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  • APOPTOSIS  (23)
  • LINE  (10)
  • carcinoma  (10)
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  • 1
    Keywords: CARCINOMAS ; sensitivity ; resistance ; CANCER-THERAPY ; CASPASE 8 ; APOPTOSIS ; CANCER ; carcinoma ; THERAPY
    Type of Publication: Patent
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  • 2
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; carcinoma ; CELL ; Germany ; INHIBITION ; THERAPY ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; TISSUE ; LINES ; MICE ; PATIENT ; IMPACT ; INDUCTION ; CELL-LINES ; treatment ; hepatocellular carcinoma ; resistance ; AGE ; metastases ; NUDE-MICE ; CELL-LINE ; chemotherapy ; leukemia ; LINE ; MODULATION ; p53 ; CANCER-PATIENTS ; CARCINOMAS ; CISPLATIN ; CANCER PATIENTS ; cell lines ; CANCER-THERAPY ; protein expression ; P53 STATUS ; GEMCITABINE ; RE ; cancer therapy ; GENDER ; dexamethasone ; GLUCOCORTICOID-INDUCED APOPTOSIS ; NAUSEA ; HISTOLOGY ; corticosteroids ; GLUCOCORTICOIDS ; correlation ; GAMMA-IRRADIATION ; viability ; 5-FU ; xenograft
    Abstract: The glucocorticoid dexamethasone is frequently used as co-treatment in cytotoxic cancer therapy, e.g. to prevent nausea, to protect normal tissue or for other reasons. While the potent pro-apoptotic properties and the supportive effects of glucocorticoids to tumour therapy in lymphoid cells are well studied, the impact to cytotoxic treatment of colorectal and hepatocellular carcinoma is unknown. We tested apoptosis-induction, viability, tumour growth and protein expression using 8 established cell lines, 18 surgical specimen and a xenograft on nude mice. In the presence of dexamethasone we found strong inhibition of apoptosis in response to 5-FU, cisplatin, gemcitabine or gamma-irradiation, enhanced viability and tumour growth of colorectal and hepatocellular carcinomas. No correlation with age, gender, histology, TNM, the p53 status and induction of therapy resistance by dexamethasone cotreatment could be detected. These data show that glucocorticoid-induced resistance occurs not occasionally but is common in colorectal and hepatocellular carcinomas implicating that the use of glucocorticoids may be harmful for cancer patients. (c) 2005 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16338063
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  • 3
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; carcinoma ; Germany ; IN-VIVO ; INHIBITION ; THERAPY ; VITRO ; GENE ; GENES ; LINES ; MICE ; PATIENT ; IMPACT ; INDUCTION ; treatment ; 5-FLUOROURACIL ; prevention ; resistance ; AGE ; NUDE-MICE ; CELL-LINE ; chemotherapy ; LINE ; CARCINOMAS ; specificity ; CISPLATIN ; pancreatic cancer ; CANCER-THERAPY ; CYTOTOXICITY ; signaling ; GEMCITABINE ; RE ; PANCREATIC-CANCER ; cancer therapy ; pancreatic ; GENDER ; dexamethasone ; GLUCOCORTICOID-INDUCED APOPTOSIS ; NAUSEA ; HISTOLOGY ; in vivo ; surgical resection
    Abstract: Background: Chemotherapy for pancreatic carcinoma often has severe side effects that limit its efficacy. The glucocorticoid (GC) dexamethasone (DEX) is frequently used as co-treatment to prevent side effects of chemotherapy such as nausea, for palliative purposes and to treat allergic reactions. While the potent pro-apoptotic properties and the supportive effects of GCs to tumour therapy in lymphoid cells are well studied, the impact of GCs to cytotoxic treatment of pancreatic carcinoma is unknown. Methods: A prospective study of DEX-mediated resistance was performed using a pancreatic carcinoma xenografted to nude mice, 20 surgical resections and 10 established pancreatic carcinoma cell lines. Antiapoptotic signaling in response to DEX was examined by Western blot analysis. Results: In vitro, DEX inhibited drug-induced apoptosis and promoted the growth in all of 10 examined malignant cells. Ex vivo, DEX used in physiological concentrations significantly prevented the cytotoxic effect of gemcitabine and cisplatin in 18 of 20 freshly isolated cell lines from resected pancreatic tumours. No correlation with age, gender, histology, TNM and induction of therapy resistance by DEX co-treatment could be detected. In vivo, DEX totally prevented cytotoxicity of chemotherapy to pancreatic carcinoma cells xenografted to nude mice. Mechanistically, DEX upregulated pro-survival factors and anti-apoptotic genes in established pancreatic carcinoma cells. Conclusion: These data show that DEX induces therapy resistance in pancreatic carcinoma cells and raise the question whether GC-mediated protection of tumour cells from cancer therapy may be dangerous for patients
