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)

Immunotoxins are hybrid molecules which combine the exquisite selectivity of monoclonal antibodies with the potent toxicity of protein toxins. An immunotoxin was constructed by linking a murine monoclonal antibody against the human transferrin receptor (TR) to the plant toxin, ricin. The cytotoxic activity of the anti-TR-ricin immunotoxin was tested in vitro and demonstrated highly potent and cell type-specific killing of cells derived from human glioblastoma, medulloblastoma, and leukemia. The anti-TR-ricin immunotoxin killed more than 50% of "target" cells at a concentration of 5.6 X 10(-13) M after an 18-hour incubation with the ionophore, monensin. This potency exceeds that of any other anti-TR immunotoxin reported in the literature. When the activity of the anti-TR-ricin immunotoxin against "target" tumor-derived cells was compared with the immunotoxin's activity against "non-target" cells, it could be predicted that a selective toxicity of anti-TR-ricin immunotoxin between tumor cells and normal brain was more than 150- to 1380-fold. Solid-phase indirect radioimmunoassay techniques were used to demonstrate significantly higher levels of TR in the glioblastoma- and medulloblastoma-derived cell lines, as well as in surgical tissue samples of medulloblastoma and glioblastoma, as compared to normal brain. Immunotoxins targeted to the TR may possess sufficient specificity to be of therapeutic importance, particularly to treat neoplastic disease of the central nervous system involving compartments (such as intrathecal, intraventricular, or cystic) where delivery of immunotoxins to tumor would not require transvascular transport.
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PMID:Potent and specific killing of human malignant brain tumor cells by an anti-transferrin receptor antibody-ricin immunotoxin. 303 71

Anatomists are exposed to a wide range of solvents, stains, and preservatives used to prepare biologic specimens. One fixative, formaldehyde, has recently been shown to cause nasal cancer in laboratory rodents. A retrospective cohort study was conducted to assess whether anatomists have an increased risk of mortality from cancer, particularly from cancers of the respiratory tract. The cohort included 2,317 men who joined the American Association of Anatomists between 1888 and 1969 and who were living in the United States when they joined this association. Standardized mortality ratios were 0.3 for lung cancer [95% confidence interval (CI) = 0.1-0.5], 1.5 for leukemia (95% CI = 0.7-2.7), and 2.7 for brain cancer (95% CI = 1.3-5.0) when mortality rates for U.S. white males, available for 1925-79, were used as the referent. When rates for male members of the American Psychiatric Association, available for 1900-69, were used as the referent, standardized mortality ratios were 0.5 for lung cancer (95% CI = 0.2-1.1) and 6.0 for brain cancer (95% CI = 2.3-15.6). Each of the 10 anatomists who died of brain cancer between 1925 and 1979 had a neuroglial cell tumor (either astrocytoma or glioblastoma). The increased risk for leukemia was limited to the myeloid cell type. An etiologic agent associated with these increased risks was not identified.
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PMID:Brain cancer and other causes of death in anatomists. 346 14

Antineoplaston AS2-1 is a mixture of two products of hydrolysis of Antineoplaston A10 and consists of sodium salts of phenylacetylglutamine and phenylacetic acid in the ratio of 1:4. Antineoplaston AS2-1 injections were administered to 20 patients diagnosed with 21 types of neoplastic diseases. The patients' diagnoses included: lung cancer, stage III, 4 cases; colorectal, stage IV, 3; breast, stage IV, 2; breast in remission, 1; glioblastoma, 3; head and neck, stage IV, 3; uterine cervix, stage IA, 1; chronic myelocytic leukaemia, 2; lymphocytic lymphoma, stage IV, 1; and leiomyosarcoma of the uterus, stage IVB, 1. Antineoplaston AS2-1 was administered every 6 h i.v. through subclavian vein catheter. The treatment was administered from 38 to 872 days. The highest dosage taken was 160 mg/kg/24 h. The treatment was associated with minimal side-effects, including slight nausea and vomiting in one patient, mild allergic reaction in the form of maculopapular rash in another patient and moderate elevation of blood pressure in an additional patient. One patient developed febrile reaction and three patients had mild electrolyte imbalance. Only one patient showed slight decrease of WBC. Desirable side-effects included improved healing of chronic atrophic ulceration. The response to the treatment included 6 complete remissions, 2 partial remissions, 7 cases of stabilization and 6 cases of increasing disease. Three patients are alive, well and free from cancer 5 years after the beginning of the study. The hypothetical mechanism of action of Antineoplaston AS2-1 as an anticancer agent is described.
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PMID:Toxicology studies on antineoplaston AS2-1 injections in cancer patients. 374 78

