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  • 1
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    German Medical Science; Düsseldorf, Köln
    In:  27. Deutscher Krebskongress; 20060322-20060326; Berlin; DOCPO269 /20060320/
    Publication Date: 2006-04-21
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
    Keywords: SYSTEM ; CANCER ; APOPTOSIS ; THERAPY ; INDUCTION ; treatment ; CANCER-THERAPY ; TRAIL ; function ; CANCER-TREATMENT ; cancer therapy
    Type of Publication: Book chapter
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  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; INHIBITOR ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; human ; IN-VIVO ; INHIBITION ; DEATH ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; PROTEINS ; RNA ; LINES ; MICE ; TRANSDUCTION ; NF-KAPPA-B ; COMPLEX ; COMPLEXES ; MECHANISM ; CONTRAST ; hepatocytes ; CELL-LINES ; signal transduction ; SUPPRESSION ; 5-FLUOROURACIL ; ALPHA ; hepatocellular carcinoma ; resistance ; CARCINOMA CELLS ; EFFICACY ; SIGNAL-TRANSDUCTION ; LINE ; CANCER-CELLS ; CARCINOMA-CELLS ; KAPPA-B ; RECEPTORS ; FLOW-CYTOMETRY ; cell lines ; PROTEASOME ; TRAIL ; SIGNALING COMPLEX ; HUMAN HEPATOCYTES ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; CASPASE-8 ACTIVATION ; INHIBITORS ; signaling ; RE ; INTERFERENCE ; CASPASE-8 ; MEDIATED APOPTOSIS ; TUMORICIDAL ACTIVITY ; interaction ; SIGNALING COMPLEXES ; CLINICAL-RELEVANCE ; carcinoma cell ; death receptor
    Abstract: TRAIL exhibits potent anti-tumor activity on systemic administration in mice. Because of its proven in vivo efficacy, TRAIL may serve as a novel anti-neoplastic drug. However, approximately half of the tumor cell lines tested so far are TRAIL resistant, and potential toxic side effects of certain recombinant forms of TRAIL on human hepatocytes have been described. Pretreatment with the proteasome inhibitor MG132 and PS-341 rendered TRAIL-resistant hepatocellular carcinoma (HCC) cell lines but not primary human hepatocytes sensitive for TRAIL-induced apoptosis. We investigated the different levels of possible MG132-induced interference with resistance to apoptotic signal transduction. Although proteasome inhibition efficiently suppressed nuclear factor-kappaB (NF-kappa B) activity, specific suppression of NF-kappa B by mut kappa B alpha failed to sensitize TRAIL-resistant cell lines for TRAIL-induced apoptosis. In contrast to the previously reported mechanism of sensitization by 5-fluorouracil (5-FU), cellular FLICE-inhibitory protein (cFLIP)(L) and cFLIP(S) were markedly upregulated in the TRAIL death inducing signaling complex (DISC) by proteasome inhibitor pretreatment. Compared with 5-FU pretreatment, caspase-8 was more efficiently recruited to the DISC in MG132 pretreated cells despite the presence of fewer death receptors and more cFLIP in the DISC., But downregulation of cFLIP by short interference RNA (siRNA) further sensitized the HCC cell lines. In conclusion, these results show that otherwise chemotherapy-resistant tumor cells can be sensitized for TRAIL-induced apoptosis at the DISC level in the presence of high levels of cFLIP, which suggests the existence of an additional factor that modulates the interaction of FADD and the TRAIL death receptors. Of clinical relevance, proteasome inhibitors sensitize HCC cells but not primary human hepatocytes for TRAIL-induced apoptosis
    Type of Publication: Journal article published
    PubMed ID: 16037944
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  • 4
    Keywords: APOPTOSIS ; SURVIVAL ; Germany ; PATHWAY ; HYBRIDIZATION ; TIME ; PROGRESSION ; COMPARATIVE GENOMIC HYBRIDIZATION ; MALIGNANCIES ; meta-analysis ; ABERRATIONS ; REGIONS ; CHROMOSOMAL IMBALANCES ; GLIOMAS ; MALIGNANCY ; RE ; SOLID TUMORS ; oligodendroglioma ; 19Q ; LOSSES ; ARMS 1P
