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G Schackert

Publications and source records attributed to G Schackert.

At least 55 records · Page 3Linked to original sources
PubMed1997

The putative tumor suppressor gene FHIT at 3p14.2 is rarely affected by loss of heterozygosity in primary human brain tumors.

To elucidate the role of the recently identified FHIT gene, located at 3p14.2 in human brain tumor carcinogenesis, a total of 259 tumors were analyzed for loss of heterozygosity (LOH) at microsatellite loci D3S1313, D3S1234, D3S1300, and D3S1481. In primary brain tumors, LOH was detected at a frequency of 8.4% (n = 214). Low-grade gliomas exhibited insignificantly lower LOH rates in comparison to high-grade gliomas (5.3%, n = 19, versus 11.1%, n = 90). Notably, no allelic loss was observed in 12 recurrent glioblastomas analyzed in comparison to their corresponding primary tumor lesions and in two astrocytomas with progression to higher grades of malignancy. Our data indicate that allelic loss of the FHIT gene is neither a critical event in carcinogenesis of primary brain tumors nor tumor grade-associated in astrocytic tumors. In contrast, observed LOH rate for brain metastases was as high as 54.5% (n = 45), in accordance with data thus far accumulated from analyses of corresponding primary tumors.

Acid Anhydride Hydrolases↗
PubMed1996

Combined detection of CD44 isoforms by exon-specific RT-PCR and immunohistochemistry in primary human brain tumors and brain metastases.

Expression of CD44 has been implicated in tumor growth and metastasis. Here we demonstrate CD44 expression in primary human brain tumors (n = 44) and brain metastases (n = 7) by RT-PCR and immunohistochemistry. Standard CD44 was found to be expressed by the majority of primary brain tumors and brain metastases. For the first time to our knowledge, CD44 expression is demonstrated for acoustic neurinomas and pituitary adenomas. Exon-specific analysis by RT-PCR and indirect immunofluorescence revealed expression of alternatively spliced CD44 isoforms in the group of brain metastases only. However, in one glioblastoma multiforme, expression of CD44v5 and CD44v6 was found immunohistochemically. This tumor took an unusual clinical course giving rise to multiple intrahepatic and lymph node metastases. Quantitatively different expression of standard CD44 in gliomas versus meningiomas is reported (p < 0.01).

Alternative Splicing↗
PubMed1994

Activated monocytes kill malignant brain tumor cells in vitro.

The purpose of our study was to investigate the susceptibility of human glioblastoma multiforme (GBM) cells to lysis by human peripheral-blood monocytes following activation with biological response modifiers (BRM) and to lysis by various BRMs directly. Cytotoxic effects were determined using a monocyte-/BRM-mediated tumor cytotoxicity assay. Human peripheral-blood monocytes from healthy donors were activated in vitro by incubation for 24 h with different BRMs such as gamma- and beta-interferon (gamma, beta-IFN), lipopolysaccharide (LPS), muramyldipeptide (MDP) and tumor necrosis factor-alpha (TNF-alpha) in varying concentrations and combinations. Seven human GBM cell lines as well as an adenocarcinoma brain metastasis cell line and a malignant melanoma cell line served as target cells. Radiolabeled target cells were cocultivated with activated monocytes or with BRMs directly. Cytotoxicity was calculated after 72 h of cocultivation. High levels of cytotoxicity were mediated by monocytes activated with beta-IFN in six out of eight brain tumor cell lines and with TNF-alpha in five cell lines. The combination of two BRMs, in particular the combination of gamma-IFN + beta-IFN and gamma-IFN + TNF-alpha, was associated with an enhanced monocyte mediated lysis exceeding LPS control, whereas the combination of gamma-IFN + MDP was very effective against the metastasis cell line. Monocyte-mediated cytotoxicity against tumor target cells was up to ten fold higher than direct cytotoxicity of soluble BRMs. Our data indicate that BRM-stimulated peripheral-blood monocytes exert cytotoxic properties against human glioblastoma cells in vitro, which exceed those of BRMs alone up to ten fold. The higher tumoricidal activities observed after stimulation with combined BRMs suggest mutual promoting mechanisms of BRMs acting on the stimulation of lyctic activity in human peripheral blood monocytes.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1991

Malignant potential of cells isolated from lymph node or brain metastases of melanoma patients and implications for prognosis.

