment that approximates the in vivo situation.

Topics: Animals; Bombesin; Calcium; Cell Membrane; Cytosol; Egtazic Acid; Enzyme Activation; Epidermal Growth Factor; Humans; Lymphoma; Mice; Molecular Weight; Phosphoproteins; Protein Kinase C; Rats; Substrate Specificity; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

A high false negative rate from endoscopic forceps biopsy is well-known in gastric carcinoma. The initial aim of the present study was to determine whether possible thickening of adjacent nontumorous mucosa by nonspecific or specific trophic factors could contribute to this observation; 167 gastrectomy specimens (77 carcinomas, 14 lymphomas, 76 gastric ulcers) were examined and mucosal thickness measured. Mean thickness of uninvolved mucosa near carcinoma (1.4 +/- 0.08 mm, mean +/- SEM) and near lymphoma (1.5 +/- 0.1 mm) was in each case significantly greater than mucosal thickness near ulcer (1.14 +/- 0.05 mm) or at a distance in the same specimen (P less than 0.01 for each comparison). A subset of specimens representing 20% of carcinomas, showed marked mucosal thickening (2.01 +/- 0.05 mm) above the control mean. Immunohistochemical evaluation for intratumoral epidermal growth factor content (EGF) correlated with mucosal thickness in all groups examined (R = 0.67). Immunostaining for EGF receptor showed similar patterns of expression to those of EGF. EGF and EGF receptor contents were also correlated with depth of invasion when possible. In conclusion, the mucosal thickening adjacent to gastric malignancy may well contribute to the insensitivity of endoscopic forceps biopsy. More importantly, the higher tumor EGF and EGF-receptor contents seen in these lesions may prove to be a useful marker of biologic behavior and predictor of prognosis in these tumors.

Topics: Biomarkers, Tumor; Carcinoma; Epidermal Growth Factor; ErbB Receptors; False Negative Reactions; Female; Gastrectomy; Gastric Mucosa; Humans; Lymphoma; Male; Stomach Neoplasms

Topics: Aged; Cell Division; Cells, Cultured; Child, Preschool; Dermatitis, Seborrheic; Epidermal Growth Factor; Female; Growth Substances; Humans; Keratosis; Lymphocytes; Lymphoma; Sezary Syndrome; Skin; Thymidine; Tritium

Mink cells nonproductively-infected with the weakly-transforming T-8 isolate of murine leukemia virus (MuLV) express a 110,000 mol wt polyprotein designated T-8 P110. By immunoprecipitation analysis, T-8 P110 is shown to contain AKR-MuLV amino terminal gag gene-specific components (p15, p12) but to lack p30, p10, gp70, and p15(E) antigenic determinants. These observations are further substantiated by tryptic peptide analysis indicating T-8 P110 to share approximately six lysine-containing tryptic peptides with AKR-MuLV Pr65gag, and none with AKr-MuLV Pr82env. Furthermore, of seven methionine-containing T-8 P110 tryptic peptides, at least four can be conclusively shown not to be present in either AKr-MuLV Pr180gag/pol or Pr82env. A clonal mink cell line nonproductively infected by T-8, and expressing high levels of P110, although not morphologically transformed, is shown to lack elevated levels of tyrosine-specific protein kinase activity and reduction of epidermal growth factor binding sites characteristic of cells transformed by many other RNA-transforming viruses. These findings argue either that the T-8 viral genome contains acquired cellular sequences encoding a portion of P110, or that T-8 P110 represents an inphase deletion of AKR-MuLV Pr180gag/pol with extensive posttranlational modification and that an as yet unidentified protein is responsible for T-8 associated transformation.

Topics: Animals; Cells, Cultured; Epidermal Growth Factor; Genes, Viral; Leukemia Virus, Murine; Lymphoma; Mink; Peptide Fragments; Protein Kinases; Retroviridae; Trypsin; Viral Proteins