    Type of Publication: Journal article published
    PubMed ID: 16539710
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  • 4
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; IN-VITRO ; tumor ; AGENTS ; carcinoma ; CELL ; Germany ; IN-VIVO ; INHIBITION ; THERAPY ; VITRO ; VIVO ; SAMPLES ; TUMORS ; TIME ; PATIENT ; INDUCTION ; cell cycle ; CELL-CYCLE ; CYCLE ; treatment ; PROGRESSION ; resistance ; INDUCED APOPTOSIS ; PLASMA ; prostate cancer ; PROSTATE-CANCER ; chemotherapy ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; DERIVATIVES ; HEPATOMA-CELLS ; EPITHELIAL-CELLS ; CARCINOMAS ; PHARMACOKINETICS ; AGENT ; SINGLE ; ONCOLOGY ; RE ; EX-VIVO ; SOLID TUMORS ; MEDIATED APOPTOSIS ; MOLECULAR-MECHANISMS ; LEVEL ; analysis ; methods ; PLASMA-LEVELS ; dexamethasone ; PROMOTION ; USA ; GLUCOCORTICOIDS ; prospective ; in vivo ; clinical study
    Abstract: Background: Glucocorticoids have been used widely in conjunction with cancer therapy due to their ability to induce apoptosis in hematological cells and to prevent nausea and emesis. However, recent data including ours, suggest induction of therapy resistance by glucocorticoids in solid tumors, although it is unclear whether this happens only in few carcinomas or is a more common cell type specific phenomenon. Material and Methods: We performed an overall statistical analysis of our new and recent data obtained with 157 tumor probes evaluated in vitro, ex vivo and in vivo. The effect of glucocorticoids on apoptosis, viability and cell cycle progression under diverse clinically important questions was examined. Results: New in vivo results demonstrate glucocorticoid - induced chemotherapy resistance in xenografted prostate cancer. In an overall statistical analysis we found glucocorticoid - induced resistance in 89% of 157 analysed tumor samples. Resistance is common for several cytotoxic treatments and for several glucocorticoid - derivatives and due to an inhibition of apoptosis, promotion of viability and cell cycle progression. Resistance occurred at clinically achievable peak plasma levels of patients under anti - emetic glucocorticoid therapy and below, lasted for a long time, after one single dose, but was reversible upon removal of glucocorticoids. Two nonsteroidal alternative anti - emetic agents did not counteract anticancer treatment and may be sufficient to replace gluco corticoids in cotreatment of carcinoma patients. Conclusion: These data demonstrate the need for prospective clinical studies as well as for detailed mechanistic studies of GC - induced cell - type specific pro - and anti - apoptotic signalling
    Type of Publication: Journal article published
    PubMed ID: 17224649
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  • 5
    Keywords: APOPTOSIS ; CELLS ; INHIBITION ; ACTIVATION ; resistance ; KAPPA ; NF kappa B
    Type of Publication: Journal article published
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; carcinoma ; IN-VIVO ; THERAPY ; GENE ; GENE-EXPRESSION ; HYBRIDIZATION ; TUMORS ; radiation ; PATIENT ; NF-KAPPA-B ; FAMILY ; MEMBER ; NUCLEAR-FACTOR ; NORMAL TISSUE ; CISPLATIN ; PROGRAMMED CELL-DEATH ; ALPHA-INDUCED APOPTOSIS ; DNA-DAMAGING AGENTS ; GLOMERULAR ENDOTHELIAL-CELLS ; GRANULOSA-CELLS ; LEUKEMIA- CELLS ; LUNG-CARCINOMA ; T- LYMPHOCYTES
    Abstract: Chemotherapy and radiation therapy for cancer often have severe side effects that limit their efficacy. Glucocorticoids (GCs) are frequently used as cotreatment because they may have potent proapoptotic properties and reduce nausea, hyperemesis, and acute toxicity on normal tissue. In contrast to the proapoptotic effect of GCs in lymphoid cells, resistance toward cancer therapy-mediated apoptosis was induced in solid tumors of human cervix and lung carcinomas. Filter hybridization, expression data, as well as functional assays identified multiple core apoptosis molecules, which are regulated by GCs in a pro- or antiapoptotic manner. Both antiapoptotic genes such as FLIP and members of the Bcl-2 and IAP family as well as proapoptotic elements of the death receptor and mitochondrial apoptosis pathways were down-regulated in carcinomas resulting in a decreased activity of caspase-8, caspase-9, and caspase-3. In contrast, death receptor and mitochondrial apoptosis signaling as well as caspase activity was enhanced by dexamethasone in lymphoid cells. To restore apoptosis sensitivity in dexamethasone-treated carcinomas, caspase-8 and caspase-9 were transfected. This resensitized tumor cells in vitro and xenografts in vivo to cisplatin induced cell death. These data therefore raise concern about the widespread combined use of GCs with antineoplastic drugs or agents in the clinical management of cancer patients