    Abstract: Many oligodendrogliomas (ODG) have been investigated by comparative genomic hybridization (CGH), To visualize characteristic aberration profiles of non-anaplastic in a comparison with anaplastic ODGs, we performed a meta-analysis of the CGH results of all 89 cases published so far. Therefore, we expanded all given aberrations to the maximum of 850 GTG band resolution. The frequencies of each chromosomal band affected by a genetic imbalance were calculated for WHO grades II and III separately. In non-anaplastic ODGs, -1p and -19q were the most prominent aberrations. In anaplastic ODGs, +7, -4q, -9p, -10, and -15q emerged additionally. We could confirm the existence of three disjunct genetically defined subgroups of ODGs, characterized by -1p/-19q (n = 58, 65%, subgroup A), +7/-10 (n = 6, 7%, subgroup B) or the absence of either of the two patterns (n = 25, 28%, subgroup C). Interestingly, we found a unique aberration pattern in subgroup C (-1p31; -4q, -11p15, -18q, -22q, +17p, + 17q) that was different from subgroups A and B, which could indicate a unique molecular carcinogenetic pathway of this ODG subset. Scrutinizing published putative progression markers of ODG, we found that only + 7, -10, and -15q significantly correlated with a higher grade of malignancy. Summing up, the expansion of the CGH results to the 850 GTG band resolution enabled a meta-analysis to visualize WHO grade-specific aberration profiles in ODG for the first time. (c) 2005 Elsevier GmbH. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16356658
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  • 5
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; carcinoma ; CELL ; Germany ; IN-VIVO ; INHIBITION ; PATHWAY ; DEATH ; GENE ; PROTEIN ; LINES ; ACTIVATION ; LIGAND ; DNA ; INFECTION ; REDUCTION ; DOMAIN ; CARCINOGENESIS ; INDUCTION ; T cells ; T-CELLS ; CELL-LINES ; CELL-LINE ; LYMPHOCYTES ; MITOCHONDRIA ; STOMACH ; RECEPTORS ; TRAIL ; REGULATOR ; inflammation ; FAS ; methods ; IMMUNE PRIVILEGE ; leukaemia ; death receptor ; INHIBIT ; Helicobacter pylori ; GASTRIC EPITHELIAL APOPTOSIS ; INFILTRATING MUCOSAL LYMPHOCYTES ; VACUOLATING CYTOTOXIN
    Abstract: Background Chronic infection with Helicobacter pylori is related to the pathogenesis of the noncardia carcinoma of the stomach. In this study we investigated the mechanisms of H. pylori-induced apoptosis in T lymphocytes, which could explain a mechanism of immune evasion facilitating chronic inflammation of the mucosa and gastric carcinogenesis. Materials and methods The supernatant of H. pylori culture was used to study the mechanism of apoptosis induction in human leukaemia T cell lines Jurkat and CEM and in primary T cells. The cytotoxin associated gene A (CagA) and vacuolating cytotoxin A (Vac A) positive bacterial strain H. pylori 60190 (CagA+, VacA+) and as a control the less toxic H. pylori strain Tx30a (CagA-, VacA-) were used to produce the supernatant. Cell death was determined by DNA fragmentation and protein expression by Western blot. Results H. pylori 60190-induced apoptosis was neither blocked by inhibition of the death ligands TRAIL (TNF-related apoptosis-inducing ligand), CD95L/FasL and TNF-alpha (tumour necrosis factor-a) in wild type Jurkat cells nor in FADD(def) (Fas-associated death domain protein) and caspase-8(def) subclones of the Jurkat cell line. Yet, the pancaspase inhibitor zVAD-fmk could inhibit up to 90% of H. pylori-induced apoptosis. Stable transfection of Jurkat wild type cells with Bcl-x(L and) Bcl-2 resulted in marked reduction of H. pylori-induced apoptosis, showing that the mitochondrial pathway is the key regulator. This is supported by the finding that surviving primary human lymphocytes upregulate Bcl-2 when exposed to H. pylori supernatant. Conclusions H. pylori-induced apoptosis of T cells is mediated by the mitochondrial pathway and could create a local environment that facilitates life-long infection by immune evasion
    Type of Publication: Journal article published