We studied the correlation between the formation of brain metastasis and the malignant growth potential of seven human melanoma cell lines, isolated from lymph node metastases (A375-SM, TXM-1, DM-4) or from brain metastases (TXM-13, TXM-18, TXM-34, TXM-40), and the potential of three variants of the mouse K-1735 melanoma. Growth rates in different concentrations of fetal bovine serum and colony-forming efficiency in semisolid agarose were measured, and the tumorigenicity and metastatic ability were determined in nude mice (for the human melanoma cell lines) or in C3H/HeN mice (for the K-1735 variants). The ability to form brain metastasis was tested by injection of cells into the carotid artery. A high colony-forming efficiency in agarose, especially at concentrations of agarose greater than 0.6%, corresponded with high tumor take rates, rapid tumor growth rates, and metastatic colonization of the lungs of the recipient mice. For the human melanomas, the lymph node metastasis-derived cells were more tumorigenic and metastatic than the brain metastasis-derived cells. In the K-1735 mouse melanoma, the tumorigenic and metastatic behavior of the cells after i.v. and s.c. injection corresponded with growth in agarose cultures. However, for growth in the brain after intracarotid injection, the different melanoma cell lines showed similar frequencies of tumor take, regardless of tumorigenicity in other sites of the recipient mice, although mice given injections of brain metastasis-derived cells survived longer than mice given injections of lymph node metastasis (human melanoma) or lung metastasis (K-1735 M-2)-derived cell lines. The results from the human and mouse melanoma cell lines show that the brain metastasis-derived cell lines were not more malignant than the lymph node or lung metastasis-derived cells. These data imply that the production of brain metastasis is not always the final stage of a metastatic cascade.

Animals↗
PubMed1991

[Primary non-Hodgkin lymphomas of the central nervous system].

Primary non-Hodgkin's lymphomas (NHL) of the central nervous system are rare brain tumours developing independently of or secondary to disorders of the immune system. In the following review the diagnostic repertoire and various therapeutic modalities are discussed. According to data reported in the literature the therapeutic approach of choice is cranial irradiation with 50 Gy. A positive effect may be expected from additional chemotherapy.

Brain Neoplasms↗
PubMed1990

Regional growth of different human melanomas as metastases in the brain of nude mice.

Cells from eight different human melanomas and two murine melanomas were injected into the internal carotid artery of anesthetized nude mice. Although all were injected by the same route, particular melanomas produced lesions in different regions of the brain. Two melanoma cell lines isolated originally from brain metastases in patients produced metastases predominantly in the brain parenchyma. In contrast, melanoma cells from subcutaneous or lymph node metastases produced more lesions in the meninges, choroid plexus, and ventricles than in the brain parenchyma. All of the melanomas grew in the brain after a direct intracerebral injection. The pattern of brain metastasis did not correlate with tumorigenicity per se or with the ability of the melanomas to grow in the lungs of nude mice. Two mouse melanomas showed different patterns of experimental metastasis after internal carotid artery injection, with one growing predominantly in the parenchyma and the other more frequently in the meninges and choroid plexus. The growth pattern of human melanoma metastasis in the brain of T cell-deficient nude mice suggests that it is determined by properties unique to each tumor interacting with the host's organ microenvironment.

Animals↗
PubMed1989

Unique patterns of brain metastasis produced by different human carcinomas in athymic nude mice.

The purpose of this study was to develop an in vivo model to study the growth pattern and biological behavior of brain metastases produced by different human carcinomas. To do so, human tumor cells from 8 different carcinomas of the colon, breast, kidney and lung were injected into athymic nude mice either by a direct intracerebral route or into the internal carotid artery. All carcinoma cells invaded through the blood-brain barrier and produced progressively growing lesions in the brain parenchyma. Unique patterns of growth were discernible among the carcinomas. Human colon carcinomas produced multiple lesions that spread by extension. Lung carcinoma cells produced widespread lesions throughout the brain. A very high degree of vascularization was associated with lesions produced by renal-cell carcinoma. The influence of estrogen on the growth of estrogen-receptor-positive human breast carcinoma cells was well demonstrated in this model. We conclude that the athymic nude mouse can be a useful model for studies of the biology and perhaps therapy of brain metastases produced by human carcinoma cells.

Animals↗
PubMed1989

Metastatic potential of cloned murine melanoma cells transfected with activated c-Ha-ras.

