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  • DKFZ Publication Database  (15)
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  • DKFZ Publication Database  (15)
  • 1
    Keywords: ANGIOGENESIS ; CANCER ; CELLS ; GROWTH ; INHIBITOR ; tumor ; CELL ; COMBINATION ; Germany ; human ; INHIBITION ; MODEL ; THERAPY ; tumor growth ; MICE ; PATIENT ; REDUCTION ; animals ; T-CELLS ; treatment ; LYMPHOMA ; chemotherapy ; CANCER-PATIENTS ; STRATEGIES ; CANCER PATIENTS ; CANCER-THERAPY ; COMPLETE REMISSION ; MULTIPLE-MYELOMA ; CYTOTOXICITY ; targeting ; RECOMBINANT ; ANGIOGENESIS INHIBITION ; TUMOR-GROWTH ; cancer therapy ; DEFICIENT MICE ; CD3 ; LYSIS ; thalidomide ; OCT ; CD19 ; BISPECIFIC ANTIBODIES ; diabody
    Abstract: Combining different treatment strategies offers the possibility of improving treatment results for cancer patients. The aim of our study was therefore to investigate the combination of treatment of established s.c. human B non-Hodgkin's lymphoma in severe immune deficient mice using a recombinant bispecific CD19 x CD16 diabody (targeting natural killer cells to CD19(+) cells) and the angiogenesis inhibitor thalidomide. Monotherapy with either thalidomide or diabody caused an approximate 50% reduction in tumor growth rate. The combined treatment showed evidence for a synergistic effect resulting in a 74% reduction in median tumor size. In the combined treatment group, two of five animals had complete remissions of their s.c. tumor. These results suggest that a combination treatment with recombinant diabodies and angiogenesis inhibition represents a useful approach in cancer therapy. (C) 2004 Lippincott Williams Wilkins
    Type of Publication: Journal article published
    PubMed ID: 15457133
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  • 2
    Keywords: CANCER ; SURVIVAL ; tumor ; COMBINATION ; Germany ; PHASE-I ; THERAPY ; TOXICITY ; DEATH ; DISEASE ; RISK ; TUMORS ; TIME ; PATIENT ; RESPONSES ; 5-FLUOROURACIL ; ACID ; TRIAL ; PROGRESSION ; AGE ; chemotherapy ; doxorubicin ; SAFETY ; FLUOROURACIL ; CISPLATIN ; GASTRIC-CANCER ; BOLUS ; PHASE-II ; SINGLE ; ELDERLY-PATIENTS ; SODIUM ; gastric cancer ; INTERVAL ; PHASE ; TOLERABILITY ; PLUS ; EUROPEAN-ORGANIZATION ; NAUSEA ; COOPERATIVE GROUP ; EPIRUBICIN ; GASTROINTESTINAL CANCER ; HIGH-DOSE METHOTREXATE ; mitomycin C ; pegylated liposomal ; phase II ; SUPPORTIVE CARE ; LIPOSOMAL DOXORUBICIN
    Abstract: Mitomycin C (MMC) in combination with infusional 5-fluorouracil (5-FU) is a well-tolerated active combination therapy for advanced gastric cancer. Pegylated liposomal doxorubicin (Caelyx) has been combined with this regimen in a phase I study exhibiting promising activity in patients with upper gastrointestinal tumors. In the present study, we investigated activity and tolerability of this three-drug regimen in patients with gastric cancer. Patients with advanced or metastatic gastric cancer were recruited to receive weekly infusional 5-FU (2000 mg/m(2)) mixed with sodium folinic acid (FA; 500 mg/m(2)) in one pump (days 1, 8,15, 22, 29, 36). On days 1 and 29, Caelyx (20 mg/m(2)) was given as a 1-h, and MMC (7 mg/m(2)) was applied as bolus injection on days 8 and 36. Treatment courses were repeated on day 57. Twenty-seven patients with a median age of 66 years were recruited in a single center; 56% had histologically proven peritoneal carcinomatosis and 26 patients are evaluable for toxicity. Common Toxicity Criteria of the National Cancer Institute grade 3 toxicity was recorded in 34% of the patients (anemia 12%, leukocytopenia 8%, febrile neutropenia 4%, thrombocytopenia 12%, nausea 15%, diarrhea 8% and mucositis 4%). One patient developed hemolytic-uremic syndrome. One complete (5%) and eight partial responses (42%) were observed in 19 patients evaluable for response according to WHO criteria. Seven patients had no change (37%) and three (16%) progressive disease. Six patients with peritoneal carcinomatosis not amenable to WHO response assessment had progression-free intervals between 8 and 21 months. Median survival for all patients was 14.7 months and median time to progression was 8.4 months. We conclude that this new three-drug combination regimen yields a promising overall response rate (47%) in patients with gastric cancer despite the inclusion of a majority of elderly patients at moderate or high risk of death in this trial. Its safety and good tolerability as established in the phase I trial was confirmed. (c) 2005 Lippincott Williams M Wilkins