    PubMed ID: 17217377
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; IN-VITRO ; tumor ; TUMOR-CELLS ; CELL ; COMBINATION ; Germany ; human ; IN-VIVO ; TOXICITY ; VITRO ; DEATH ; RISK ; RNA ; cell line ; LINES ; ACTIVATION ; LIGAND ; MECHANISM ; colon ; hepatocytes ; CELL-LINES ; DOWN-REGULATION ; treatment ; UP-REGULATION ; CELL-LINE ; LINE ; CANCER-CELLS ; cell lines ; pancreatic cancer ; TUMOR CELLS ; TRAIL ; MULTIPLE-MYELOMA ; HUMAN HEPATOCYTES ; APOPTOSIS-INDUCING LIGAND ; RE ; PANCREATIC-CANCER ; CAPACITY ; INTERFERENCE ; RNA INTERFERENCE ; pancreatic ; TUMOR-CELL ; CHEMOTHERAPEUTIC DRUGS ; LIGAND TRAIL ; NECROSIS ; HEPATOCELLULAR-CARCINOMA CELLS ; comparison ; BORTEZOMIB ; CAUSAL ROLE ; PROTEASOME INHIBITION
    Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a novel promising anticancer biotherapeutic. However, TRAIL-resistant tumor cells require combinatorial regimens to sensitize tumor but not normal cells for TRAIL-induced apoptosis. Here, we investigated the mechanism of the synergistic antitumor effect of bortezomib in combination with TRAIL in hepatoma, colon, and pancreatic cancer cells in comparison to the toxicity in primary human hepatocytes (PHH). TRAIL cotreatment at high but clinically relevant concentrations of bortezomib caused toxicity in PHH which potentially limits the clinical applicability of bortezomib/TRAIL cotreatment. However, at low concentrations of bortezomib TRAIL-resistant hepatoma, colon and pancreatic cancer cell lines but not PHH were efficiently sensitized for TRAIL-induced apoptosis. RNA interference and TRAIL receptor blockage experiments revealed that in bortezomib-treated hepatoma cells TRAIL-R1/TRAIL-R2 up-regulation, enhanced TRAIL DISC formation and cFLIP(L) down-regulation in addition to accumulation of Bak cooperatively sensitized for TRAIL. Bim, although accumulated upon bortezomib treatment, did not play a causal role for TRAIL sensitization in Hep3b cells. Combined treatment with bortezomib and TRAIL massively reduced the clonogenic capacity of hepatoma cells in vitro. Surviving clones could be resensitized for repeated TRAIL treatment. Conclusion: Bortezomib/TRAIL cotreatment bears the risk of severe hepatoroxicity at high but clinically relevant concentrations of bortezomib. However, within a wide therapeutic window bortezomib sensitized different cancer cells but not PHH for TRAIL-induced apoptosis
    Type of Publication: Journal article published
    PubMed ID: 17326159
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  • 7
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    Keywords: CANCER ; CELLS ; tumor ; CELL ; Germany ; HYBRIDIZATION ; chromosome ; FREQUENCY ; polymorphism ; single nucleotide polymorphism ; FREQUENCIES ; DELETION ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; EXPERIENCE ; NUMBER ; CHROMOSOMAL-ABERRATIONS ; genetics ; SNP ; ABERRATIONS ; DELETIONS ; EPITHELIAL-CELLS ; FLUORESCENCE ; IMBALANCES ; heredity ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; CHROMOSOMES ; in situ hybridization ; SINGLE ; ONCOLOGY ; ARRAY ; GRADE ; CYTOGENETIC ANALYSIS ; analysis ; methods ; single-nucleotide ; paranasal sinuses ; CHROMOSOMAL-ABNORMALITIES ; EWING SARCOMA ; aberration ; OLFACTORY NEUROBLASTOMA ; SOFT-TISSUE TUMORS ; TRISOMY-8
    Abstract: Esthesioneuroblastoma is a malignant neuroectodermal tumor originating from olfactory epithelial cells in the nasal vault. Due to the rarity of this tumor entity, cytogenetic data are very limited. Therefore, we performed comprehensive cytogenetic analyses of an esthesioneuroblastoma, Hyam's grade III-IV, using trypsin-Giemsa staining (GTG banding), multicolor fluorescence in situ hybridization (M-FISH), and locus-specific FISH complemented by molecular karyotyping using high-density single nucleotide polymorphism arrays. GTG banding of 25 metaphases revealed 54 structural intrachromosomal