المؤلفون: Piao, H. L., Kuan, C. T., Chandramohan, V., Keir, S. T., Pegram, C. N., Bao, X. H., Månsson, Jan-Eric, 1946, Pastan, I. H., Bigner, D. D.

المصدر: Mabs. 5(5):748-762

مصطلحات موضوعية: Clinical Medicine, Klinisk medicin, ganglioside, recombinant immunotoxin, single-chain variable fragment, glioblastoma, affinity, SINGLE-CHAIN IMMUNOTOXIN, IN-VITRO, MONOCLONAL-ANTIBODIES, TUMORS, BRAIN, EXPRESSION, GROWTH, GD3, MENINGITIS, XENOGRAFTS

الوصف: About 60 percent of glioblastomas highly express the gangliosides 3-isoLM1 and 3,6-isoLD1 on the cell surface, providing ideal targets for brain tumor immunotherapy. A novel recombinant immunotoxin, DmAb14m-(scFv)-PE38KDEL (DmAb14m-IT), specific for the gangliosides 3-isoLM1 and 3,6-isoLD1, was constructed with improved affinity and increased cytotoxicity for immunotherapeutic targeting of glioblastoma. We isolated an scFv parental clone from a previously established murine hybridoma, DmAb14, that is specific to both 3-isoLM1 and 3,6-isoLD1. We then performed in vitro affinity maturation by CDR hotspot random mutagenesis. The binding affinity and specificity of affinity-matured DmAb14m-IT were measured by surface-plasmon resonance, flow cytometry, and immunohistochemical analysis. In vitro cytotoxicity of DmAb14m-IT was measured by protein synthesis inhibition and cell death assays in human cell lines expressing gangliosides 3-isoLM1 and 3,6-isoLD1 (D54MG and D336MG) and xenograft-derived cells (D2224MG). As a result, the K-D of DmAb14m-IT for gangliosides 3-isoLM1 and 3,6-isoLD1 was 2.6 x 10(-9)M. Also, DmAb14m-IT showed a significantly higher internalization rate in cells expressing 3-isoLM1 and 3,6-isoLD1. The DmAb14m-IT IC50 was 80 ng/mL (1194 pM) on the D54MG cell line, 5 ng/ml (75 pM) on the D336MG cell line, and 0.5 ng/ml (7.5 pM) on the D2224MG xenograft-derived cells. There was no cytotoxicity on ganglioside-negative HEK293 cells. Immunohistochemical analysis confirmed the specific apparent affinity of DmAb14m-IT with 3-isoLM1 and 3,6-isoLD1. In conclusion, DmAb14m-IT showed specific binding affinity, a significantly high internalization rate, and selective cytotoxicity on glioma cell lines and xenograft-derived cells expressing 3-isoLM1 and 3,6-isoLD1, thereby displaying robust therapeutic potential for testing the antitumor efficacy of DmAb14m-IT at the preclinical level and eventually in the clinical setting.

الوصول الحر: https://gup.ub.gu.se/publication/192088Test

المؤلفون: López, G. Y., Grant, G. A., Fuchs, H. E., Leithe, L. G., Gururangan, S., Bigner, D. D., Yan, H., McLendon, R. E., He, Y.

المصدر: Neuropathology & Applied Neurobiology; Apr2014, Vol. 40 Issue 2, p217-220, 4p

مصطلحات موضوعية: MYELOID leukemia, HISTOPATHOLOGY, LYMPHOCYTIC leukemia, MEDULLOBLASTOMA, HEADACHE, VOMITING in children, NAUSEA, PATIENTS

مستخلص: The article focuses on the study regarding the histopathological characteristics of three cases of myeloid/lymphoid or mixed lineage leukaemia (MLL) family genes MLL2 and MLL3 gene mutations. The first patient is a five-year old boy experiencing profound frontal headache associated with nausea and vomiting while the second patient is experiencing decreased appetite and headache. The study shows that MLL2/3 mutations add one more genetic variable for medulloblastoma subclassification.

