Papers by Geir Olav Hjortland
The distribution of protoporphyrin IX (Pp IX) was investigated in a novel animal model followng a... more The distribution of protoporphyrin IX (Pp IX) was investigated in a novel animal model followng administration of 5-aminolevulinic acid (ALA) or its hexyl ester (h-ALA). Pre-cultured tumor spheroids prepared from cell lines or tumor biopsy fragments were injected into the brains of immunodeficient rats. Approximately 3 months after spheroid implantation, Rowett nude rats were injected intra-cranially with the maximum tolerable ALA or h-ALA dose. Animals were sacrificed 4 hours post-injection and their brains removed for fluorescence microscopy analysis. The primary finding of this study is that, in the tumor biopsy model, the tumor-to-normal brain PpIX fluorescence ratio is approximately 3 times higher following direct in situ h-ALA adminstration compared to ALA.
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Journal of Neurosurgery, 2004
The aim of this study was to target immunotoxin treatment to the high-molecular-weight melanoma-a... more The aim of this study was to target immunotoxin treatment to the high-molecular-weight melanoma-associated antigen (HMW-MAA) and thereby examine any changes in the survival of immunodeficient rats with human glioblastoma multiforme (GBM). To target treatment specifically to human glioma cells, Pseudomonas exotoxin A (PE) was conjugated to the 9.2.27 antibody, which recognizes the HMW-MAA. Treatment of the antigen-positive glioma cell line U87MG with the resulting 9.2.27-PE caused cytotoxicity with a median inhibitory concentration of 1 ng/ml. Intratumoral 9.2.27-PE treatment of intracranial U87MG tumors in nude rats prolonged the survival of these animals by 43% compared with controls. In additional studies on the use of this targeted treatment, the authors precultured freshly dissected glioblastoma multiforme (GBM) biopsy tissue for 1 to 2 weeks. Inoculation of this tissue into the rat brain resulted in diffuse infiltrative gliomas. The markers glial fibrillary acidic protein and S100 protein were found to be expressed in the original biopsy specimens, as well as in the glioma xenografts in nude rat brains. Intratumoral immunotoxin treatment of such established tumors with 9.2.27-PE was effective and prolonged survival time from 30% to as high as 90% in animals with tumors originating from four different GBM specimens. Targeted treatment of highly invasive GBMs proved effective, and these results emphasize the clinical relevance of this antigen as a target molecule for immunotoxin treatment of human GBMs.
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Clinical & Experimental Metastasis, 2003
A number of studies have emphasized the role of PAI-1 as an important regulator of tumor cell inv... more A number of studies have emphasized the role of PAI-1 as an important regulator of tumor cell invasion and metastasis. The hallmark of primary tumors of the central nervous system and glioblastomas in particular is the diffuse invasion into the normal brain tissue. Since PAI-1 is expressed in such tumors, we studied the effect of adenoviral-mediated transfer of the PAI-1 gene in regulating the in vitro invasiveness of D54Mg glioma cells into Matrigel, and into fetal rat brain aggregates. Treatment of D54Mg cells with 50 MOI (multiplicity of infection) of the replication defective vector AdCMVPAI-1 increased PAI-1 expression 23-fold compared to control vectors, and the invasion through Matrigel was reduced by 67%. The motility of the cells was reduced by 58% compared to controls (indicating that inhibition of motility was the principal effect of PAI-1 in these cells). The ability of D54Mg tumor spheroids to invade fetal rat brain aggregates was not reduced by the PAI-1 gene transfer. The results show that overexpression of PAI-1 can inhibit glioma cell motility and invasion through extracellular matrix (ECM) components, like laminin and collagen, but does not inhibit tumor cell invasion in a three-dimensional invasion assay, simulating normal brain tissue having a different ECM and interstitial composition. The different results obtained in the two invasion assays reflect the complex biological effects of the uPA/PAI-1 system, and questions a simplistic view of PAI-1 as an inhibitor of brain tumor invasion.