    Type of Publication: Journal article published
    PubMed ID: 15746580
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  • 3
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; Germany ; DRUG ; DIFFERENTIATION ; INDUCTION ; ACID ; NERVOUS-SYSTEM ; ASSAY ; CANCER-CELLS ; HISTONE DEACETYLASE ; histone deacetylase inhibitor ; p21(waf1) ; neuroblastoma ; INVITRO ; LEUKEMIA-CELLS ; ONCOLOGY ; CHILDHOOD ; RE ; medulloblastoma ; cell proliferation ; ASSAYS ; pharmacology ; USA ; anticancer drug ; childhood cancer ; HELMINTHOSPORIUM-CARBONUM (HC)-TOXIN ; HKI46F08
    Abstract: Embryonic childhood cancer such as neuroblastoma and medulloblastoma are still a therapeutic challenge requiring novel treatment approaches. Here, we investigated the antitumoral effects of HKI 46F08, a novel trifluoromethyl ketone histone deacetylase (HDAC) inhibitor with a nonhydroxamic acid type structure. HKI 46F08 inhibits in-vitro HDAC activity in cell-free assays with a half maximal inhibitory concentration of 0.6 mu mol/l and intracellular HDAC activity with a half maximal inhibitory concentration of 1.8 mu mol/l. The compound reduces viability of both cultured neuroblastoma and medulloblastoma cells with an EC50 of 0.1-4 mu mol/l. HKI 461708 efficiently arrests tumor cell proliferation, represses clonogenic growth and induces differentiation and apoptosis in both MYCN-amplified and nonamplified neuroblastoma cells. In summary, we identified HKI 48F08 as a structural novel, potent HDAC inhibitor with strong antitumoral activity against embryonic childhood cancer cells in the low micromolar range
    Type of Publication: Journal article published
    PubMed ID: 18765999
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  • 4
    Keywords: APOPTOSIS ; CELLS ; GROWTH ; tumor ; TUMOR-CELLS ; CELL ; Germany ; IN-VIVO ; MODEL ; VIVO ; SYSTEM ; POPULATION ; DRUG ; TUMORS ; MICE ; NF-KAPPA-B ; LYMPH-NODES ; T cells ; T-CELL ; T-CELLS ; GROWTH-FACTOR RECEPTOR ; MEMORY ; MOUSE ; HEALTH ; PROMOTER ; transgenic ; MELANOMA ; DERIVATIVES ; SIGNALING PATHWAY ; CANCER-CELLS ; NK cells ; POPULATIONS ; CD8(+) ; immunosuppression ; ANTICANCER DRUGS ; CYTOTOXICITY ; traditional Chinese medicine ; IMMUNE-SYSTEM ; artemisinin ; artesunate ; MELANOCYTES ; memory T cells ; ANTIMALARIAL ARTESUNATE ; pharmacology ; USA ; TRANSGENIC MOUSE MODEL ; anticancer drug ; NOV ; immune system ; CYTOTOXIC ACTIVITY ; WELL ; ANTICANCER ; ret transgene ; IMMUNE CELL ; Anti-cancer ; Melanocyte ; anticancer activity ; ARTEMISININ DERIVATIVE SM905 ; COMBINATION-TREATMENT ; IMMUNOSUPPRESSIVE ACTIVITY
    Abstract: The antimalarial artesunate also exerts profound cytotoxicity toward tumor cells, Earlier investigations controversially discussed a possible immunosuppressive function of artemsinin and its derivatives. This poses the question, whether immunosuppressive activity counteracts the anticancer activity in vivo. To clarify this issue, we used a transgenic mouse spontaneous melanoma model, in which ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. ret-transgenic mice were previously reported to accumulate melanomaspecific effector memory T cells and natural killer (NK) cells in the primary tumors and metastatic lymph nodes. In the present investigation, we monitored effects of artesunate on the CD4(+) and CD8(+) T cells as well as Treg and NK cells from ret-transgenic tumor-bearing mice and nontransgenic littermates in vivo. In addition, we investigated cytostatic and cytotoxic activity of artesunate on ret-tumor cells established from the mouse primary tumor. Artesunate inhibited growth