المؤلفون: Reardon, D A, Herndon, J E, Peters, K B, Desjardins, A, Coan, A, Lou, E, Sumrall, A L, Turner, S, Lipp, E S, Sathornsumetee, S, Rich, J N, Sampson, J H, Friedman, A H, Boulton, S T, Bigner, D D, Friedman, H S, Vredenburgh, J J

المصدر: British Journal of Cancer; 10/23/2012, Vol. 107 Issue 9, p1481-1487, 7p, 1 Diagram, 4 Charts, 1 Graph

مصطلحات موضوعية: BEVACIZUMAB, DISEASE relapse, GLIOBLASTOMA multiforme, HEALTH outcome assessment, CLINICAL trials, CONFIDENCE intervals, PATIENTS

مستخلص: Background:Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries.Methods:We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome.Results:The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04).Conclusion:The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial. [ABSTRACT FROM AUTHOR]

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المؤلفون: Wheeler, S. E., Suzuki, S., Thomas, S. M., Sen, M., Leeman-Neill, R. J., Chiosea, S. I., Kuan, C-T., Bigner, D. D., Gooding, W. E., Lai, S. Y., Grandis, J. R.

المصدر: Oncogene; 9/16/2010, Vol. 29 Issue 37, p5135-5145, 11p, 5 Black and White Photographs, 1 Graph

مصطلحات موضوعية: EPIDERMAL growth factor, SQUAMOUS cell carcinoma, TUMOR growth, MONOCLONAL antibodies, CETUXIMAB, METASTASIS, CELL migration, CANCER cell proliferation, THERAPEUTICS

مستخلص: Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) where aberrant signaling downstream of this receptor contributes to tumor growth. EGFR variant III (EGFRvIII) is the most commonly altered form of EGFR and contains a truncated ligand-binding domain. We previously reported that EGFRvIII is expressed in up to 40% of HNSCC tumors where it is associated with increased proliferation, tumor growth and chemoresistance to antitumor drugs including the EGFR-targeting monoclonal antibody cetuximab. Cetuximab was FDA-approved in 2006 for HNSCC but has not been shown to prevent invasion or metastasis. This study was undertaken to evaluate the mechanisms of EGFRvIII-mediated cell motility and invasion in HNSCC. We found that EGFRvIII induced HNSCC cell migration and invasion in conjunction with increased signal transducer and activator of transcription 3 (STAT3) activation, which was not abrogated by cetuximab treatment. Further investigation showed that EGF-induced expression of the STAT3 target gene HIF1-α, was abolished by cetuximab in HNSCC cells expressing wild-type EGFR under hypoxic conditions, but not in EGFRvIII-expressing HNSCC cells. These results suggest that EGFRvIII mediates HNSCC cell migration and invasion by increased STAT3 activation and induction of HIF1-α, which contribute to cetuximab resistance in EGFRvIII-expressing HNSCC tumors. [ABSTRACT FROM AUTHOR]

: Copyright of Oncogene is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Reardon, D. A., Desjardins, A., Vredenburgh, J. J., Gururangan, S., Sampson, J. H., Sathornsumetee, S., McLendon, R. E., Herndon, J. E., Marcello, J. E., Norfleet, J., Friedman, A. H., Bigner, D. D., Friedman, H. S., Herndon, J E 2nd

المصدر: British Journal of Cancer; 12/15/2009, Vol. 101 Issue 12, p1986-1994, 9p, 1 Black and White Photograph, 3 Charts, 1 Graph

مصطلحات موضوعية: BEVACIZUMAB, ETOPOSIDE, GLIOMAS, NEOVASCULARIZATION, VASCULAR endothelial growth factors, DRUG therapy, ANTINEOPLASTIC agents, VASCULAR endothelial growth factor antagonists, BRAIN tumors, CANCER relapse, CLINICAL trials, COMPARATIVE studies, RESEARCH methodology, MEDICAL cooperation, MONOCLONAL antibodies, ORAL drug administration, RESEARCH, RESEARCH funding, EVALUATION research, TREATMENT effectiveness

مستخلص: Background: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial.Methods: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome.Results: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism.Conclusion: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430). [ABSTRACT FROM AUTHOR]

: Copyright of British Journal of Cancer is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Shi, Q., Bao, S., Song, L., Wu, Q., Bigner, D. D., Hjelmeland, A. B., Rich, J. N.