aberrations, predominantly located on 2q, 6q, 21q, and 22q, which were confirmed by FISH analysis. Interestingly, we found two novel, so far not described deletions, del(2)(q37) and del(21)(q22). Using GTG banding, locus-specific FISH, and M-FISH, we detected numeric changes of chromosomes 5, 17,19, and 22, as well as trisomy 8 at low frequency. Applying SNP array karyotyping, we confirmed the chromosomal aberrations del(2)(q37.3), del(3)(q27.2), del(10)(q26.11), chromosomal imbalance on 17q, del(21)(q22), and revealed a number of so far unknown aberrations (gain of 2q14.3, 13q33.3, and 13q34). While the cytogenetically revealed low frequency mosaic del(6)(q22q24) was not visible using SNP array karyotyping, some of the smaller imbalances (SNP array data) could not have been detected by classic cytogenetic analysis. Therefore, our study supports the usefulness of applying complementary methods for cytogenetic analysis. (c) 2007 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17321323
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  • 9
    Keywords: brain ; CANCER ; CELLS ; INHIBITOR ; tumor ; CELL ; Germany ; THERAPY ; DISEASE ; LONG-TERM ; NEW-YORK ; HYBRIDIZATION ; TUMORS ; PATIENT ; primary ; chromosome ; polymorphism ; single nucleotide polymorphism ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; ARRAYS ; CHROMOSOMAL-ABERRATIONS ; genetics ; SNP ; ABERRATIONS ; HUMAN HOMOLOG ; CENTRAL-NERVOUS-SYSTEM ; TRANSLOCATION ; DE-NOVO ; CHILDREN ; FLUORESCENCE ; fluorescence in situ hybridization ; PROTEASOME ; heredity ; TRAIL ; TRAIL-INDUCED APOPTOSIS ; CHROMOSOMES ; in situ hybridization ; SINGLE ; CYTOKINE ; molecular ; ONCOLOGY ; ADULT ; ADULTS ; BRAIN-TUMORS ; HUMAN CANCER ; THERAPIES ; ARRAY ; GRADE ; medulloblastoma ; PRIMITIVE NEUROECTODERMAL TUMORS ; CHEMOTHERAPEUTIC DRUGS ; single-nucleotide ; BASAL-CELL CARCINOMAS ; USA ; RESISTANT ; RARE ; aberration ; chromosomal aberration ; ACUTE MYELOID LEUKEMIAS ; BORTEZOMIB ; CHROMOSOMAL CHANGES ; PARTIAL UNIPARENTAL DISOMY
    Abstract: Medulloblastoma is a malignant invasive embryonal tumor, occurring in children mainly. It is rare in adults (〈 1 % of adult brain tumors), and so comprehensive cytogenetic and molecular biological data on adult medulloblastomas are very limited. Conventional therapies provide disappointing long-term disease control, and new therapeutic options are being tested. We performed comprehensive cytogenetic analyses of an adult medulloblastoma, WHO grade IV, using trypsin-Giemsa staining (GTG-banding), multicolor fluorescence in situ hybridization (M-FISH), and locus-specific FISH, complemented by molecular karyotyping using high-density single nucleotide polymorphism (SNP) arrays. GTG-banding of 25 metaphases revealed 31 structural chromosomal aberrations, predominantly located on chromosomes 4q, 9q, 10q, l l p, and 20q, which were confirmed by M-FISH. Two novel, so far not described translocations were found: t(4;11)(q25;p15) and t(9;20)(p23;p12). GTG-banding, locus-specific FISH, and M-FISH detected numerical changes of chromosomes 8, 14, 18, 19, 20, 21, and 22. Molecular karyotyping by SNP array confirmed chromosomal changes -2p, -10q, -16q, and -Xq and revealed de novo partial uniparental disomy 1q and 9q. Applying an upcoming therapeutic approach, we found that primary medulloblastoma cells were resistant to TRAIL, a novel anticancer cytokine, but could be efficiently sensitized by cotreatment with the proteasome inhibitor bortezomib. Bortezomib-TRAIL cotreatment may serve as a powerful therapeutic option for medulloblastoma patients. (c) 2007 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17954265
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  • 10
    Keywords: APOPTOSIS ; CANCER ; Germany ; UP-REGULATION ; ONCOLOGY ; RE ; USA ; cancer research
    Type of Publication: Journal article published
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