We studied two children who had rhabdomyosarcoma and glioblastoma and who were from a family with a hereditary cancer syndrome that was characterized by sarcoma, breast cancer, brain tumors, lung cancer, laryngeal carcinoma, leukemia, and adrenocortical carcinoma. The deleterious genotype has now been expressed through the fourth generation of this large kindred. The pedigree emphasizes the need for an extended history of several generations to arrive at a hereditary-syndrome diagnosis. A limited pedigree may result in nonappreciation of the genetic component. The pedigree illustrates that, in certain circumstances, the highly specific varieties of cancer may occur in children before it is expressed in the parent who carries the putative gene. Pediatricians, in evaluating the causes of childhood cancer, must be cognizant of cancer among adult relatives, since this recognition may aid in the diagnosis of those hereditary cancer syndromes that are characterized by cancer occurrence in children as well as adults.
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PMID:The sarcoma, breast cancer, lung cancer, and adrenocortical carcinoma syndrome revisited. Childhood cancer. 397 85

Forphenicinol (FPL) is a low molecular immunomodifier derived from forphenicine, a microbial product found by Umezawa and co-workers. We studied the antitumor effect of FPL, cyclophosphamide (CY), and the combination of the two on several syngeneic murine tumors. The tumors used were mammary carcinoma, L1210 leukemia, B16 melanoma, Lewis lung carcinoma, and glioblastoma. A single ip injection of CY on Day 1 followed by eight consecutive daily oral doses of FPL beginning 6 days after tumor inoculation showed strong cooperation in curing syngeneic mammary carcinoma inoculated intradermally in C3H/HeN mice, most mice being cured of the tumor by the combination therapy and subsequently having acquired strong specific immunity. Treatment with FPL alone (either pre- or post-treatment) also significantly inhibited the growth of the mammary tumor. FPL and CY also showed cooperation in inhibiting the growth of L1210 leukemia transplanted intradermally into CDF1 (BALB/c X DBA/2) mice and markedly prolonged the survival time but FPL treatment alone had no effect. The FPL-CY treatment also affected Lewis lung carcinoma and glioblastoma in syngeneic C57BL/6 mice and produced therapeutic synergism. FPL alone significantly inhibited the growth of B16 melanoma in C57BL/6 mice as well as the syngeneic mammary carcinoma in C3H/HeN mice. These findings suggest that oral administration of FPL in combination with chemotherapeutic agents can be used for treating cancer without causing toxicity, because of the synergistic efficacy of the combination.
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PMID:Effect of forphenicinol, a small molecular immunomodifier, in combination with cyclophosphamide on growth of and immunity to syngeneic murine tumors. 397 57