المصدر: Oncogene; 6/14/2007, Vol. 26 Issue 28, p4084-4094, 11p

مصطلحات موضوعية: GLIOMAS, NERVOUS system tumors, CANCER invasiveness, ONCOGENES, RNA, CYSTEINE proteinases

مستخلص: Secreted protein acidic and rich in cysteine (SPARC) is an extracellular glycoprotein expressed in several solid cancers, including malignant gliomas, upon adoption of metastatic or invasive behaviors. SPARC expression in glioma cells promotes invasion and survival under stress, the latter process dependent on SPARC activation of AKT. Here we demonstrate that downregulation of SPARC expression with short interfering RNA (siRNA) in glioma cells decreased tumor cell survival and invasion. SPARC siRNA reduced the activating phosphorylation of AKT and two cytoplasmic kinases, focal adhesion kinase (FAK) and integrin-linked kinase (ILK). We determined the contributions of FAK and ILK to SPARC effects using SPARC protein and cell lines engineered to overexpress SPARC. SPARC activated FAK and ILK in glioma cells previously characterized as responsive to SPARC. Downregulation of either FAK or ILK expression inhibited SPARC-mediated AKT phosphorylation, and targeting both FAK and ILK attenuated AKT activation more potently than targeting either FAK or ILK alone. Decreased SPARC-mediated AKT activation correlated with a reduction in SPARC-dependent invasion and survival upon the downregulation of FAK and/or ILK expression. These data further demonstrate the role of SPARC in glioma tumor progression through the activation of intracellular kinases that may provide novel therapeutic targets for advanced cancers.Oncogene (2007) 26, 4084–4094; doi:10.1038/sj.onc.1210181; published online 8 January 2007 [ABSTRACT FROM AUTHOR]

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المؤلفون: Cavazos, Christina M., Keir, Stephaen T., Yoshinari, Tomoko, Bigner, Darell D., Friedman, Henry S., Cavazos, C M, Keir, S T, Yoshinari, T, Bigner, D D, Friedman, H S

المصدر: Cancer Chemotherapy & Pharmacology; Sep2001, Vol. 48 Issue 3, p250-254, 5p

مصطلحات موضوعية: ASTROCYTOMAS, RODENTS, LABORATORY animals, INTRAPERITONEAL injections, BRAIN tumors, CLINICAL medicine

مستخلص: Purpose: The in vivo antitumor activity of a novel topoisomerase I inhibitor, J-107088, was tested in athymic nude mice bearing subcutaneous or intracranial pediatric and adult malignant CNS tumor-derived xenografts.Methods: J-107088 was administered to animals on days 1-5 and 8-12 via intraperitoneal injection at a dose of 54 mg/kg (162 mg/m2) per day in 10% dimethyl sulfoxide in 0.9% saline. The xenografts evaluated were derived from a childhood glioblastoma multiforme (D-456 MG), a childhood medulloblastoma (D-341 MED), an adult anaplastic astrocytoma (D-54 MG), an adult glioblastoma multiforme (D-245 MG), and a procarbazine-resistant subline of D-245 MG [D-245 MG (PR)].Results: J-107088 produced regressions and significant growth inhibition in all five of the xenograft lines growing subcutaneously. Growth delays ranged from 7.6 days with D-245 MG to 62.1 days with D-456 MG (P < 0.001). J-107088 also produced an 83% increase in survival in mice bearing intracranial D-456 MG (P < 0.001).Conclusion: These results indicate that J-107088 may be active in the treatment of childhood and adult malignant brain tumors and provide the rationale for initiation of clinical trials with this agent. [ABSTRACT FROM AUTHOR]

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المؤلفون: Keir, Stephen T., Hausheer, Frederick, Lawless, Amy A., Bigner, Darell D., Friedman, Henry S., Keir, S T, Hausheer, F, Lawless, A A, Bigner, D D, Friedman, H S