We sought to determine whether the transfection of tumorigenic but not metastatic cells with the activated c-Ha-ras oncogene was invariably associated with acquisition of the metastatic phenotype. Three clonally derived lines of the K-1735 murine melanoma, characterized as nonmetastatic or poorly metastatic, were transfected with plasmids containing the 6.6-kilobase BamHI fragment of the mutant human c-Ha-ras gene and the neo gene, that confers resistance to neomycin (pSV2neoEJ). Cells transfected with pSV2neo, a plasmid containing the neo gene, served as controls for the procedure of Polybrene-mediated transfection. All cell lines were injected into syngeneic C3H/HeN and into athymic mice, and the results were compared with those produced by highly metastatic K-1735 M-2 cells. Although the pSV2neoEJ-transfected cells produced more rapidly growing s.c. tumors than the control cell lines did, the incidence of spontaneous metastasis was not increased. Following i.v. inoculation, the c-Ha-ras transfectants were retained in lung vasculature in greater proportions than pSV2neo counterpart transfectants were. The c-Ha-ras transfectants also produced significantly more lung tumor colonies, which grew faster than the few lung tumor colonies in mice given injections of control melanoma cells. We concluded that transfection of the activated c-Ha-ras oncogene into nonmetastatic K-1735 melanoma cells leads to accelerated tumor growth in vivo and can confer the ability to form lung colonies after i.v. injection but not the ability to metastasize from a primary s.c. tumor.

Animals↗
PubMed1989

Systemic immunity against a murine colon tumor (CT-26) produced by immunization with syngeneic cells expressing a transfected viral gene product.

We have previously shown that CT-26 tumor cells expressing the transfected hemagglutination antigen of influenza virus elicit an immune response in syngeneic hosts that is cross-protective against an s.c. challenge with non-transfected parental cells. Since CT-26 is a murine colorectal carcinoma we sought to determine whether the same immuno-protective effect could be achieved after a challenge with parent tumor cells injected into the usual sites of colon tumor growth and metastasis. We now show that the protection afforded by this immunization protocol is systemic and that animals can be protected against tumor growth in the cecum, lymphatics of the mesentery, liver and lung.

Adenocarcinoma↗
PubMed1989

Arrest and retention of multilamellar liposomes in the brain of normal mice or mice bearing experimental brain metastases.

The blood-brain barrier presents a major obstacle to the systemic treatment of malignant brain tumors and brain metastases. We investigated whether the direct injection of liposomes into the internal carotid artery of normal mice or mice with experimental brain-melanoma metastases could allow delivery of anticancer drugs across this barrier. Liposomes of different sizes (greater than 5 microns, less than 1 micron, 40-80 nm) and lipid compositions were injected i.v. or into the internal carotid artery. The retention of liposomes in the brain of normal C3H/HeN mice was similar to that observed in mice with experimental brain cancer metastasis. The highest accumulation of liposomes in the brain occurred with large multilamellar vesicles, which also produced severe toxicity presumably due to embolism. Smaller liposomes were not toxic but did not accumulate in the brain. Liposomes injected i.v. did not accumulate in the brain, either. Thus, neither i.v. nor intracarotid administration of liposomes produce results suitable for therapy of brain tumors/metastases.

Animals↗
PubMed1988

Macrophage infiltration into experimental brain metastases: occurrence through an intact blood-brain barrier.

The purpose of this study was to examine the nature of the blood-brain barrier in experimental brain metastases. Syngeneic fibrosarcoma or melanoma cells were injected into the internal carotid arteries of mice. Several weeks later, once the experimental brain metastases were established, the mice were given injections iv of sodium fluorescein. The capillaries within the metastatic foci were enlarged and irregular, but there was no leakage of sodium fluorescein, showing that the blood-brain barrier was intact. The neoplastic lesions were infiltrated by mononuclear phagocytes, which were identified by immunohistochemical localization of the macrophage-specific antigen F4/80, class II major histocompatibility complex (MHC) antigens, and the macrophage product interleukin-1 (IL-1). The metastatic foci contained numerous stellate macrophages that expressed F4/80 and MHC class II antigens, but little IL-1. Round, monocyte-like F4/80 and MHC class II-positive cells were also observed within the tumor lesions and adhering to walls of the tumor microvasculature. Mice with fibrosarcoma brain metastases also had edematous lesions at sites remote from the metastatic foci that contained numerous astrocytes expressing class II MHC but not F4/80 antigens. In conclusion, the blood-brain barrier is intact within experimental brain metastases, yet macrophages of blood monocyte origin can infiltrate the lesions.

Animals↗
PubMed1988

Site-specific metastasis of mouse melanomas and a fibrosarcoma in the brain or meninges of syngeneic animals.

Different subpopulations of cells from two different murine melanomas (K-1735 and B16) and a fibrosarcoma (UV-2237) were injected into the internal carotid artery of anesthetized syngeneic mice. Despite the common route of tumor cell injection, tumor lesions in the brain were unique to each tumor type and developed at different sites in the brain. Gross and histological examinations revealed that different subpopulations of cells derived from the K-1735 melanoma produced only parenchymal lesions, cells of the B16 melanoma produced lesions in the meninges and ventricles, and cells of the UV-2237 fibrosarcoma produced lesions throughout the brain. This site specificity for tumor growth was not due to the initial tumor cell arrest in the microvasculature of different regions-areas in the brain as evidenced by detailed studies with radiolabeled cells. The site specificity of this experimental brain metastasis was not random and correlated well with the clinical situation. The exact interactions of tumor cells with different microenvironments in the brain need further elucidation.