Secondary malignancies after marrow transplantation have been observed in 20 patients: 19 patients underwent marrow transplantation for the treatment of a hemopoietic malignancy and one for aplastic anemia. All but three were given total body irradiation at doses of 8.0-15.75 Gy as part of the conditioning regimen. Secondary malignancies were composed of three groups: (a) Six patients had recurrence of leukemia (three acute lymphoblastic, two acute myeloblastic, and one chronic myelocytic) in cells of donor origin 62-1074 days after grafting. (b) Eight patients developed lymphoproliferative disorders (four of immunoblastic sarcoma type, one lymphoblastic, one follicular center cell, and one Hodgkin's lymphoma and one acute lymphoblastic leukemia) 54-730 days after grafting. In four of seven patients with appropriate studies these tumors were of donor-cell origin and in three of four tested the cells contained Epstein-Barr virus genome or expressed viral antigens. (c) Six patients developed solid tumors (two glioblastoma multiforme, two adenocarcinomas, one squamous cell carcinoma, and one sarcoma) 347-1875 days after grafting. All but two patients (one with glioblastoma and one with squamous cell carcinoma) have died. These data suggest that patients undergoing marrow transplantation for a hemopoietic malignancy may be at risk of developing secondary malignancies. The etiology appears to be multifactorial, including irradiation, immunosuppression, Epstein-Barr virus infections, and other factors.
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PMID:Secondary malignancies after marrow transplantation. 638 5

Alpha and beta interferon were tested for antitumor activity and clinical toxicity in 15 children suffering from cancer. The drug was administered IV, IM, IT or intralesionally daily in the majority of cases in total doses of 18 X 10(6) to 9,634 X 10(5) IU. Major toxicities were a flulike syndrome, elevation of transaminase activity and leukopenia. A minor response (less than 50%) was observed in one patient with glioblastoma, treated by intrathecal administration, and an objective local response was noted in one rhabdomyosarcoma patient with multiple subcutaneous metastases, who was treated by intralesional administration. CNS leukemia in two patients improved without hematological response. Further trials are warranted.
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PMID:[Clinical experience with alpha and beta interferon in childhood cancer]. 659 60

The growth of a panel of 22 different human tumor, leukemia, and lymphoma cell lines was examined in a human tumor cloning assay in agar or methylcellulose and a tritiated thymidine uptake assay. The cultures were performed in the absence or presence of increasing concentrations (0.5-500 ng/ml) of nerve growth factor (NGF). The growth of 17 of the 22 cell lines was not significantly and reproducibly affected by NGF. There was minor (1.2-fold) but reproducible stimulation of clonal growth in one glioblastoma cell line (86-HG-39) by NGF, but in this cell line NGF induced no growth modulation in a tritiated thymidine uptake assay. However, clonal growth of another glioblastoma cell line (87-HG-31) and all three lung cancer cell lines tested (HTB 119, HTB 120, CCL 185) could be stimulated up to 3-fold by NGF with a dose-response relationship for the growth factor. Growth stimulation by NGF could be completely reversed by neutralizing anti-NGF antibody and by the tyrosine kinase inhibitor genistein. Evaluation of secondary plating efficiency revealed the stimulation of colony formation as representing self-renewal and not terminal differentiation. Reverse transcriptase-PCR experiments in the five responding cell lines showed expression of both low-affinity NGF receptor (glycoprotein 75) and c-trk transcripts on the mRNA level. Of the five responding cell lines, only 86-HG-39, the cell line with the lowest responsiveness, revealed low-affinity NGF receptor on the protein level; the other four cell lines with high responsiveness, including the three lung cancer cell lines, expressed no low-affinity NGF receptor as shown by fluorescence-activated cell sorter analysis and immunoprecipitation using the ME 20.4 antibody. Immunoprecipitation using anti-trk antibodies was negative in all five responding cell lines. However, binding studies with iodinated NGF showed only low-affinity binding on the 86-HG-39 cell line and only high-affinity binding on the high-responder cell lines CCL 185 and 87-HG-31. In summary, our data suggest that NGF can be operative in stimulation of clonal growth of malignant tumor cells. High-affinity but not low-affinity binding sites mediate signal transduction for clonal growth and signaling involves tyrosine kinase activity.
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PMID:Nerve growth factor stimulates clonal growth of human lung cancer cell lines and a human glioblastoma cell line expressing high-affinity nerve growth factor binding sites involving tyrosine kinase signaling. 753 48