    Type of Publication: Journal article published
    PubMed ID: 12810637
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  • 7
    Keywords: brain ; APOPTOSIS ; CANCER ; CELLS ; IN-VITRO ; SURVIVAL ; AGENTS ; CELL ; Germany ; IN-VIVO ; VITRO ; DEATH ; DRUG ; SURGERY ; LINES ; TIME ; PATIENT ; LIGAND ; primary ; INDUCTION ; tumour ; treatment ; culture ; ACID ; CELL-DEATH ; PLASMA ; RATES ; RESECTION ; PHARMACOKINETICS ; CISPLATIN ; FUTURE ; TRAIL ; AGENT ; POTENT ; REGRESSION ; IV ; GRADE ; brain tumour ; betulinic acid ; CERAMIDE ; glioblastoma multiforme WHOIV
    Abstract: Background. Glioblastoma multiforme (WHO Grade IV, GBM) is the most malignant brain tumour with a mean survival time of less than one year. Betulinic acid, ceramide and TRAIL (TNF-related apoptosis inducing ligand) represent novel therapeutic agents for potential use in GBM. Method. Primary GBM cells of 21 patients with macroscopically complete tumour resection were tested in vitro for cell death induction by betulinic acid, ceramide, TRAIL and established therapeutics (BCNU, cisplatin, doxorubicin, vincristin and gamma-irradiation). Findings. At peak plasma concentrations (PPC), Betulinic acid, ceramide and TRAIL induced cell death in primary GBM cells at higher rates than established cytotoxic drugs. Specific cell death greater than or equal to75% was observed in 43% (9/21), 38% (8/21), and 19% (4/21) for betulinic acid, ceramide, and TRAIL respectively, while this was only found in 5% (1/21) of gamma-irradiated and cisplatin-treated cells, and in none of the GBM cultures, where BCNU or vincristin were applied in PPC. Conclusion. Due to a markedly improved cell death of GBM cells as compared with established therapeutics, Betulinic acid, ceramide and TRAIL might represent potent substances for future treatment of GBM
    Type of Publication: Journal article published
    PubMed ID: 15197616
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  • 8
    Keywords: RECEPTOR ; APOPTOSIS ; EXPRESSION ; IN-VITRO ; tumor ; carcinoma ; CELL ; CELL LUNG-CANCER ; Germany ; human ; IN-VIVO ; LUNG ; MODEL ; MODELS ; VITRO ; VIVO ; DEATH ; NEW-YORK ; GENE ; TUMORS ; LINES ; MICE ; FAMILY ; MEMBER ; MEMBERS ; treatment ; immunohistochemistry ; MALIGNANCIES ; ASSAY ; resistance ; CELL-DEATH ; INDUCED APOPTOSIS ; Western-blot ; NUDE-MICE ; chemotherapy ; CARCINOMAS ; STRATEGIES ; western blot ; FAILURE ; LUNG-CARCINOMA ; CASPASE 8 ; nude mice ; Bcl-2 ; CD95 ; DRUG-INDUCED APOPTOSIS ; XENOGRAFTS ; CD95/Fas/APO-1,TRAIL,gene therapy,drug reststance,cancer therapy ; IMMUNE-SYSTEM
    Abstract: Non small cell lung carcinoma (NSCLC) is a highly lethal malignancy that often becomes resistant to chemotherapy. To determine whether alterations in apoptotic signaling might contribute to such resistance, we established in vitro and in vivo models for sensitive and resistant human NSCLC. We found that resistance is due to multiple defects found in expression of CD95-L, CD95 and members of the Bcl-2 and IAP family, as well as caspase-8, -9 and -3 as examined by immunohistochemistry, Western blot analysis, gene array analysis and functional assays. Failure to activate death receptor, as well as mitochondrial apoptosis signaling, points to a central role of caspases. To restore apoptosis signaling we transfected NSCLC xenografts on nude mice with caspase-8 and -9. This treatment strongly induced apoptosis per se and sensitized the tumors to cisplatin-induced cell death. Thus, these findings indicate that re-expression of caspases might be an effective strategy to restore sensitivity for chemotherapy in NSCLC in vivo. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
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  • 9
    Keywords: brain ; APOPTOSIS ; CANCER ; CELLS ; GROWTH ; carcinoma ; CELL ; Germany ; THERAPY ; screening ; TISSUE ; LINES ; PATIENT ; MECHANISM ; CONTRAST ; CELL-LINES ; treatment ; BREAST ; breast cancer ; BREAST-CANCER ; resistance ; INDUCED APOPTOSIS ; CERVIX ; metastases ; CELL-LINE ; chemotherapy ; LINE ; MELANOMA ; RESECTION ; CISPLATIN ; cell lines ; CANCER-THERAPY ; LUNG-CARCINOMA ; neuroblastoma ; signaling ; MALIGNANT-CELLS ; RE ; cancer therapy ; SOLID TUMORS ; dexamethasone ; NAUSEA ; corticosteroids ; GLUCOCORTICOIDS ; prospective ; BONE ; EXTENT ; clinical studies ; surgical resection ; steroids