Animals↗
PubMed1988

Development of in vivo models for studies of brain metastasis.

To develop an in vivo model for studies of brain metastasis, varying doses of K-1735 tumor cells with differing metastatic potentials were injected into the carotid arteries of anesthetized mice. Direct intracerebral administration of cells produced tumors in the brain parenchyma, and all tumor cells produced melanotic lesions at these sites. Studies with radioactively-labelled tumor cells confirmed that tumor cells reached the meninges and extracerebral organs. Distant metastases were found in the lungs and hearts of mice which received K-1735 cells into the carotid artery, but not in animals which received tumorigenic non-metastatic cells. Regardless of the type of cells injected, no growths were found in the meninges. The high degree of reproducibility recommends this model for studies designed to investigate the biology and therapy of cancer metastasis to the brain.

Animals↗
PubMed1987

In vitro model for the response to irradiation of different types of human intracranial tumours.

Twenty-seven human low and high grade gliomas and five meningiomas were cultured in vitro as tumour tissue and/or tumour cells. Cell survival or growth was taken as a measure of radiation response. Astrocytomas II-III and glioblastomas manifested individual patterns of radiosensitivity, ranging from 10 to 90 Gy. Meningiomas did not react. Our findings are consistent with the differences in radiosensitivity of human gliomas experienced clinically and corroborate the validity of the in vitro model.

Brain Neoplasms↗
PubMed1984

[Vascular loop. A contributing factor to vascular cerebellopontile syndrome].

Modern diagnostic methods such as brainstem-evoked response audiometry and CT scanning with positive and negative contrast enhancement represent a major advance in the diagnostic evaluation even of small acoustic neuromas. However difficulties arise in differentiation between tumours and other cerebellopontine angle lesions, as shown by means of a case report. An arterial loop of the anterior inferior cerebellar artery (AICA) between the facial and the eighth cranial nerve was the cause of progredient neural hearing loss, peripheral vestibular dysfunction and hemifacial spasm. Vascular decompression was performed with total relief of spasm and partial restitution of hearing. In differential diagnosis of the pathology of the cerebellopontine angle region and the internal auditory canal the clinical symptoms are important.

Cerebellopontine Angle↗
PubMedDate not supplied

Angiogenesis, metastasis, and endogenous inhibition.

Angiogenesis and the development of metastases are intrinsically connected. Experimental data suggest that establishment and growth of metastases are influenced by soluble factors secreted from the originating solid tumor. Among these factors are so-called endogenous inhibitors of angiogenesis which keep metastasis in a non-proliferating quiescent state. For a number of tumors it has been shown that this dormant state is mediated through inhibition of angiogenesis. This dormant state is characterized by normal proliferation, increased apoptosis, and insufficient neo-vascularization. Removal of inhibiting anti-angiogenic factors led to growth of dormant metastases. A number of endogenous inhibitors have been identified and have shown success in experimental therapeutic trials. This might be of special interest for the treatment of cerebral metastases which are the most common type of malignant brain tumors. Similar to the spread of metastases, it is known that single glioma cells can be found in distant parts of the brain. While local recurrence is a common phenomenon in glioma, formation of clinical apparent distant metastasis occurs rarely. Several lines of evidence suggest that growth inhibition of remote glioma cells may be mediated by an endogenous inhibitory mechanism.

Angiostatins↗
PubMedDate not supplied

Anti-angiogenic treatment strategies for malignant brain tumors.

The use of angiogenesis inhibitors may offer novel strategies in brain tumor therapy. In contrast to traditional cancer treatments that attack tumor cells directly, angiogenesis inhibitors target at the formation of tumor-feeding blood vessels that provide continuous supply of nutrients and oxygen. With respect to brain tumor therapy, inhibitors of angiogenesis display unique features that are unknown to conventional chemotherapeutic agents. The most important features are independence of the blood-brain barrier, cell type specificity, and reduced resistance. Malignant brain tumors, especially malignant gliomas, are among the most vascularized tumors known. Despite multimodal therapeutic approaches, the prognosis remains dismal. Thus, angiogenesis inhibitors may be highly effective drugs against these tumors. In a clinical setting, they could be applied in the treatment of multiple tumors or postsurgically as an adjuvant therapy to prevent recurrence. This article provides an overview of current anti-angiogenic treatment strategies with emphasis on substances already in clinical trials or candidate substances for clinical trials. The cellular and molecular basis of these substances is reviewed.

Angiogenesis Inhibitors↗