of ret-tumor cells and induces their apoptosis in a concentration-dependent manner (0.1-200 mu mol/l). Furthermore, we did not find considerable effects of artesunate on the immune function as measured by major cell populations of the immune system; that is, CD4(+) and CD8(+) T cells as well as Treg and NK cells both from ret-transgenic mice and nontransgenic C57BL/6 littermates treated for 2 weeks with a daily dose of 1 mg artesunate. These results indicate that the cytostatic and apoptotic effects of artesunate are not diminished by concomitant immunosuppression. Anti-Cancer Drugs 20:910-917 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins
    Type of Publication: Journal article published
    PubMed ID: 19745721
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  • 5
    Keywords: SURVIVAL ; EPIDEMIOLOGY ; FLUOROURACIL ; OXALIPLATIN ; irinotecan ; PHASE-III TRIAL ; cetuximab ; LEUCOVORIN ; BRAF mutation ; 2 SIDES
    Abstract: he aim of this study was to investigate the impact of midgut versus hindgut as the primary tumor site in patients with metastatic colorectal cancer (mCRC) receiving chemotherapy with FuFIRI or mIROX. We analyzed 423 patients from a phase III trial that randomized patients in a 1 : 1 fashion to either FuFIRI or mIROX. The cohort was grouped into midgut (n=82) and hindgut (n=341) primary tumors. The primary tumor site (midgut vs. hindgut) was correlated with parameters of treatment efficacy and survival. Our cohort comprised 82 patients presenting with primary midgut tumors and 341 with primary hindgut tumors. Tumors of midgut origin compared with hindgut origin were associated with inferior outcome. Objective response rate was 37 versus 43% (P=0.34), median progression-free survival was 6.0 versus 8.2 months (P=0.024, hazard ratio: 0.75), and median overall survival was 13.6 versus 21.8 months (P=0.001, hazard ratio: 0.65). Patients with midgut mCRC showed a clear trend toward inferior outcome in both study arms. However, the effect appeared less pronounced in the mIROX arm. Further datasets from large trials with various regimens are required as confirmation.
    Type of Publication: Journal article published
    PubMed ID: 24201305
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  • 6
    Keywords: LUNG-CANCER ; ERBB SIGNALING NETWORK ; GENE-MUTATIONS ; PHASE-II ; K-RAS MUTATIONS ; HUMAN-CELLS ; GROWTH-FACTOR-RECEPTOR ; cetuximab ; METASTATIC COLORECTAL-CANCER ; CODON 12
    Abstract: The aim of this study was to investigate the impact of different KRAS mutations on the inhibitory potential of afatinib and gefitinib in SW48 colorectal cancer cells. The influence of afatinib/gefitinib on cell viability and cell cycle was evaluated in isogenic SW48 KRAS wild-type/mutant cells. Protein levels of phosphorylated/total EGFR, HER-2, HER-3, ERK, and AKT were compared between treated/untreated samples using western blotting. The activity of both afatinib and gefitinib was the lowest in KRAS G12C/G12S/G12D and the highest in G13D/G12A mutant subtypes. A 50% decrease in cell viability was achieved at concentrations of 3.0-7.7 mumol/l for afatinib and 5.4-19.5 mumol/l for gefitinib. The effect of both drugs on apoptosis appeared to be stronger than their influence on proliferation and was generally less pronounced in mutant cells than in wild-type cells. The average number of apoptotic cells after treatment with afatinib was 2.6 times as high as the corresponding value following treatment with gefitinib (P〈0.01). Levels of pEGFR, pHER-2, pERK, and pAKT were reduced more extensively by afatinib than by gefitinib (P〈0.001). Some KRAS mutations (G12C/G12S/G12D) appear to weaken the activity of afatinib and gefitinib whereas others seem to increase sensitivity to treatment (G13D/G12A) compared with the parental clone (KRAS wild-type). In SW48 colorectal cancer cells, afatinib seems to be more potent than gefitinib because of its superior efficacy in inhibiting both EGFR and HER-2, suppressing signaling along both MEK/ERK and PI3K/AKT pathways to a greater extent.