المصدر: Cancer Chemotherapy & Pharmacology; Jul2001, Vol. 48 Issue 1, p83-87, 5p

مصطلحات موضوعية: CANCER treatment, TRANSPLANTATION of organs, tissues, etc., NERVOUS system, ANTINEOPLASTIC agents, NEUROSCIENCES, ANTIVIRAL agents

مستخلص: Purpose: Camptothecins have emerged as an important new class of antitumor drugs. Camptothecin derivatives such as CPT-11 and topotecan are commercially available and approved for the treatment of colorectal (CPT-11) and ovarian and small-cell lung cancer (topotecan). This study was designed to test the efficacy of karenitecin, a novel highly lipophilic camptothecin derivative, against a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies growing in athymic nude mice.Methods: Xenografts evaluated were derived from childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D-341 MED, D-487 MED), and ependymomas (D-528 EP, D-612 EP), as well as sublines with demonstrated resistance to procarbazine (D-245 MG (PR)) and busulfan (D-456 (BR)). In replicate experiments, karenitecin was given at 1.0 mg/kg per dose via intraperitoneal injection for a period of 10 consecutive days, which is the dosage lethal to 10% of treated animals.Results: Karenitecin produced statistically significant (P < or = 0.001) growth delays in all subcutaneous xenografts tested, including the sublines resistant to procarbazine and busulfan. Growth delays ranged from 12.1 days in D-456 MG (BR) to 90+ days in D-212 MG and D-341 MED. Karenitecin also produced statistically significant (P < or = 0.001) increases in survival of animals bearing D-341 MED intracranial xenografts (69% increase) and those bearing D-456 MG xenografts (62% increase).Conclusion: These preclinical studies confirm that karenitecin is active against human central nervous system xenografts and should undergo clinical evaluation in patients with malignant central nervous system tumors. [ABSTRACT FROM AUTHOR]

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المؤلفون: Kuan, C-T, Wikstrand, C. J., Bigner, D. D.

المصدر: Endocrine-Related Cancer; Jun2001, Vol. 8 Issue 2, p83-96, 14p

المؤلفون: Keir, Stephen T., Dolan, M. Eileen, Pegg, Anthony E., Lawless, Amy, Moschel, Robert C., Bigner, Darell D., Friedman, Henry S., Keir, S T, Dolan, M E, Pegg, A E, Lawless, A, Moschel, R C, Bigner, D D, Friedman, H S

المصدر: Cancer Chemotherapy & Pharmacology; Jun2000, Vol. 45 Issue 6, p437-440, 4p

مصطلحات موضوعية: CANCER treatment, TUMORS, CANCER patients, CANCER, REGRESSION analysis, TRANSPLANTATION of organs, tissues, etc.

مستخلص: Purpose: To evaluate the role of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus O6-benzylguanine (O6-BG) in the treatment of both Mer+ and Mer- tumors.Methods: The effect of pretreatment with O6-BG on the activity of BCNU against Mer- human central nervous tumor xenografts D-54 MG and D-245 MG was evaluated in athymic nude mice.Results: BCNU (1.0 LD10; dose lethal to 10% of treated animals) produced growth delays of 8.9 days and 7.5 days and tumor regressions in six of ten and one of nine animals against D-54 MG, which was derived from a human malignant glioma xenograft. Dose reduction of BCNU to 0.38 LD10 eliminated antitumor activity. The combination of BCNU (0.38 LD10) plus O6-BG produced growth delays of 8.8 days and 7.9 days, with tumor regressions in four of ten and two of nine animals, respectively. BCNU (1.0 LD10) produced a growth delay of 49.8 days and ten of ten tumor regressions against D-245 MG, which was derived from a glioblastoma multiforme. BCNU (0.38 LD10) produced a growth delay of 19.4 days, with nine of ten tumor regressions. The combination of BCNU (0.38 LD10) plus O6-BG produced a growth delay of 65.7 days and seven of eight tumor regressions.Conclusion: These results suggest that the combination of BCNU plus O6-BG may be a rational intervention for both Mer+ as well as Mer- tumors. [ABSTRACT FROM AUTHOR]

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