    Abstract: Glucocorticoids (GCs) such as dexamethasone (DEX) have been widely used as co-medication in cancer therapy because they have potent proapoptotic properties in lymphoid cells, can reduce nausea, and alleviate acute toxic effects in healthy tissue. However, GCs are used in a supportive-care role, even though no prospective clinical studies have assessed the effect of these steroids on the growth of solid tumours. Data from preclinical and, to some extent, clinical studies, suggest that GCs induce treatment resistance in some solid tumours. Since it is unknown whether GC-induced resistance occurs only occasionally or is a more common phenomenon, we performed a screening study using several established cell lines from bone, brain, breast and cervix carcinoma as well as melanoma and neuroblastoma together with fresh surgical resections from patients with breast cancer. We found that DEX inhibits cisplatin and 5-fluorouracil- induced apoptosis and promotes the growth of the majority of examined malignant cells. In contrast, and as expected, DEX acted pro-apoptotically and promoted the cytotoxic effect of chemotherapy in established and primary lymphoid cells. Thus, these data demonstrate the need for detailed molecular studies to clarify the mechanism of differential glucocorticoid signaling as well as controlled, prospective clinical studies
    Type of Publication: Journal article published
    PubMed ID: 17016664
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  • 10
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; SURVIVAL ; tumor ; carcinoma ; CELL ; COMBINATION ; Germany ; IN-VIVO ; MODEL ; MODELS ; THERAPY ; VITRO ; VIVO ; PROTEINS ; SAMPLE ; SAMPLES ; TIME ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; INDEX ; TISSUES ; CONTRAST ; ANTITUMOR-ACTIVITY ; TARGET ; MOUSE ; resistance ; CARCINOMA CELLS ; CELL-DEATH ; MEMBRANE ; CARCINOMA-CELLS ; adenocarcinoma ; NORMAL TISSUE ; REVEALS ; CHILDREN ; pancreatic cancer ; pancreatic carcinoma ; TRAIL ; HUMAN PROSTATE-CANCER ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; DRUG-INDUCED APOPTOSIS ; INHIBITORS ; PANCREATIC-CANCER ; THERAPIES ; DECOY RECEPTORS ; development ; X-LINKED INHIBITOR ; pancreatic adenocarcinoma ; USA ; ANTAGONISTS ; pancreatic tumor ; IRRADIATION-INDUCED APOPTOSIS ; XIAP ; therapeutic ; ALPHA-DEPENDENT APOPTOSIS
    Abstract: Evasion of apoptosis is a characteristic feature of pancreatic cancer, a prototypic cancer that is refractory to current treatment approaches. Hence, there is an urgent need to design rational strategies that counter apoptosis resistance. To explore X-linked inhibitor of apoptosis (XIAP) as a therapeutic target in pancreatic cancer, we analyzed the expression of XIAP in pancreatic tumor samples and evaluated the effect of small molecule XIAP inhibitors alone and in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against pancreatic carcinoma in vitro and in vivo. Here, we report that XIAP is highly expressed in pancreatic adenocarcinoma samples compared with normal pancreatic ducts. Small molecule XIAP inhibitors synergize with TRAIL to induce apoptosis and to inhibit long-term clonogenic survival of pancreatic carcinoma cells. In contrast, they do not reverse the lack of toxicity of TRAIL on nonmalignant cells in vitro or normal tissues in vivo, pointing to a therapeutic index. Most importantly, XIAP inhibitors cooperate with TRAIL to trigger apoptosis and suppress pancreatic carcinoma growth in vivo in two preclinical models, i.e., the chorioallantoic membrane model and a mouse xenograft model. Parallel immunohistochemical analysis of tumor tissue under therapy reveals that the XIAP inhibitor acts in concert with TRAIL to cause caspase-3 activation and apoptosis. In conclusion, our findings provide, for the first time, evidence in vivo that XIAP inhibitors prime pancreatic carcinoma cells for TRAM-induced apoptosis and potentiate the antitumor activity of TRAIL against established pancreatic carcinoma. These findings build the rationale for further (pre)clinical development of XIAP inhibitors and TRAIL against pancreatic cancer. [Cancer Res 2009;69(6):2425-34]
    Type of Publication: Journal article published
    PubMed ID: 19258513
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