    Type of Publication: Journal article published
    PubMed ID: 25514114
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  • 7
    Keywords: APOPTOSIS ; CANCER ; INVASIVENESS ; GLIOBLASTOMA
    Abstract: Glioblastoma is a disease characterized by rapid invasive tumour growth. Studies on the proapoptotic CD95/CD95L signalling pathway recently suggested a significant contribution of CD95 signalling towards the high degree of motility in glioma cells. Apogenix has developed APG101, a clinical phase II compound designed to bind and neutralize CD95L, and thus to interfere with CD95/CD95L-based signalling. APG101 has shown clinical efficacy in a controlled randomized phase II trial in patients with recurrent glioma. Because APG101 is not cytotoxic to tumour cells in vitro, we postulated that the anti-invasive function of APG101 is the main mechanism of action for this compound. Using three-dimensional spheroid invasion assays in vitro and in murine brain tissue cultures, we found that knockdown of endogenous CD95L reduced the invasive phenotype in our two glioblastoma model cell lines U87-MG and U251-MG. Invasion was restored in CD95L knockdown cells upon the addition of soluble recombinant CD95L and this effect was inhibited by APG101. We conclude that CD95L from autocrine and paracrine sources contributes towards the invasive phenotype of glioblastoma cells and that APG101 acts as a suppressor of proinvasive signalling by the CD95/CD95L pathway in glioblastoma.
    Type of Publication: Journal article published
    PubMed ID: 25850884
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  • 8
    Keywords: CANCER ; CELLS ; IN-VITRO ; tumor ; TUMOR-CELLS ; AGENTS ; CELL ; human ; MODEL ; TOXICITY ; SYSTEM ; VOLUME ; DEATH ; CLONING ; DRUG ; TUMORS ; MICE ; COMPLEXES ; REDUCTION ; INDUCTION ; ANTITUMOR-ACTIVITY ; BREAST ; breast cancer ; BREAST-CANCER ; MOUSE ; NO ; CELL-DEATH ; MOUSE MODEL ; sensitivity ; CISPLATIN ; TUMOR CELLS ; ONCOLOGY ; RE ; TRANSITION ; development ; TUMOR-CELL ; cell death ; pharmacology ; USA ; anticancer drug ; antitumor activity ; FULVENES ; human tumor cloning assay ; HUMAN-BREAST ; hydridolithiation ; MCF-7 xenograft ; METALLOCENES ; ORGANIC-CHEMISTRY ; POTENTIAL ANTICANCER DRUGS ; SUBSTITUTED ANSA-TITANOCENE ; super hydride ; TITANIUM DICHLORIDE ; titanocene
    Abstract: Bis-[(p-methoxybenzyl)cyclopentadienyl] titanium dichloride, better known as Titanocene Y, is a newly synthesized transition metal-based anticancer drug. We studied the antitumor activity of Titanocene Y with concentrations of 2.1, 21 and 210 mu mol/l against a freshly explanted human breast cancer, using an in-vitro soft agar cloning system. The sensitivity against Titanocene Y was highly remarkable in the breast cancer tumor in the full concentration range. Titanocene Y showed cell death induction at 2.1 mu mol/l, well comparable to cisplatin, given at a concentration of 1.0 mu mol/l. A further preclinical development of Titanocene Y was warranted and therefore an MCF-7 human breast cancer xenograft nonobese diabetic/severe combined immunodeficient mouse model was used. Titanocene Y was given for 21 days at 30 mg/kg/ day (75% of the maximum tolerable dose of Titanocene Y), which resulted in the reduction of the tumor volume to around one-third, whereas no mouse was lost because of the surprisingly low toxicity of Titanocene Y
    Type of Publication: Journal article published
    PubMed ID: 17264764
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  • 9