Mutations in the receptor for the epidermal growth factor provide valuable insight into mechanisms of growth control. Oncogenic mutants of this receptor tyrosine kinase cause erythroid leukemia, fibrosarcoma, angiosarcoma, glioblastoma, and melanoma. Mutations in the avian protooncogene occur by retroviral mechanisms. Deletion of the ligand-binding domain results in erythroblastosis, while additional mutations in cytoplasmic structures broaden the disease potential to other cell types. A carboxyl-terminal structure of erbB oncogenes modulates growth responses in a complex, cell-specific manner; this tissue-specificity region appears to promote growth in erythroblasts and to produce trans-dominant inhibition in fibroblasts. Human glioblastoma multiforme frequently contains receptor mutations that are reminiscent of avian oncogenes. In hereditary melanoma of Xiphophorus, aberrant regulation of transcription by a recombinant promoter determines tissue-specific tumorigenesis. The diversity of oncogenic mutations raises important questions concerning the roles of several receptor structures. The extracellular domain inhibits the receptor when unoccupied by ligand, for example, through a mechanism that is unknown. The auto-phosphorylation sites are dispensable for transformation, so their function in neoplastic growth is unclear. The carboxyl-terminal region promotes or blocks transformation in different tissues, suggesting complex regulation by unknown cellular factors. These issues are critical to understanding of the mechanisms of receptor activation and tissue tropism for this family of oncogenes.
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PMID:Tissue-specific transformation by oncogenic mutants of epidermal growth factor receptor. 771 Nov 15

Thirteen tumor-derived cell lines of human and nonhuman origin and from various tissues were examined for the presence and density of sigma-1 and sigma-2 receptors. Sigma-1 receptors of a crude membrane fraction were labeled using [3H](+)-pentazocine, and sigma-2 receptors were labeled with [3H]1,3-di-o-tolylguanidine ([3H]DTG); in the presence or absence of dextrallorphan. [3H](+)-Pentazocine-binding sites were heterogeneous. In rodent cell lines (e.g., C6 glioma, N1E-115 neuroblastoma, and NG108-15 neuroblastoma x glioma hybrid), human T47D breast ductal carcinoma, human NCI-H727 lung carcinoid, and human A375 melanoma, [3H](+)-pentazocine bound to high- and low-affinity sites with Kd1 = 0.67-7.0 nM, Bmax1 = 25.5-108 fmol/mg protein, Kd2 = 127-600 nM, and Bmax2 = 942-5431 fmol/mg protein. However, [3H](+)-pentazocine bound to a single site in other cell lines. In human U-138MG glioblastoma, SK-N-SH neuroblastoma, and LNCaP.FGC prostate, Kd = 28-61 nM and Bmax = 975-1196 fmol/mg protein, whereas in ThP-1 leukemia Kd = 146 nM and Bmax = 1411 fmol/mg protein. The sigma-1-like nature of [3H](+)-pentazocine-binding sites was confirmed by competition studies which revealed high affinity for haloperidol and enantioselectivity for (+)-pentazocine over (-)-pentazocine. Interestingly, human MCF-7 breast adenocarcinoma showed little or no specific binding of [3H](+)-pentazocine, suggesting the absence of sigma-1 receptors in this cell line. All cell lines examined expressed a high density of sigma-2 receptors with Kd values for [3H]DTG ranging from 20 to 101 nM and Bmax values of 491 to 7324 fmol/mg protein. Competition studies indicated possible heterogeneity of sigma-2 receptors. While sites labeled by [3H]DTG in all cell lines tested exhibited affinity for haloperidol and preference for (-)-pentazocine over the (+)-enantiomer, human cell lines generally showed 4- to 7-fold lower affinity for haloperidol and approximately 10-fold lower affinity for (-)-pentazocine compared with the rodent cell lines. The high density of sigma-1 and sigma 2-binding sites in these cell lines suggests important cellular functions in cancer, as well as potential diagnostic utility for tumor-imaging agents which target sigma sites. These cell lines may be useful as model systems in which to study the functions of sigma sites in normal tissues, as well as their possible role in tumor biology.
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PMID:Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines. 781 73


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