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Breast Cancer Research, 2005
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International Journal of Cancer, 2002
Treatment of malignant brain tumors remains a clinical challenge. New treatment modalities are un... more Treatment of malignant brain tumors remains a clinical challenge. New treatment modalities are under investigation and among these are intratumoral infusion of immunotoxins that bind to specific cell surface molecules on the malignant cells. We have compared the efficacy of the 425.3-PE immunotoxin (which targets the epidermal growth factor [EGF] receptor) with the well-known immunotoxin Tfn-CRM107 (which targets the transferrin receptor), for the treatment of subcutaneous and intracranial human gliomas in nude animals. Bolus intratumoral administration of 1 μg Tfn-CRM107 or 425.3-PE into sc U87Mg tumors in nude mice reduced the tumor volume to 29 and 79%, respectively, of that in the control group 18 days after start of treatment. Higher doses of Tfn-CRM107 were toxic to the animals, whereas 425.3-PE was tolerated, with a dose-response relationship of up to 8 μg, a dose that reduced the tumor volume to 2% of control. In nude rats, treatment of intracerebral U87Mg tumors with Tfn-CRM107 proved ineffective and doses above 10 ng/animal were toxic to tumor-bearing rats. In contrast, intratumoral administration of 4 μg 425.3-PE increased symptom-free survival from 23 days to 40 days, with 2/9 surviving more than 90 days. We have recently shown that immunodeficient rats inoculated intracerebrally with precultured glioblastoma biopsy specimens develop highly infiltrative brain tumors. Direct interstitial infusion of immunotoxins into such tumors reduced the number of animals with detectable tumors at autopsy after 3 months, from 8/9 in the control animals to 4/6 and 2/6 in animals treated with Tfn-CRM107 and 425.3-PE, respectively. In conclusion, the anti-EGF receptor immunotoxin 425.3-PE exhibited promising efficacy, comparable to or better than that of Tfn-CRM107, an immunotoxin that in early clinical trials has been found to give responses in patients with brain tumors. © 2001 Wiley-Liss, Inc.
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Experimental Cell Research, 2004
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Journal of Neurosurgery, 1999
The aim of this study was to develop an improved animal model for brain tumor study. The need for... more The aim of this study was to develop an improved animal model for brain tumor study. The need for better and more relevant brain tumor models is generally acknowledged. Glioma tissue can be cultured directly from the biopsy specimen as tumor spheroids. Using such precultured tissue, a new in vivo model for studying human gliomas was established. Precultured small tumor spheroids (< 300 microm) prepared from cell lines or tumor biopsy fragments were injected into the brains of immunodeficient rats by using a 5-microl Hamilton syringe that had a piston in the needle. Tumors could be established by injecting a single spheroid derived from the U-87MG cell line, whereas inoculation of 10 spheroids resulted in a tumor take comparable to that attained with injection of 10(6) single cells. Biopsy specimens obtained from six patients who underwent surgery for glioblastoma multiforme were cultured as organotypic spheroids for 11 to 18 days before inoculation into the rats. The animals were killed 3 months after spheroid implantation. Microscopic examination revealed tumor growth in 87.5 to 100% of the animals inoculated with tumor spheroids from all but one of the tumor biopsy specimens. Extensive invasion and cell migration along the nerve tracts of the corpus callosum was found in tumors that originated from four of the six biopsy specimens. This approach, in which spheroids from precultured biopsy specimens are injected into the brains of immunodeficient animals, provides new means for experimental studies of human malignant brain tumors in a clinically relevant animal model.
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Molecular Oncology, 2009
The number of relevant and well-characterized cell lines and xenograft models for studying human ... more The number of relevant and well-characterized cell lines and xenograft models for studying human breast cancer are few, and may represent a limitation for this field of research. With the aim of developing new breast cancer model systems for in vivo studies of hormone dependent and independent tumor growth, progression and invasion, and for in vivo experimental therapy studies, we collected primary mammary tumor specimens from patients, and implanted them in immunodeficient mice. Primary tumor tissue from 29 patients with breast cancer was implanted subcutaneously with matrigel in SCID mice, in the presence of continuous release of estradiol. The tumors were transferred into new animals when reaching a diameter of 15 mm and engrafted tumors were harvested for morphological and molecular characterization from passage six. Further, gene expression profiling was performed using Agilent Human Whole Genome Oligo Microarrays, as well as DNA copy number analysis using Agilent Human Genome CGH 244K Microarrays. Of the 30 primary tumors implanted into mice (including two implants from the same patient), two gave rise to viable tumors beyond passage ten. One showed high expression levels of estrogen receptor-α protein (ER) while the other was negative. Histopathological evaluation of xenograft tumors was carried out at passage 10–12; both xenografts maintained the morphological characteristics of the original tumors (classified as invasive grade III ductal carcinomas). The genomic profile of the ER-positive xenograft tumor resembled the profile of the primary tumor, while the profile obtained from the ER-negative parental tumor was different from the xenograft. However, the ER-negative parental tumor and xenograft clustered on the same branch using unsupervised hierarchical clustering analysis on RNA microarray expression data of “intrinsic genes”. A significant variation was observed in the expression of extracellular matrix (ECM)-related genes, which were found downregulated in the engrafted tumors compared to the primary tumor. By IHC and qRT-PCR we found that the downregulation of stroma-related genes was compensated by the overexpression of such molecules by the mouse host tissue. The two established breast cancer xenograft models showed different histopathological characteristics and profound diversity in gene expression patterns that in part can be associated to their ER status and here described as basal-like and luminal-like phenotype, respectively. These two new breast cancer xenografts represent useful preclinical tools for developing and testing of new therapies and improving our knowledge on breast cancer biology.
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Papers by Geir Olav Hjortland