    Keywords: DNA methylation ; CENTRAL-NERVOUS-SYSTEM ; histone deacetylase inhibitor ; PROMOTER METHYLATION ; SUBEROYLANILIDE HYDROXAMIC ACID ; GROUP PROTEIN EZH2 ; ATYPICAL TERATOID/RHABDOID TUMORS ; PANCREATIC-CANCER CELLS ; PHARMACOLOGICAL DISRUPTION ; EPIGENETIC REPRESSION
    Abstract: Rhabdoid tumors (RTs) are highly aggressive pediatric malignancies with a rather poor prognosis. New therapeutic approaches and optimization of already established treatment protocols are urgently needed. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is highly overexpressed in RTs and associated strongly with epigenetic silencing in cancer. EZH2 is involved in aggressive cell growth and stem cell maintenance. Thus, EZH2 is an attractive therapeutic target in RTs. The aim of the study presented here was to analyze the effects of a pharmacological inhibition of EZH2 alone and in combination with other anticancer drugs on RTs cells in vitro. The antitumor activity of the S-adenosyl-homocysteine-hydrolase inhibitor 3-deazaneplanocin A (DZNep) alone and in combination with conventional cytostatic drugs (doxorubicin, etoposide) or epigenetic active compounds [5-Aza-CdR, suberoylanilide hydroxamic acid (SAHA)] was assessed by MTT cell proliferation assays on three RT cell lines (A204, BT16, G401). Combinatorial treatment with DZNep synergistically and significantly enhanced the antiproliferative activity of etoposide, 5-Aza-CdR, and SAHA. In functional analyses, pretreatment with DZNep significantly increased the effects of 5-Aza-CdR and SAHA on apoptosis, cell cycle progression, and clonogenicity. Microarray analyses following sequential treatment with DZNep and 5-Aza-CdR or SAHA showed changes in global gene expression affecting apoptosis, neuronal development, and metabolic processes. In-vitro analyses presented here show that pharmacological inhibition of EZH2 synergistically affects the antitumor activity of the epigenetic active compounds 5-Aza-CdR and SAHA. Sequential treatment with these drugs combined with DZNep may represent a new therapeutic approach in RTs.
    Type of Publication: Journal article published
    PubMed ID: 25415657
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  • 10
    Abstract: Small-molecule inhibitors of Inhibitor of Apoptosis proteins such as Smac mimetics have been reported to provide a promising tool to sensitize glioblastoma (GBM) cells to cytotoxic therapies including chemotherapeutic drugs. However, the underlying molecular mechanisms of action have not yet been fully unraveled. In the present study, we therefore investigated the role of reactive oxygen species (ROS) in the regulation of Smac mimetic/temozolomide (TMZ)-induced cell death in GBM cells. Here, we show that the Smac mimetic BV6 and TMZ act in concert to stimulate the production of both cytosolic and mitochondrial ROS. This accumulation of ROS contributes toward the activation of the proapoptotic factor BAX upon BV6/TMZ cotreatment as several ROS scavengers (i.e. N-acetyl-L-cysteine, MnTBAP, or alpha-tocopherol) protect GBM cells against BV6/TMZ-mediated BAX activation. In addition, ROS scavengers significantly rescue GBM cells from BV6/TMZ-triggered cell death, indicating that ROS generation is required for the induction of cell death. By showing that ROS play an important role in the regulation of Smac mimetic/TMZ-induced cell death, our work sheds light on the crucial role of the oxidative system in the cooperative antitumor activity of Smac mimetic/TMZ combination therapy against GBM cells.
    Type of Publication: Journal article published
    PubMed ID: 27669171
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